piperidines and preclamol

The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Mice; Piperazines; Piperidines; Quinolones; Schizophrenia

The discovery and characterization of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about dopamine pharmacology, came his proposal of the existence and critical role of dopamine autoreceptors in the overall regulation of dopamine-mediated neurotransmission. In this paper, the rationale, the putative mechanisms, and pertinent clinical data are reviewed to support the idea of the clinical relevance of dopamine agonists, especially partial agonists, in the treatment of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical relevance was not a reality before the application of (-)-3PPP. These clinical results are presented. Moreover, now a partial dopamine agonist, aripiprazole, has been developed and will likely be marketed by BMS and Otsuka for the treatment of psychosis and will be the first drug in this class to be commercially available. Partial dopamine agonists represent the next new class of antipsychotic drugs, effective in treating schizophrenia.

Topics: Animals; Apomorphine; Autoreceptors; Brain; Dopamine Agonists; Humans; Piperidines; Psychotic Disorders; Receptors, Dopamine

Topics: Antiparkinson Agents; Dopamine Agonists; Humans; Parkinson Disease; Piperidines

There is increasing evidence that sigma ligands and dextromethorphan (DM) bind to at least one common high-affinity site. DM and other antitussives do not produce psychotomimetic effects. This suggested that sigma ligands may produce their characteristic effects through another site, and prompted us to review critically the literature on the side effects of sigma opiates. Contrary to what is generally accepted, the dysphoric and psychotomimetic side effects of sigma opiates are mediated by the levo-and not by the dextrorotatory isomers. Moreover, these effects are unequivocally naloxone-reversible. Therefore, the current version of the "sigma receptor", with high affinity for the dextrorotatory sigma opiates, cannot explain the psychotomimetic effects of the levorotatory enantiomers. Thus, neither the "sigma ligands" nor its newly defined "receptor" are involved in the psychotomimetic effects of sigma opiates. Further experimentation with more selective drugs and with a combination of different methods will be necessary to identify the different binding sites, and to establish their physiological role and therapeutic potential.

Topics: Animals; Dextromethorphan; Endorphins; Hallucinogens; Humans; Levorphanol; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Stereoisomerism

In a companion article, we extensively reviewed the pharmacological actions of the enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP. The profiles of action exhibited by transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10-octahydrobenzo(f)quinoline (HW 165) were also described. These latter agents, along with (-)-3-PPP, exert a variety of effects at different DA receptors depending on the anatomical location of these receptor sites and the experimental conditions. In the first part of the present article, it is suggested that the intrinsic activity of these agents in different pharmacological models is dependent on the responsiveness of the relevant DA-receptors which, in turn, is related to the degree of previous agonist occupancy of these sites. In situations where these agents exhibit partial agonist activity, their pharmacological effect is also dependent on the relative concentrations of drug and endogenous DA competing for common receptor sites. A number of theoretical implications will be discussed relevant to the suggestion that DA receptors exist in various adaptational states which can influence drug action. In the second part of this review, we will consider the behavioural profile exhibited by (-)-3-PPP in relation to that observed with classical DA antagonists. In addition, the potential clinical application of (-)-3-PPP and similar-acting agents will be discussed.

Topics: Animals; Antipsychotic Agents; Apomorphine; Behavior, Animal; Corpus Striatum; Cyclic AMP; Dextroamphetamine; Dopamine; Humans; Isomerism; Lisuride; Models, Neurological; Molecular Conformation; Motor Activity; Nucleus Accumbens; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Receptors, Dopamine; Substantia Nigra; Synaptosomes

The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Behavior, Animal; Brain; Caudate Nucleus; Deoxyglucose; Dopamine; Humans; Lisuride; Models, Biological; Nerve Tissue Proteins; Phenanthrenes; Piperidines; Rats; Receptors, Dopamine; Stereoisomerism; Substantia Nigra; Synaptosomes; Tegmentum Mesencephali

Topics: alpha-Methyltyrosine; Animals; Antipsychotic Agents; Benzamides; Cattle; Dopamine; Hallucinogens; Hypothalamo-Hypophyseal System; Indoles; Methyltyrosines; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Receptors, Dopamine; Serotonin; Tetrahydronaphthalenes

In an ongoing effort to characterize the clinical pharmacologic profile of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP], we administered it to drug-free schizophrenic patients in two consecutive studies.. In a preliminary dose-finding study, 9 patients were treated using a 6-week placebo-controlled crossover design. Then, to properly demonstrate the antipsychotic effect, we carried out an early efficacy study; here 10 patients received (-)-3PPP, 300 mg B.I.D., in a 1-week placebo-controlled crossover study.. Dose-Finding Study: (-)-3PPP showed apparent antipsychotic effect in repeated dosing, with 300 mg B.I.D. being the most effective dose for antipsychotic action; however, the apparent antipsychotic action was not sustained for longer than 1 week, presumably because of desensitization of the receptor by the agonist. Early Efficacy Study: Positive symptoms as measured by the Psychosis Change Scale decreased in 1 week by 30% with (-)-3PPP compared to placebo, and negative symptoms measured with the Brief Psychiatric Rating Scale Withdrawal subscale decreased by 28% with the drug. In both studies, (-)-3PPP lacked any evidence of motor side effects.. These data show that psychotic symptoms decrease with (-)-3PPP and suggest that the treatment of schizophrenia with partial dopamine agonist is a promising strategy. Future attention will be directed toward testing techniques to diminish the tachyphylaxis to allow an ongoing therapeutic effect.

Topics: Adult; Antiparkinson Agents; Antipsychotic Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

The role of dopamine in opioid reward is unresolved. Furthermore, the issue is somewhat unclear regarding cocaine and the place preference paradigm. In the present study we investigated whether the drugs activating dopamine autoreceptors affect cocaine- and morphine-induced place preference in rats. Neither the dopamine D2/D3 receptor agonist, quinpirole (0.05 mg/kg, SC), nor the partial dopamine autoreceptor agonist, preclamol (2 or 8 mg/kg, SC), induced place conditioning by itself. Quinpirole had no significant influence on the place preference induced either by morphine (3 mg/kg, SC) or cocaine (5 mg/kg, IP). Preclamol, when given at the dose of 8 mg/kg SC, significantly attenuated the effect of cocaine but failed to modify the effect of morphine. Our results suggest that the rewarding properties of morphine involve DA-independent mechanisms whereas in the cocaine-induced reward the role of brain DA is critical. Furthermore, as regards place conditioning, we propose that the activation of DA autoreceptors is not sufficient to reliably modify the rewarding effect of cocaine.

Topics: Animals; Cocaine; Conditioning, Operant; Dopamine Agonists; Male; Morphine; Narcotics; Piperidines; Rats; Rats, Wistar; Synaptic Transmission

The motor effects of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3-PPP, preclamol] were evaluated in nine patients with Parkinson's disease using a double-blind, placebo-controlled design. (-)-3-PPP monotherapy had an antiparkinsonian effect in five of nine patients at a mean dose of 37 +/- 10 mg intramuscularly. The co-administration of (-)-3-PPP and a mildly dyskinetic dose of levodopa, infused intravenously at steady-state, resulted in complete suppression of dyskinesias and reemergence of parkinsonian signs in two of seven patients. These dopamine antagonist effects of (-)-3-PPP occurred at relatively low (2.5 and 5 mg) doses. Our results suggest that partial dopamine agonists can exert agonist or antagonist activity in parkinsonian patients depending on concurrent dopaminergic tone. Although this dual action of (-)-3-PPP and other partial agonists could be therapeutically important on theoretical grounds, the small number of patients manifesting a clinically significant response and the frequently inconsistent effects could indicate that this class of agents may have relatively limited clinical utility.

Topics: Aged; Antiparkinson Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Injections, Intramuscular; Levodopa; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Piperidines

Preclamol, the (-)enantiomer of 3-PPP (= 3(3-hydroxyphenyl)-N-n-propyl piperidine), has a selective dopamine autoreceptor- and postsynaptic mixed agonist-antagonist profile. Its action on patients with disabling on-off parkinsonian fluctuations has been studied and compared with those of placebo and subcutaneous apomorphine. Preclamol had a mild but unequivocal antiakinetic effect, less than that caused by subcutaneous apomorphine, but it provoked less dyskinesia. Further studies to explore the therapeutic potential of preclamol seem justified.

Topics: Antiparkinson Agents; Apomorphine; Blood Pressure; Dopamine Agonists; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Movement; Parkinson Disease; Piperidines; Receptors, Dopamine D1; Receptors, Dopamine D2

The dopamine (DA) autoreceptor agonist (-)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar "rising dose" placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200-500 pmoles/ml after the intramuscular drug doses of 30-40 mg. Drug half life is 2-2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (-)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.

Topics: Administration, Oral; Adult; Chromatography, Gas; Dopamine Agents; Double-Blind Method; Half-Life; Humans; Injections, Intramuscular; Male; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Huntington's disease is a hereditary neurodegenerative disease that primarily affects striatal neurons. Recent studies demonstrated abnormalities in calcium regulation in striatal neurons in Huntington's disease, which leads to elimination of synaptic connections between cortical and striatal neurons. In the present study, we focused on the neuroprotective properties of σ1-receptor, because one of its main functions is associated with modulation of calcium homeostasis in cells. The application of selective σ1-receptor agonists to the corticostriatal cell culture restores synaptic connections between the cortical and striatal neurons. Based on the obtained data, we assume that σ1-receptor is a promising target for the development of drugs for the therapy of Huntington's disease.

Topics: Animals; Anisoles; Calcium; Cerebral Cortex; Corpus Striatum; Dendritic Spines; Gene Expression; Homeostasis; Huntington Disease; Male; Mice; Models, Biological; Morpholines; Neurons; Piperidines; Primary Cell Culture; Propylamines; Receptors, sigma; RNA, Small Interfering; Sigma-1 Receptor; Synapses; Synaptic Transmission; Transduction, Genetic

The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated "dopamine stabilizer", has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca

Topics: Aging; Animals; Calbindins; Calcium; Cations, Divalent; Coculture Techniques; Corpus Striatum; Dendritic Spines; Disease Models, Animal; Endoplasmic Reticulum; Humans; Huntington Disease; Mice; Mice, Transgenic; Neuroprotective Agents; Piperidines; Rats, Inbred SHR; Receptors, sigma; Sigma-1 Receptor; Synapses

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that 'kinetic context', as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.

Topics: Animals; Aripiprazole; CHO Cells; Cricetulus; Dopamine; Dopamine Agonists; Indoles; Kinetics; Ligands; Piperazines; Piperidines; Principal Component Analysis; Protein Stability; Receptors, Dopamine D2

A cooperative Cu/Pd-catalyzed asymmetric three-component reaction of styrenes, B2(pin)2, and allyl carbonates was reported. This reaction, in the presence of chiral CuOAc/SOP and achiral Pd(dppf)Cl2 catalysts, occurs smoothly with high enantioselectivities (up to 97% ee) . The allylboration products, which contain alkene (or diene) unite and alkylboron group, are easily functionalized. The utility of this protocol was demonstrated through the synthesis of an antipsychotic drug, (-)-preclamol.

Topics: Alkenes; Allyl Compounds; Boranes; Catalysis; Copper; Molecular Structure; Organometallic Compounds; Palladium; Piperidines; Stereoisomerism

In this study, the regional rat brain distribution of radioiodinated o-iodo-trans-decalinvesamicol ([(125) I]OIDV) was determined in vivo to evaluate its potential as a single-photon emission computed tomography (SPECT) imaging probe for vesicular acetylcholine transporter (VAChT). Following intravenous injection, [(125) I]OIDV passed freely across the blood-brain barrier and accumulated in rat brain. The accumulation of [(125) I]OIDV in rat brain was significantly reduced by coadministration of (+/-)-vesamicol (0.125 µmol). In contrast, the coadministration of σ-receptor ligands, such as (+)-pentazocine (0.125 µmol) as a σ-1 receptor ligand and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (0.125 µmol) as a σ-1 and σ-2 receptor ligands, barely affected the accumulation of [(125) I]OIDV in rat brain. These findings in vivo were corroborated by autoradiographic analysis ex vivo. The authors found that the tracer binds with pharmacological selectivity to VAChT in rat brain and predicted that it may likewise serve in translational SPECT imaging studies of this marker in the integrity of cholinergic innervations.

Topics: Animals; Autoradiography; Blood-Brain Barrier; Brain; Iodine Radioisotopes; Ligands; Male; Narcotic Antagonists; Pentazocine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Tomography, Emission-Computed, Single-Photon; Vesicular Acetylcholine Transport Proteins

We investigated the characteristics of the regional rat brain distribution of radio-brominated o-bromo-decalinvesamicol (OBDV) in vivo to evaluate its potential as a PET ligand for vesicular acetylcholine transporter (VAChT). In in vivo biodistribution study, the specific brain regional accumulation of [(77) Br]OBDV was revealed 30 min after intravenous injection. The specific brain regional accumulation of [(77) Br]OBDV was significantly inhibited by co-injection of (+/-)-vesamicol. In contrast, no significant inhibition of the uptake of [(77) Br]OBDV in all brain regions was observed with co-injection of (+)-pentazocine (selective σ-1 receptor agonist) and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine, [(+)-3-PPP] (σ-1 and σ-2 receptor agonist) with [(77) Br]OBDV. [(77) Br]OBDV accumulation in VAChT-rich brain regions was observed in ex vivo autoradiography. These results showed that [(77) Br]OBDV selectively bound to VAChT with high affinity in rat brain in vivo. Hence, OVBDV radiolabelled with more suitable (76) Br was suggested to be a potent VAChT ligand for PET.

Topics: Animals; Autoradiography; Brain; Bromine Radioisotopes; Central Nervous System Agents; Male; Pentazocine; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Rats, Sprague-Dawley; Receptors, sigma; Vesicular Acetylcholine Transport Proteins

The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D₂ receptors, where its degree of efficacy as a partial agonist remains controversial.. We examined the properties of aripiprazole at D₂-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K(+), low dopaminergic tone) and a stimulated condition (15 mM K(+), where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions.. Aripiprazole under the basal condition acted as an agonist at D₂-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D₂-like autoreceptor activation. Under the stimulated (15 mM K(+)) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole.. Under high dopaminergic tone, aripiprazole acts as a D₂-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D₂-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D₂R ligand.

Topics: Animals; Aripiprazole; Autoreceptors; Corpus Striatum; Dopamine; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Piperidines; Potassium; Presynaptic Terminals; Quinpirole; Rats, Sprague-Dawley; Receptors, Dopamine D2

The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D(2) ligands remains controversial.

Topics: Animals; Aripiprazole; Corpus Striatum; Dopamine; Dopamine Agonists; Drug Partial Agonism; In Vitro Techniques; Male; Piperazines; Piperidines; Quinolones; Quinpirole; Rats; Rats, Wistar

The partial agonist profile of novel antipsychotics such as aripiprazole has hardly been demonstrated in biochemical assays on animal tissues. As it is established that responses induced by dopamine D₂ receptor agonists are increased in models of dopaminergic sensitization, this paradigm was used in order to facilitate the detection of the partial agonist properties of aripiprazole. At variance with all other partial and full agonists tested, the partial agonist properties of aripiprazole were not revealed in guanosine 5′-O-(γ-[³⁵S]thiotriphosphate ([³⁵S]GTPγS) binding assays on striatal membranes from haloperidol-treated rats. Hence,aripiprazole behaved as an antagonist, efficiently inhibiting the functional response to dopamine. Similarly, in behavioural assays, aripiprazole dose-dependently inhibited the stereotypies elicited by apomorphine. However, at variance with haloperidol, repeated administrations of aripiprazole(3 weeks) at the doses of 10 and 30 mg/kg did not induce any up-regulation or hyperfunctionality of the dopamine D₂ receptors in the striatum. These data highlight the putative involvement of other pharmacological targets for aripiprazole that would support in the prevention of secondary effects commonly associated with the blockade of striatal dopamine D₂ receptors. Hence, in additional experiments, aripiprazole was found to efficiently promote [³⁵S]GTPγS binding in hippocampal membranes through the activation of 5-HT(₁A) receptors. Further experiments investigating the second messenger cascades should be performed so as to establish the functional properties of aripiprazole and understand the mechanism underlying the prevention of dopamine receptor regulation in spite of the observed antagonism.

Topics: Animals; Apomorphine; Aripiprazole; Buffers; Catalepsy; Cell Membrane; Cerebral Cortex; Corpus Striatum; Domperidone; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Antagonism; Drug Partial Agonism; Guanosine 5'-O-(3-Thiotriphosphate); Haloperidol; Hippocampus; Male; Piperazines; Piperidines; Pyridines; Quinolones; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Stereotyped Behavior; Up-Regulation

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.

Topics: Animals; Aripiprazole; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Hyperprolactinemia; Lactotrophs; Male; Methyltyrosines; Piperazines; Piperidines; Prolactin; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine

The first example of Pd-catalyzed, C3-selective arylation of unprotected pyridines has been developed by employing a catalytic system consisting of Pd(OAc)(2) and 1,10-phenanthroline. This protocol provides an expeditious route to an important class of 3-arylpyridines and 3-arylpiperidines frequently found in bioactive compounds. A brief synthesis of the drug molecule (±)-preclamol is also reported.

Topics: Ligands; Molecular Structure; Organometallic Compounds; Palladium; Piperidines; Pyridines; Stereoisomerism

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Calcium Signaling; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Immunoblotting; Lisuride; MAP Kinase Signaling System; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1; Phosphorylation; Piperazines; Piperidines; Quinolones; Raclopride; Receptors, Dopamine D2; Schizophrenia; Time Factors; Transfection

Aripiprazole and the candidate antipsychotics, S33592, bifeprunox, N-desmethylclozapine (NDMC) and preclamol, are partial agonists at D(2) receptors. Herein, we examined their actions at D(2L) and D(3) receptors expressed separately or together in COS-7 cells. In D(2L) receptor-expressing cells co-transfected with (D(3) receptor-insensitive) chimeric adenylate cyclase-V/VI, drugs reduced forskolin-stimulated cAMP production by approximately 20% versus quinpirole (48%). Further, quinpirole-induced inhibition was blunted by aripiprazole and S33592, confirming partial agonist properties. In cells co-transfected with equal amounts of D(2L)and D(3) receptors (1 : 1), efficacies of aripiprazole and S33592 were attenuated. Further, in cells co-transfected with D(2L) and an excess of D(3) receptors (1 : 3), aripiprazole and S33592 were completely inactive, and they abolished the actions of quinpirole. Likewise, bifeprunox, NDMC and preclamol lost agonist properties in cells co-transfected with D(2L)and D(3) receptors. Accordingly, at split D(2trunk)/D(3tail) and D(3trunk)/D(2tail) chimeras, agonist actions of quinpirole were blocked by aripiprazole and S33592 that, like bifeprunox, NDMC and preclamol, were inactive alone. Conversely, when a 12 amino acid sequence in the third intracellular loop of D(3) receptors was replaced by the homologous sequence of D(2L) receptors, aripiprazole, S33592, bifeprunox, NDMC and preclamol inhibited cAMP formation by approximately 20% versus quinpirole (42%). Moreover, at D(2L) receptor-expressing cells co-transfected with modified D(3i3(D2)) receptors, drugs behaved as partial agonists. To summarize, low efficacy agonist actions of aripiprazole, S33592, bifeprunox, NDMC and preclamol at D(2L) receptors are abrogated upon co-expression of D(3) receptors, probably due to physical association and weakened coupling efficacy. These findings have implications for the functional profiles of antipsychotics.

Topics: Adenylyl Cyclases; Animals; Antipsychotic Agents; Aripiprazole; Benzamides; Benzoxazoles; Carrier Proteins; Chlorocebus aethiops; Clozapine; COS Cells; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Piperazines; Piperidines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Transfection

Dopamine D2 partial agonists have been successfully used as schizophrenia therapeutics. Radiolabeled D2 partial agonists may have application in elucidating dopaminergic transmission. It was the goal of this work to radiolabel (S)-(-)propyl-3-(3-hydroxyphenyl)piperidine (preclamol; (-)3-PPP), a partial dopamine D2 agonist with carbon-11 (half-life=20.4 min) and to evaluate this novel radiopharmaceutical for dopaminergic imaging in rodent models. [11C]Preclamol was synthesized by acylation of (S)-3-(3-hydroxyphenyl)piperidine hydrochloride with [11C]propionyl chloride, followed by LiAlH4 reduction, and HPLC purification. Male Sprague-Dawley rats were injected in the tail vein with a saline solution of [11C]preclamol (1.1 mug/kg) and sacrificed at 5, 15, 30 and 60 min postinjection. Brain regions were excised, weighed, and measured for radioactivity. In vivo binding kinetics of [11C]preclamol were determined with beta-sensitive microprobes implanted into the striatum and cerebellum of an anesthetized rat. A full production of [11C]preclamol resulted in 34 mCi ready for injection (corresponding to 4% uncorrected radiochemical yield, based on starting [11C]CO2) with specific activity of 535 mCi/micromol. The total synthesis time was 45 min and resulted in chemically and radiochemically pure [11C]preclamol (>99%; n=3). High levels of radioactivity were observed in rat brain indicating good blood-brain barrier penetration of [11C]preclamol, with 0.5 to 0.7% injected dose per gram of wet tissue present in all brain regions at 5 minutes postinjection. Unfortunately, [11C]preclamol displayed minimal preferential uptake in dopaminergic brain regions. A low striatal specific binding (SB) ratio of 0.32 was determined ex vivo at 60 min postinjection and was in close agreement with the microprobe study over 60 min (peaked at 27 min postinjection; SB ratio=0.6). The binding potential value was only 0.34 over a 1 hour time course, suggesting that [11C]preclamol is not suitable for cerebral PET studies.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Chemistry; Chemical Phenomena; Chemistry, Physical; Dopamine Agonists; Indicators and Reagents; Injections, Intravenous; Isotope Labeling; Male; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

We evaluated the effects of phenytoin (DPH) on the affinity for sigma-1 (sigma(1)) receptors of agonist or antagonist sigma(1) ligands in guinea pig brain. Heterologous competition experiments showed that DPH (250 microM and 1 mM) concentration-dependently increased the affinity of the sigma(1) agonists dextromethorphan, (+)-SKF-10,047, (+)-3-PPP, and PRE-084. However, neither DPH 250 microM nor 1 mM increased (in fact, they slightly decreased) the affinity of the sigma(1) receptor antagonists haloperidol, BD 1063, NE-100, progesterone, and BD 1047. These findings suggest that allosteric modulation by DPH of the affinity of sigma(1) receptor ligands depends on the agonist or antagonist characteristics of the ligand. Therefore, determining in vitro the differential modulation by DPH of sigma(1) ligand affinity appears to constitute a procedure that can predict the pharmacological profile of different sigma(1) ligands.

Topics: Allosteric Regulation; Animals; Anisoles; Anticonvulsants; Binding, Competitive; Brain; Dextromethorphan; Drug Interactions; Ethylenediamines; Guinea Pigs; Haloperidol; Ligands; Male; Morpholines; Neurons; Phenazocine; Phenytoin; Piperazines; Piperidines; Progesterone; Propylamines; Receptors, sigma; Synaptic Transmission

Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated cAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Binding, Competitive; Cell Membrane; CHO Cells; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; DNA, Complementary; Dopamine; Dopamine Agonists; Dopamine Antagonists; Haloperidol; Humans; Lisuride; Piperazines; Piperidines; Quinolones; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Risperidone; Transfection; Tritium

We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.

Topics: Animals; Behavior, Animal; Cell Division; Cell Line, Tumor; Corpus Striatum; Dopamine; Dopamine Agonists; Humans; Mice; Mice, Inbred C57BL; Monoamine Oxidase; MPTP Poisoning; Neuroprotective Agents; Piperidines; Treatment Failure

The role of MS-377, a novel selective sigma1 ligand currently being developed for the treatment of schizophrenia, in modulating the activities of phencyclidine (PCP) on NMDA-induced calcium increase was examined in primary cultured neocortical neurons using calcium-imaging technique combined with a confocal laser scanning microscope. PCP significantly blocked NMDA-induced increases in intracellular calcium. The blockade by PCP of NMDA response was attenuated by both MS-377 and another highly selective sigma1 ligand, 3-PPP. The results agree with the interpretation that sigma ligands may directly or indirectly modulate NMDA receptor complex functions, and may suggest that MS-377 might be therapeutically useful in cases of PCP-induced psychosis or schizophrenia.

Topics: Algorithms; Animals; Calcium; Cells, Cultured; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Image Processing, Computer-Assisted; Ligands; Microscopy, Confocal; Neocortex; Phencyclidine; Piperidines; Pyrrolidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Tartrates

We investigated the effects of sigma receptor ligands on neuronal death induced by chemical ischemia using primary cultures of rat cerebral cortical neurons. The induction of chemical ischemia by sodium azide and 2-deoxy-D-glucose led to delayed neuronal death in a time- and concentration-dependent manner, as determined by trypan blue exclusion. The neurotoxicity was inhibited by N-methyl-D-aspartate (NMDA) receptor antagonists, indicating the involvement of glutamate. The sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and haloperidol, but not carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), prevented chemical ischemia-induced neurotoxicity in a concentration-dependent manner. The protective effects of (+)-SKF10,047 and haloperidol were not affected by the sigma receptor antagonists. (+)-SKF10,047 and haloperidol, but not carbetapentane and (+)-3PPP, inhibited the glutamate-induced increase in intracellular Ca(2+), and the inhibitory effects were not attenuated by sigma receptor antagonists. These results suggest that direct interaction with NMDA receptors but not sigma receptors is crucial to the neuroprotective effects of sigma receptor ligands with affinity for NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Animals; Calcium; Cell Hypoxia; Cell Survival; Cells, Cultured; Cerebral Cortex; Cyclopentanes; Deoxyglucose; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fetus; Glucose; Glutamates; Haloperidol; Neurons; Phenazocine; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sodium Azide

The antipsychotic drugs have been shown to be inverse agonists at the D(2) dopamine receptor. We have examined the mechanism of this inverse agonism by making mutations in residue T343 in the base of the sixth transmembrane spanning region of the receptor. T343R, T343S and T343K mutant D(2) dopamine receptors were made and the T343R mutant characterized in detail. The T343R mutant D(2) dopamine receptor exhibits properties of a receptor that resides more in the activated state, namely increased agonist binding affinity (independent of G-protein coupling and dependent on agonist efficacy), increased agonist potency in functional tests (adenylyl cyclase inhibition) and increased inverse agonist effects. The binding of agonists to the mutant receptor also shows sensitivity to sodium ions, unlike the native receptor, so that isomerization of the receptor to its inactive state may be driven by sodium ions. The binding of inverse agonists to the receptor is, however, unaffected by the mutation. We conclude that inverse agonism at this receptor is not achieved by the inverse agonist binding preferentially to the non-activated state of the receptor over the activated state. Rather the inverse agonist appears to bind to all forms of the receptor but then renders the receptor inactive.

Topics: 1-Methyl-3-isobutylxanthine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Apomorphine; Binding, Competitive; Bromocriptine; Butaclamol; Chlorpromazine; CHO Cells; Clozapine; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; GTP-Binding Proteins; Haloperidol; Humans; Macromolecular Substances; Mutagenesis, Site-Directed; Phenethylamines; Piperidines; Protein Binding; Protein Conformation; Radioligand Assay; Receptors, Dopamine D2; Recombinant Fusion Proteins; Sodium; Spiperone; Structure-Activity Relationship; Sulpiride; Transfection; Tyramine

The effects of trazodone and putative sigma (sigma) receptor ligands were investigated on KCl-stimulated release of glutamate (Glu) and gamma-aminobutyric acid (GABA) from cerebellar mossy fibre synaptosomes. Both trazodone and serotonin (5-HT) inhibited the increase of Glu and GABA release evoked by 15 mM KCl. Trazodone increased the inhibition of Glu release caused by 0.01 microM 5-HT, while it antagonized the inhibition induced by higher 5-HT concentrations. Despite the low affinity of trazodone for both sigma(1) and sigma(2) binding sites, with a pK(i) of 5.9 and 6.0 respectively, two sigma receptor ligands, (+)-3-[3-hydroxypheny]-N-(1-propyl)piperidine ((+)-3-PPP) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047) antagonized the effects of trazodone. The putative sigma receptor ligand N-allylnormetazocine ((+)-SKF 10,047) mimicked the inhibitory effect of trazodone. As with trazodone, (+)-3-PPP and BD 1047 antagonized the activity of (+)-SKF 10,047 but not that of 5-HT. On the whole, these results suggest that trazodone shares a common molecular target with sigma compounds distinct from that of 5-HT and is involved in K(+)-stimulated Glu and GABA release from mossy fibre cerebellar synaptosomes.

Topics: Animals; Antidepressive Agents, Second-Generation; Cerebellum; Ethylenediamines; gamma-Aminobutyric Acid; Glutamic Acid; Male; Nerve Fibers; Phenazocine; Piperidines; Potassium Chloride; Rats; Rats, Sprague-Dawley; Receptors, sigma; Serotonin; Synaptosomes; Trazodone

(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine (3-PPP; a sigma receptor ligand), administered at 30 mg kg-1, 30 min before the test, significantly decreased the electroconvulsive threshold in mice, being ineffective in lower doses. 3-PPP (20 mg kg-1) diminished the protective activity of diphenylhydantoin, phenobarbital and valproate, but not that of carbamazepine against maximal electroshock. The effect of 3-PPP upon the electroconvulsive threshold and the 3-PPP-induced inhibition of the protective action of antiepileptics was reversed by haloperidol (0.5 mg kg-1). Moreover, 3-PPP did not alter the total and free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of 3-PPP with antiepileptic drugs, providing a 50% protection against maximal electroshock, did not affect motor performance in mice, although resulted in significant long-term memory deficits. Our data indicate that sigma receptor-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.

Topics: Animals; Anticonvulsants; Avoidance Learning; Dizocilpine Maleate; Female; Guanidines; Mice; Phenobarbital; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Valproic Acid

1. Male CD-1 mice were tested for prepulse inhibition (PPI) following administration of PCP and the PCP site ligand, (+)MK-801, as well as the dopamine (DA) agonist (-)-apomorphine and DA releaser d-amphetamine. Similar to reports in rats, PCP (0.36-36.0 mumol/kg), (+)MK-801 (0.03-3.0 mumol/kg), (-)-apomorphine (3.3 and 10.0 mumol/kg) and d-amphetamine (3.0 and 8.0 mumol/kg) significantly reduced PPI when administered prior to testing. 2. Because PCP also binds to sigma receptors, the authors tested the sigma ligand (+)-3-PPP at (118 mumol/kg) which marginally increased the PPI. 3. Haloperidol (1.1 mumol/kg) pretreatment attenuated the reduction in PPI following (-)-apomorphine (10.0 mumol/kg), however no effects of haloperidol or clozapine pretreatment on (+)MK-801 disruption of PPI were observed. 4. Because of the pharmacological similarities between mouse data and previously published rat data, it is concluded that the mouse is a viable alternative to the rat for testing PPI.

Topics: Acoustic Stimulation; Animals; Apomorphine; Clozapine; Dextroamphetamine; Dizocilpine Maleate; Dopamine Agonists; Dose-Response Relationship, Drug; Haloperidol; Male; Mice; Mice, Inbred Strains; Phencyclidine; Piperidines; Rats; Receptors, sigma; Reflex, Startle; Species Specificity

The abilities of dopamine (DA) and the partial DA D2 receptor agonist (-)-(3-hydroxyphenyl)-N-n-propylpiperidine, (-)-3-PPP, to suppress prolactin (PRL) release induced by any of five different PRL secretagogues in GH4C1 cells transfected with the human D2 receptor (short isoform) were investigated. Whereas DA reduced the response to all five secretagogues. (-)-3-PPP reduced the response to vasoactive intestinal peptide (VIP) and thyrotropin-releasing hormone (TRH), but not to high medium potassium (K+) or to the potassium channel antagonist tetraethylammonium (TEA). (-)-3-PPP tended to reduce the PRL release induced by the Ca2+ channel agonist BAY K-8644 (BAY); however, this effect of the partial agonist was modest and not significant. Whereas the effects of both DA and (-)-3-PPP on the PRL response to VIP and TRH were counteracted by co-incubation with the D2 antagonist raclopride, the effects of DA on the PRL response to K+, BAY, and TEA were antagonized by co-incubation with either raclopride or (-)-3-PPP. The results show that, at a given receptor density, the intrinsic activity of a partial D2 agonist with respect to D2-mediated suppression of PRL release may vary from agonism to antagonism depending on which intracellular transduction systems that are being concomitantly activated.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Cell Line; Dopamine; Dopamine Agonists; Humans; Piperidines; Potassium; Prolactin; Receptors, Dopamine D2; Tetraethylammonium; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

The effects of two potent sigma receptor agonists (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine) and DTG (N,N'-di-(o-tolyl)guanidine) on the insulin secretory responses in rat islets of Langerhans were investigated. Both sigma receptor ligands were able to potentiate the insulin secretory response of islets incubated at 6 mM glucose, in a dose-dependent manner and were also able to reverse the effects of diazoxide on insulin release. When islets were treated with efaroxan, a well-characterised imidazoline insulin secretagogue, and either (+)-3-PPP or DTG together, there was an unexpected and profound absence of stimulation of insulin release as compared to when islets were incubated with each compound alone. Experiments performed with islets where there was desensitization of DTG/sigma receptor or efaroxan/imidazoline binding site mediated responses suggest that at least two distinct receptor systems appear to be involved. The complex interactions of these two classes of drug require further investigation.

Topics: Adrenergic alpha-Antagonists; Animals; Azides; Benzofurans; Dopamine Agonists; Dose-Response Relationship, Drug; Guanidines; Imidazoles; Imidazoline Receptors; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Ligands; Male; Piperidines; Rats; Rats, Wistar; Receptors, Drug; Receptors, sigma

In CHO cells transfected with the rat dopamine D2 receptor (long isoform), administration of dopamine per se elicited a concentration-dependent increase in arachidonic acid (AA) release. The maximal effect was 197% of controls (EC50=25 nM). The partial D2 receptor agonist, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3-PPP], also induced AA release, but with somewhat lower efficacy (maximal effect: 165%; EC50=91 nM). The AA-releasing effect of dopamine was counteracted by pertussis toxin, by the inhibitor of intracellular Ca2+ release, 8-(N N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), by excluding calcium from the medium, by the phospholipase A2 (PLA2) inhibitor, quinacrine, and by long-term pretreatment with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). In addition, it was antagonized by the D2 antagonists, raclopride and (-)-sulpiride--but not by (+)-sulpiride--and absent in sham-transfected CHO cells devoid of D2 receptors. The results obtained contrast to the previous notion that dopamine and other D2 receptor agonists require the concomitant administration of calcium-mobilizing agents such as ATP, ionophore A-23187 (calcimycin), thrombin, and TRH, to influence AA release from various cell lines.

Topics: Adenosine Triphosphate; Animals; Arachidonic Acid; Calcium; Calcium Channel Blockers; CHO Cells; Cricetinae; Cyclooxygenase Inhibitors; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Gallic Acid; Pertussis Toxin; Piperidines; Receptors, Dopamine D2; Transfection; Virulence Factors, Bordetella

Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (-)-[18F] FEOBV,(-)-(2R,3R)-trans-2-hydroxy-3-(4-phenylpiperidino)-5-(2-[18F ]fluoroethoxy)-1,2,3,4-tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (-)-[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare-like effects of FEOBV were associated with the "(-)"-enantiomer exclusively. (-)-[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)-3-PPP, or E-2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or sigma receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (-)-[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (-)-[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET.

Topics: Acetylcholine; Animals; Autoradiography; Brain; Calibration; Carrier Proteins; Cholinesterase Inhibitors; Donepezil; Dopamine Agonists; Female; Fluorine Radioisotopes; Haloperidol; Humans; Indans; Kinetics; Male; Membrane Transport Proteins; Mice; Organ Specificity; Piperidines; Rats; Rats, Sprague-Dawley; Stereoisomerism; Synapses; Tissue Distribution; Tomography, Emission-Computed; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

1. Electrically induced contractions of the epididymal portion of rat vas deferens were potentiated in concentration-dependent manner (0.1-30 microM) by different sigma and PCP receptor ligands (PCP, TCP, (+)-MK-801, dextromethorphan and (+)-3-PPP); dextrorphan did it in a minor extent. 2. Sigma and PCP receptor ligands also potentiated the effect of noradrenaline, inducing a reduction of the noradrenaline EC50 value in the rat vas deferens. The rank order of potencies was: PCP > TCP > (+)-3-PPP > (+)-MK-801 > dextrorphan > > > dextrometorphan. 3. In contrast, haloperidol (1 microM), a sigma receptor ligand, inhibited both the neurogenic and noradrenaline-induced responses in this tissue. 4. The effect of PCP and sigma receptor ligands on noradrenaline uptake was evaluated. All compounds tested, including haloperidol, inhibited the tritiated noradrenaline incorporation to the tissue. IC50 values were in the micromolar range, between 1.09 microM for dextrophan and 18 microM for dextrometorphan. 5. It is concluded that a direct interaction with the noradrenaline uptake system is involved in the potentiating effect of some sigma and PCP receptor ligands in the epididymal portion of rat vas deferens.

Topics: Adrenergic alpha-Agonists; Animals; Dextromethorphan; Dizocilpine Maleate; Dopamine Agonists; Electric Stimulation; Excitatory Amino Acid Antagonists; Ligands; Male; Muscle Contraction; Neuroprotective Agents; Norepinephrine; Phencyclidine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Phencyclidine; Receptors, sigma; Tritium; Vas Deferens

Intraperitoneal administration of 4-cyclohexyl-1-[(1R)-1,2-diphenylethyl]-piperazine (CDEP) immediately after the training session produced significant memory impairment in the mouse passive avoidance performance. Interestingly, this memory impairment was alleviated by subcutaneous administrations of sigma receptor agonists, (+)-N-allylnormetazocine ((+)-SKF-10,047), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and 1,3-di(2-tolyl)guanidine (DTG) immediately after the training session. In particular, the remarked recovery for this memory impairment was produced by (+)-SKF-10,047. A receptor binding study showed that CDEP possessed high affinities for both sigma 1 and sigma 2 receptor subtypes (IC50 1.4 +/- 0.3 nM for sigma 1 receptor subtype, 1.8 +/- 0.3 nM for sigma 2 receptor subtype), while (+)-SKF-10,047 had a high selectivity for the sigma 1 receptor subtype. These findings suggest that the sigma receptor, particularly sigma 1 receptor subtype, may play an important role in the CDEP-induced impairment of learning and memory processes.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Binding, Competitive; Brain Chemistry; Dopamine Agonists; Guinea Pigs; Male; Membranes; Memory Disorders; Mice; Phenazocine; Piperazines; Piperidines; Radioligand Assay; Receptors, sigma

In vitro receptor autoradiography was used to localize sigma 1 receptors, sigma 2 receptors, and novel haloperidol/DTG-inaccessible sites for sigma and opiate ligands in rat spleen. Sigma-1 receptors were present throughout the spleen, but were most concentrated in the T cell zones. Binding under "sigma 2 receptor-selective' conditions was 70% nonspecific, and sigma 2 receptors could not be detected. Haloperidol/DTG-inaccessible sites had a coarse, punctate distribution in the red pulp and marginal zones of the white pulp. This anatomical localization suggests types of cells and functions that should be examined for modulation by sigma receptors.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Antipsychotic Agents; Autoradiography; Binding Sites; Dopamine Agonists; Dopamine Antagonists; Female; Guanidines; Haloperidol; Image Processing, Computer-Assisted; Ligands; Male; Naltrexone; Narcotic Antagonists; Pentazocine; Phenazocine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Spleen; Tritium

We examined the ameliorating effects of several sigma receptor agonists on scopolamine-induced memory impairment in mice. Scopolamine was administered IP 30 min before the training session. Each sigma receptor agonist was administered 60 min before or immediately after the training session, or 60 min before the retention test in the passive-avoidance performance experiments. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype sigma 1 receptor agonist, showed an ameliorating effect on the scopolamine-induced memory impairment in these 3 administration schedules, and (-)-SKF-10,047, a stereoisomer with low affinity for the sigma 1 receptor subtype, failed to reduce this memory impairment in mice. In addition, 1,3-di(2-toly1)guanidine (DTG) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), nonselective sigma receptor agonists, did not affect this memory impairment. Physostigmine, an acetylcholinesterase (AChE) inhibitor, alleviated the scopolamine-induced memory impairment in all these drug administration schedules. In addition, (+)-SKF-10,047-induced antiamnesic effect was antagonized by the concurrent administration of haloperidol, a sigma receptor antagonist, or N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy) phenyl)ethylamine monohydrochloride (NE-100), a selective sigma 1 receptor antagonist. These findings indicate that the sigma 1 receptor agonist has ameliorating effects on all phases of learning and memory processes. This profile of sigma 1 receptor agonist is similar to that of an AChE inhibitor.

Topics: Acetylcholinesterase; Animals; Antipsychotic Agents; Avoidance Learning; Brain; Dose-Response Relationship, Drug; Guanidines; Male; Mental Recall; Mice; Mice, Inbred Strains; Phenazocine; Piperidines; Receptors, sigma; Scopolamine

The behavioural effects of selective serotonin reuptake inhibitors (paroxetine, sertraline, citalopram, fluvoxamine, fluoxetine) and reference compounds (N,N'-di(o-tolyl)guanidine, haloperidol, 3-(3-hydroxyphenyl)-N-(l-propyl)piperidine and chlorpromazine) were studied for their ability to produce dystonia and torticollis following direct micro injection into the left red nucleus of the rat, an area of the brain containing a high density of sigma2 receptors but relatively devoid of biogenic amine receptors. Each animal was monitored for abnormalities in posture and movement for a period of 30 min and then sacrificed 40 min following drug administation. Only fluvoxamine (100 nmol) and fluoxetine (100 nmol) elicited acute dystonic behaviour (1-5 min). The onset of dystonia was accompanied by facial spasticity, vacuous chewing movements and grooming behaviour which reflected the extent of dystonia. The dystonic behaviour following the direct intrarubal injection of fluvoxamine and fluoxetine suggest the possible activation of sigma2 receptors while citalopram, sertraline and paroxetine were without effect. The results of this study support the role of sigma2 receptors in the regulation and control of movement and coordination and provides preliminary evidence to suggest the in vivo activity of sigma receptors by fluoxetine and fluvoxamine.

Topics: 1-Naphthylamine; Animals; Behavior, Animal; Chlorpromazine; Citalopram; Fluoxetine; Fluvoxamine; Guanidines; Haloperidol; Male; Microinjections; Motor Activity; Paroxetine; Piperidines; Posture; Rats; Rats, Sprague-Dawley; Receptors, sigma; Red Nucleus; Selective Serotonin Reuptake Inhibitors; Sertraline

Several antipsychotic drugs, belonging to various chemical classes, were compared for their affinity for the sigma, dopamine-D2, and muscarinic receptors. Many neuroleptic drugs were found to bind with high affinity to sigma 2 receptors, and the binding affinity was clearly different from that observed for dopamine-D2 receptors. The dopaminergic and muscarinic theories for the physiopathology of acute dystonia are not completely satisfactory. Since the sigma receptors were reported to play a role in the control of movement, the high affinity of some neuroleptics for these sites suggests their possible involvement in some side effects, such as drug-induced dystonia. There was a correlation between the clinical incidence of neuroleptic-induced acute dystonia and binding affinity of drugs for the sigma receptor, except for some drugs, with a lower incidence, displaying significant affinity for the cholinergic muscarinic receptor. Therefore, we conclude that the affinity for the sigma receptor might be involved in neuroleptic-induced acute dystonia, but this might be partially corrected by the intrinsic anticholinergic properties of the drug.

Topics: Animals; Antipsychotic Agents; Dopamine Agonists; Dyskinesia, Drug-Induced; Male; Piperidines; Quinuclidinyl Benzilate; Radioligand Assay; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Muscarinic; Receptors, sigma; Spiperone

[3H]-Nemonapride has been the ligand of choice to label D4 dopamine receptors. Its specificity was questioned when it was discovered that sigma (sigma) sites were also labeled by [3H]-nemonapride. To further characterize the binding of [3H]-nemonapride, three areas of calf brain (striatum, frontal cortex and cerebellum) were examined. In all three areas, [3H]-nemonapride labeled multiple sites. Dopaminergic and sigma sites were the most prominent. The sigma binding profile was sigma-1 like with a Ki binding profile as follows (in order of decreasing potency): haloperidol, PPAP, pentazocine, DTG, U-50488, R(+)-3-PPP. Experiments using sulpiride and pentazocine to block striatal dopaminergic and sigma sites, respectively, revealed additional, not previously characterized binding sites for [3H]-nemonapride. One component which was present in striatum but not in frontal cortex or cerebellum, had affinity for some neuroleptics and WB-4101, but not for typical serotonergic agents. Thus, [3H]-nemonapride has no selectivity for dopamine receptors unless stringent experimental conditions are met.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Benzamides; Binding, Competitive; Brain; Cattle; Cerebellum; Cerebral Cortex; Corpus Striatum; Dioxanes; Dopamine Agonists; Dopamine Antagonists; Guanidines; Haloperidol; In Vitro Techniques; Isotope Labeling; Narcotic Antagonists; Pentazocine; Piperidines; Propylamines; Pyrrolidines; Receptors, Dopamine D2; Receptors, sigma; Sulpiride; Tritium

Our overall goal was to investigate the mechanism by which fentanyl attenuates acetylcholine-induced contraction in porcine coronary artery. We tested the hypothesis that fentanyl attenuates muscarinic coronary contraction via sigma receptor activation. Left coronary artery vascular rings were isolated from porcine hearts and were suspended in organ chambers for isometric tension recording. In untreated coronary vascular rings, acetylcholine administration resulted in dose-dependent contraction. Fentanyl attenuated acetylcholine-induced contraction. The sigma ligands--(+)-pentazocine, (+)-cyclazocine, haloperidol, and 1,3-di-o-tolylguanidine--also inhibited acetylcholine-induced contraction. In contrast, the selective sigma ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine failed to have an inhibitory effect on acetylcholine-induced contraction. Moreover, metaphit (1-[1(3-isothiocyanatophenyl)cyclohexyl]piperidine), which causes irreversible acylation of sigma receptors, only inhibited acetylcholine-induced contraction when it was present in the organ chamber. We also assessed the effects of inhibiting various points in the signal transduction pathway distal to naloxone-sensitive opioid receptor activation on acetylcholine-induced contraction. Selective (glybenclamide) and nonselective (tetraethylammonium) K(+)-channel inhibition, guanosine triphosphate-binding protein inactivation (pertussis toxin), and Type 1 and Type 2 dopamine receptor inhibition all failed to alter the attenuating effect of fentanyl on acetylcholine-induced contraction. Thus, neither sigma or opioid receptor activation is a prerequisite for fentanyl-induced inhibition of muscarinic coronary contraction.

Topics: Acetylcholine; Anesthetics, Intravenous; Animals; Coronary Vessels; Cyclazocine; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fentanyl; Guanidines; Haloperidol; Muscarine; Muscarinic Agonists; Narcotic Antagonists; Narcotics; Pentazocine; Phencyclidine; Piperidines; Potassium Channel Blockers; Receptors, Dopamine; Receptors, sigma; Signal Transduction; Swine; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

The effects of sigma-receptor ligands on the twitch contraction elicited by the exogenous application of adenosine 5'-triphosphate (ATP) in the unstimulated mouse vas deferens were studied. (-)-Pentazocine, 1,3-di(2-tolyl)guanidine(DTG) and two pairs of optical isomers of 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine(3-PPP) and N-allylnormetazocine (SKF-10,047) potentiated the exogenous application of ATP-induced twitch-type contraction in a concentration-dependent manner, while (+)-pentazocine did not affect it. The order of potentiating ability was: (+)-3-PPP > (-)pentazocine > (-)-SKF-10,047> DTG > (-)-3-PPP > (+)-SKF-10,047. On the other hand, haloperidol and rimcazole, putataive sigma-receptor antagonists, suppressed this twitch contraction. In addition, these antagonists significantly blocked the (+)-3-PPP- and (-)-pentazocine-induced potentiation at concentrations which did not affect contractions per se. These findings indicate that the exogenous application of ATP-induced twitch contraction in the mouse vas deferens is regulated by sigma-receptors. In addition, the present ranking order suggests that the sigma-receptor potentiating the ATP-induced twitch contraction at post-junctional sites may differ from the sigma 1- and/or sigma 2-receptor subtypes.

Topics: Adenosine Triphosphate; Analgesics, Opioid; Animals; Anticonvulsants; Antipsychotic Agents; Carbazoles; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Guanidines; Haloperidol; Ligands; Male; Mice; Muscle Contraction; Muscle, Smooth; Pentazocine; Phenazocine; Piperidines; Receptors, sigma; Regression Analysis; Structure-Activity Relationship; Vas Deferens

High concentrations of novel, haloperidol- and DTG-inaccessible (+)-[3H]-3-PPP binding sites were found in human peripheral blood leukocytes rat spleen and splenocytes, but not in rat brain. Splenic sites were localized in a course punctate pattern in the marginal zones and red pulp. The pharmacology of the splenic sites was: (-)-SKF 10,047 > or = naltrexone = (-)-pentazocine > (+)-pentazocine = (-)-3-PPP = (+)-SKF 10,047 > or = (+)-3-PPP > or = dextrorphan > dextromethorphan > PCP > clorgyline. DTG, haloperidol, TCP, (-)-deprenyl and SKF 525-A did not complete. Binding activity was destroyed by heating and phospholipase C, but not by proteases or glycosidases. These sites may be involved in immunomodulation by opiate and sigma receptor agonists.

Topics: Animals; Anticonvulsants; Autoradiography; Binding Sites; Binding, Competitive; Brain Chemistry; Cytochrome P-450 Enzyme System; Dopamine Agonists; Dopamine Antagonists; Female; Guanidines; Haloperidol; Hydrogen-Ion Concentration; Kinetics; Leukocytes; Monoamine Oxidase; Naltrexone; Narcotic Antagonists; Narcotics; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Spleen; Tritium

The affinity and intrinsic activity of dopamine receptor agonists were determined at the human dopamine hD21 and hD4.4 receptors. (-)-3-Hydroxy-N-n-propylpiperidine ((-)3-PPP) had an intrinsic activity of 46% and 83%, whereas (+)-N-propylnorapomorphine ((+)-NPA) had intrinsic activities of 61% and 58% at the dopamine hD21 and hD4.4 receptors, respectively. Affinities also varied. A single, or multiple, dopamine D2-type receptor(s) may be involved in schizophrenia and agonists are being tested as therapy. Understanding their properties at the individual dopamine D2-family receptors is important.

Topics: Aminoquinolines; Animals; Cell Membrane; CHO Cells; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Humans; Piperidines; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides

The present experiments were performed to examine the behavioral effects of OPC-14597, which acts on dopamine receptors in rats. OPC-14597 administered subcutaneously (SC) at doses of 0.1-5 mg/kg elicited yawning, as did OPC-4392 (0.5-2 mg/kg, SC) and (-)-3-PPP (2.5-10 mg/kg, SC). These yawning responses were blocked by intraperitoneal (IP) pretreatment with haloperidol (0.5 mg/kg) but were increased by pindolol (20 mg/kg, IP) or reserpine (5 mg/kg, IP), which per se did not elicit yawning. The yawning induced by talipexole, a selective dopamine D2 receptor agonist, was inhibited by OPC-14597 (0.5-5 mg/kg, SC) and (-)-3-PPP (10 mg/kg, SC). Apomorphine (0.5 mg/kg, SC), a dopamine D1/D2 receptor agonist, elicited stereotypy such as sniffing and licking but OPC-14597 (5-20 mg/kg, SC) did not induce this behavior. The stereotypy induced by apomorphine was inhibited not only by haloperidol (0.5 mg/kg, IP) and (-)-3-PPP (10 mg/kg, SC) but also by OPC-14597 (5-20 mg/kg, SC), without being affected by OPC-4392 (2 mg/kg, SC). In 6-hydroxydopamine (6-OHDA)-treated rats, apomorphine (0.5 mg/kg, SC) elicited rotation behavior whereas OPC-14597, OPC-4392 and (-)-3-PPP did not produce this behavior. These findings suggest that OPC-14597 provokes yawning without causing stereotypy and rotation but markedly antagonizes the talipexole-induced yawning and apomorphine-induced stereotypy, and that OPC-14597 thus exerts partial agonistic effects on yawning behavior but antagonistic effects on stereotypy in rats.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Azepines; Dopamine Agonists; Drug Synergism; Male; Oxidopamine; Piperazines; Piperidines; Quinolones; Rats; Rats, Wistar; Receptors, Dopamine; Stereotyped Behavior; Sympathectomy, Chemical; Yawning

The present study examined whether the kappa-opioid agonists U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N[-2-(1-pyrrolidinyl)- cyclohexyl]-benzeacetamide methane sulphonate), bremazocine, spiradoline and ICI 197067 bind to sigma sites in guinea-pig tissues using in vitro, semi-quantitative receptor autoradiography and receptor binding, and compared the binding profile so obtained with those for several selective sigma ligands. Guinea-pigs were killed and their brians, livers and spleens were removed, tissue sections cut and processed for sigma binding site autoradiography using (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-[3H]-3-PPP), or tissue was wiped and determined by liquid scintillation. Serial slide-mounted sections were incubated with 9-10 concentrations (1 nM-10 microM) of kappa opioids and their potency to inhibit (+)-[3H]-3-PPP binding compared with that of the sigma ligands haloperidol, DTG (1,3 di(o)-tolylguanidine), (+)-3-PPP, (+) and (-)pentazocine, SR 31742A and rimcazole (n = 3, duplicate determinations). Binding of (+)-[3H]-3-PPP to untreated, matched serial tissue sections was used as control. Kd values were estimated in brain, liver and spleen using quantitative, saturation binding analysis, IC50 values were determined from the binding data obtained by slide wiping experiments for each drug, and Ki values were calculated using the Cheng-Prussoff equation. All four kappa opioids inhibited (+)-[3H]-3-PPP binding to sigma 1-receptors with order of potency: brain: U50,488H = spiradoline > bremazocine > ICI 197067; liver: spiradoline > U50,488H > ICI 197067 > bremazocine; spleen: U50,488H > spiradoline > ICI 197067 > bremazocine. By comparison, the sigma ligands inhibited (+)-[3H]-3-PPP binding to matched, serial slide-mounted brain tissue sections (similar results in liver and spleen) with order of potency: SR 31742A > haloperidol > (+)pentazocine > (+)-3-PPP > DTG > (-)pentazocine > rimcazole. (+)-[3H]-3-PPP autoradiography confirmed these binding data. It is concluded that the kappa opioids tested moderately inhibit (+)-[3H]-3-PPP binding to sigma 1-receptors in guinea-pig brain, liver and spleen tissue with Ki values comparable to some selective sigma ligands and therefore are not opioid selective.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Autoradiography; Benzomorphans; Binding Sites; Brain; Guinea Pigs; Liver; Piperidines; Pyrrolidines; Receptors, Opioid, kappa; Receptors, sigma; Spinal Cord; Spleen

The reactivation effects of the delta-opioid receptor blockade and D2 dopamine receptor activation on the detention-induced memory deficit in mice were investigated, in order to study possible interactions between opioid and dopamine systems in memory retrieval. Animals were trained in a one-trial passive-avoidance task. Pretesting treatment with ICI 174,864 (1, 3 or 5 mg/kg, i.p.) or quinpirole (0.5, 1 or 2 mg/kg, i.p.) facilitated retrieval of memory trace in saline-pretreated mice. Pretraining injection of the dopamine autoreceptor agonist, (+)-3PPP (2 mg/kg), having no effect alone in learning, prevented the ability of ICI 174,864 to produce the memory-enhancing effect. It is suggested that the normal functioning of the dopamine system was critical for the facilitation of retrieval by delta-antagonist. Quinpirole-induced reactivátion of memory retrieval was enhanced by pretreatment with Leu-enkephalin (0.2 mg/kg), inducing increased retention. We discuss these results in the context of an important interactions between D2 dopamine and delta-opioid receptors.

Topics: Animals; Avoidance Learning; Dopamine Agonists; Enkephalin, Leucine; Male; Memory; Mice; Mice, Inbred BALB C; Narcotic Antagonists; Piperidines; Quinpirole; Receptors, Dopamine D2; Receptors, Opioid, delta

To clarify clinical roles of sigma receptor binding affinity of neuroleptics, neck dystonia induced by microinjection of sigma receptor ligands and neuroleptics into rat red nucleus was investigated. DTG and (+)-3-PPP, putative sigma receptor agonists, induced neck dystonia in dose-dependent and reversible manner. Haloperidol and perphenazine induced dystonia in the same way as sigma receptor agonists, whereas zotepine and (-)-sulpiride did not. The rank order of potency in induction of dystonia and sigma receptor affinity of these compounds showed positive correlation. Although BMY-14802 has a high affinity for sigma receptors, it never produced dystonia by itself. On the other hand, combined injection of BMY-14802 with DTG attenuated DTG-induced dystonia. Therefore, it is suggested that typical neuroleptics such as haloperidol act agonistic and atypical neuroleptics such as BMY-14802 act antagonistic at rubral sigma receptors in the induction of neck dystonia.

Topics: Animals; Antipsychotic Agents; Dibenzothiepins; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dystonia; Guanidines; Haloperidol; Male; Microinjections; Nerve Tissue Proteins; Perphenazine; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, sigma; Red Nucleus; Sulpiride; Torticollis

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and sigma receptors, we examined the effects of sigma receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/sigma receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten-5,10-imin e ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective sigma1 receptor ligand, and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype sigma receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via sigma receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 microg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP; 3 and 6 mg/kg, i.p.), sigma1/sigma2 receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047: 8 mg/kg, i.p.), a sigma1 receptor ligand, while DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and sigma receptors are involved in PCP-induced head weaving behavior, and that sigma1 receptors play an important role in modulation of the head-weaving behavior.

Topics: Animals; Anisoles; Behavior, Animal; Binding Sites; Dizocilpine Maleate; Guanidines; Male; Phenazocine; Piperidines; Propylamines; Pyrimidines; Rats; Rats, Wistar; Receptors, Phencyclidine; Receptors, sigma

The potencies for in vivo inhibition of substantia nigra pars compacta dopamine single cell firing were determined for apomorphine, BHT 920, N-0923, (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), pramipexole, quinelorane, quinpirole, RU 24926, U-86170, and U-91356. Significant correlation was obtained between the potencies of these 11 highly efficacious dopamine receptor agonists and the in vitro binding affinities at dopamine D3 receptors, but not at dopamine D2L receptors. These results support a functional role for the dopamine D3 receptor subtype in the autoreceptor-mediated regulation of dopamine cell activity, while a role for dopamine D2 receptors awaits further analysis. In addition, the results demonstrate the limitations of using currently available dopamine receptor agonists to delineate relative in vivo roles for the dopamine D2 and D3 receptor subtypes.

Topics: Aminoquinolines; Animals; Apomorphine; Azepines; Benzothiazoles; Binding, Competitive; CHO Cells; Cricetinae; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Imidazoles; Male; Neurons; Phenethylamines; Piperidines; Pramipexole; Quinolines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Structure-Activity Relationship; Substantia Nigra; Tetrahydronaphthalenes; Thiazoles; Thiophenes; Transfection

Topics: Animals; Avoidance Learning; Dopamine Agonists; Enkephalin, Leucine; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Piperidines; Receptors, Dopamine; Receptors, Opioid, delta; Receptors, Opioid, mu

The sigma receptor/binding site, found in the brain and periphery, binds haloperidol, (+)-benzomorphans, N-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and certain atypical neuroleptics with high affinity. We have succeeded in ca. 6,000-fold purification of protein(s) from rat and bovine cerebellum which display pharmacology characteristic of the sigma receptor. This purification was achieved by affinity chromatography using a Sepharose gel linked to a new high-affinity ligand, (S)-3-(3-methoxyphenyl)-3'-oxo-3'-phenyl-N-propylpiperidine, an analog of (S)-3-PPP. Elution of the affinity column with haloperidol afforded material which, after reconstitution into bimolecular lipid vesicles, was pharmacologically characterized by specific radioligand binding assays using [3H]haloperidol combined with competitive displacement using appropriate selective ligands. Comparison of the relative rank orders of potency of the ligands in these selective sigma receptor assays corresponded well with values obtained with tissue homogenates. The observed enantioselectivity for the binding of SKF-10,047 and cyclazocine suggests that the material purified corresponds to the sigma 1 receptor subtype. SDS-PAGE indicated that the purified material consisted of two bands of approximate molecular masses 65 and 63 kilodaltons. Photoaffinity labeling of the affinity-purified receptor with [3H]azido-DTG led to incorporation of the label into material of molecular mass 50-70 kDa, by slicing of SDS gels, while similar photolabeling of crude cerebellar homogenates led to exclusive labeling of a 29 kDa polypeptide, as found previously using other tissues. Molecular sizing under non-denaturing conditions indicated the photolabeled species is a labile large receptor complex of mass ca. 300-500 kDa which gradually breaks down upon standing at -80 degrees C into the lower mass (50-70 kDa) material. The sigma receptor ligand binding subunit, which appears to be of the sigma 1 subtype, appears to be contained within the 29 kDa polypeptide, which may be a subunit of the 63-65 kDa protein, which in turn appears to be a component of a much larger receptor complex. It further appears that the 29 kDa polypeptide is readily dissociable from a larger photolabeled sigma receptor complex in tissue homogenates, but does not dissociate from the photolabeled affinity-purified CHAPS-solubilized sigma receptor.

Topics: Animals; Binding Sites; Cattle; Cerebellum; Dopamine Agonists; Haloperidol; Male; Phenazocine; Piperidines; Rats; Receptors, sigma

The role of the putative sigma receptor in mediating neuroprotection against glutamate-induced neuronal injury was examined in mature cultured rat cortical neurons. With the exception of the selective sigma 1 ligand (+)-3-PPP, all of the sigma ligands tested were neuroprotective, preventing glutamate-induced morphological changes and increases in LDH release. Their rank order of neuroprotective potency (and EC50 values) was as follows: (+)-SKF 10,047 (0.81 microM) > (+)- cyclazocine (2.3 microM) > dextromethorphan (3.1 microM) = haloperidol (3.7 microM) > (+)-pentazocine (8.5 microM) > DTG (42.7 microM) = carbetapentane (46.3 microM). When corrected for relative sigma versus PCP binding affinity, it appears that a positive correlation exists between neuroprotective potency and sigma 1 site affinity. However, there does not appear to be a significant correlation between neuroprotective potency and the sigma 2 site. Critically, none of the sigma ligands were neurotoxic when tested alone at concentrations at least 5-30 times their respective neuroprotective EC50 values. Results from preliminary experiments with the selective sigma 1 ligand (+)-pentazocine indicated that sigma-mediated neuroprotection may involve the buffering of glutamate-induced calcium flux. Collectively, the results of these in vitro experiments demonstrate that sigma ligands are neuroprotective and therefore deserve further exploration as potential therapeutic agents in in vivo models of CNS injury and neurodegenerative disorders.

Topics: Animals; Calcium; Cells, Cultured; Cyclazocine; Cyclopentanes; Dextromethorphan; Glutamic Acid; Guanidines; Haloperidol; L-Lactate Dehydrogenase; Neurons; Neuroprotective Agents; Pentazocine; Phenazocine; Piperidines; Rats; Receptors, sigma

Acute administration of (+)-N-allylnormetazocine ((+)-SKF-10,047) and (+/-)-pentazocine, was found to increase the extracellular level of 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine (DA) metabolite, in the rat frontal cortex. By contrast, these benzomorphan sigma ligands did not change the extracellular DOPAC level in the rat striatum. On the other hand, 1,3-di(2-tolyl)guanidine (DTG) increased the extracellular DOPAC level in the frontal cortex, while it decreased that level in the striatum. Another non-benzomorphan sigma ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) decreased the extracellular DOPAC level in both frontal cortex and striatum. Moreover, the increase of the extracellular DOPAC level elicited by (+)-SKF-10,047 was significantly inhibited by rimcazole, a putative sigma antagonist, while the DTG-induced increment was not reversed by rimcazole. These findings indicated that the effects of sigma ligands on the mesocortical DA neurons differed from those on the nigrostriatal DA neurons. In addition, the effects of benzomorphan sigma ligands on the central DA neurons were different from those of non-benzomorphan sigma ligands.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Anticonvulsants; Antipsychotic Agents; Carbazoles; Corpus Striatum; Extracellular Space; Frontal Lobe; Guanidines; Kinetics; Ligands; Male; Microdialysis; Pentazocine; Phenazocine; Piperidines; Rats; Rats, Wistar; Receptors, sigma; Time Factors

1. The behaviour and EEG effects of the dopamine and sigma (sigma) ligands (+) 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) were studied in mice. 2. (+) 3-PPP dose-dependently (60-100 mg/kg i.p.) produced behavioural and electrical tonic-clonic seizures. 3. The incidence of the tonic seizures elicited by 100 mg/kg of the drug was significantly (P < 0.05) prevented by spiperone (0.5 mg/kg i.p.) and haloperidol (0.5 mg/kg i.p.). 4. The results show an influence on the behavioural and electrical threshold of convulsions by (+) 3-PPP depending on a prevalent interference on dopamine receptors.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Convulsants; Dopamine Agonists; Dopamine Antagonists; Electric Stimulation; Electroencephalography; Male; Mice; Piperidines; Receptors, sigma; Seizures; Stereoisomerism

High affinity binding sites for sigma receptor ligands were found in membranes of cardiac myocytes from adult rats. The sigma receptor ligand (+)-3-hydroxyphenyl-N-(1-propyl)piperidine ((+)-3-PPP) binds with a Kd of 17.9 +/- 4.0 nM and a Bmax of 275 +/- 32.1 fmol/mg protein. Competition experiments of (+)-pentazocine with [3H]1,3-di-O-tolylguanidine ([3H]DTG) binding yielded a Ki of 6.1 +/- 1.3 nM. The majority of the sites (> 80%) were of the sigma 1 subtype. Exposure of isolated cardiomyocytes from adult rats to (+)-3-PPP (10 nM-1.0 microM) caused a marked concentration-dependent increase in the amplitude of systolic cell contraction, reaching 149% of control level, with an apparent ED50 value of 4.5 nM. The increase in the contraction amplitude was markedly inhibited by pretreatment with verapamil or thapsigargin. An increase in the amplitude of [Ca2+]i transients, similar to that in the amplitude of cell contraction, was observed in indo-1-loaded cardiomyocytes exposed to 0.1 microM (+)-3-PPP. Exposure to 10 nM of haloperidol or (+)-pentazocine induced an increase in the amplitude of contraction, reaching 188% and 138% (respectively) of control level. A lower concentration of haloperidol or (+)-pentazocine (1 nM) did not induce an increase in the contraction amplitude but rather reduced the amplitude to 70-80% of control.

Topics: Animals; Binding Sites; Calcium; Guanidines; In Vitro Techniques; Ligands; Myocardial Contraction; Myocardium; Pentazocine; Piperidines; Rats; Receptors, sigma; Stimulation, Chemical

The extracellular concentration of dopamine in the striatum and medial prefrontal cortex of the rat was determined following the systemic administration of sigma receptor ligands. The (+)-benzomorphan, (+)-pentazocine, significantly increased the extracellular concentration of dopamine in the striatum also was produced by the (+)-, but not the (-)-, enantiomer of N-allylnormetazocine, as well as by the non-benzomorphans 1-(cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoothyl-piper idi ne (DUP 734) and (-)-butaclamol. In contrast, the dopamine concentration was unaffected by di-o-tolylguanidine and markedly suppressed by (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine (3-PPP). Finally, the (+)-pentazocine-induced elevation of the extracellular concentration of dopamine was not suppressed by an inhibitor of the dopamine transporter, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR 12909). Thus, benzomorphan, e.g., (+)-pentazocine and (+)-N-allylnormetazocine, and non-benzomorphan, e.g., DUP 734 and (-)-butaclamol, sigma receptor ligands appear to facilitate dopamine release from nigrostriatal, and presumably mesocorticolimbic, neurons through a non-transporter-mediated mechanism.

Topics: Animals; Benzomorphans; Corpus Striatum; Dopamine; Guanidines; Ligands; Male; Pentazocine; Piperazines; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stereoisomerism

Compounds showing an in vitro binding preference for the dopamine D3 receptor were tested in two models designed to assess positive reinforcement in the rat: intracranial self-stimulation (ICSS) and conditioned place preference (CPP). R-(+)-7-OH-DPAT, a D3 preferring agonist, inhibited ICSS behaviour over a wide dose range. At higher doses, a facilitation of ICSS was seen. In the CPP model, 7-OH-DPAT was inactive except at the highest dose where a significant change in preference was seen. A dose of R-(+)-7-OH-DPAT, that significantly inhibited ICSS behaviour, was combined with a dose of d-amphetamine, that significantly facilitated ICSS behaviour. Surprisingly, this resulted in a significant synergistic facilitation of the amphetamine response. The putative D3 antagonist, U99194A was inactive in the ICSS model but induced significant place preference. The present results suggest that the dopamine D3 receptor, in contrast to the D2 receptor, has an inhibitory influence on reward mechanisms.

Topics: Animals; Brain; Conditioning, Operant; Dextroamphetamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Uptake Inhibitors; Indans; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Self Stimulation; Tetrahydronaphthalenes

Compounds showing an in vitro binding preference for the dopamine D3 vs. D2 receptors were tested for effects on locomotor activity after local application in the nucleus accumbens (N Acc) and the ventral tegmental area (VTA) of the rat brain. R-(+)-7-OH-DPAT, a dopamine D3 preferring agonist, inhibited spontaneous locomotor activity over a wide dose range after injection into the N Acc. A decrease in activity over a wide dose range was also seen after local application into the VTA of both R-(+)-7-OH-DPAT and the dopamine D2 preferring agonist (+)-3-PPP. Furthermore, (+)-3-PPP produced a dose dependent increase in activity after local application into the N Acc. The putative D3 antagonist, U99194A, with a 30 fold preference for the dopamine D3 vs. D2 receptor, produced an increase in activity when injected into the N Acc. A similar pattern were seen after infusion into the lateral ventricle. Local application into the VTA did, however, not produce any significant effects. The present results support the hypothesis that dopamine D3 receptors (in contrast to the D2 receptors) are mainly postsynaptically located where they display an inhibitory action on locomotor activity.

Topics: Animals; Brain; Cortical Spreading Depression; Dextroamphetamine; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Electric Stimulation; Indans; Injections, Intraventricular; Male; Microinjections; Motor Activity; Nucleus Accumbens; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydronaphthalenes; Ventral Tegmental Area

The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

Topics: Animals; Anticonvulsants; Antipsychotic Agents; Brain Diseases; Butaclamol; Carbazoles; Dizocilpine Maleate; Dopamine; Dopamine Agents; Drug Interactions; Drug Synergism; Guanidines; Ligands; Male; Methamphetamine; Mice; MPTP Poisoning; Neostriatum; Piperidines; Psychotropic Drugs; Pyrimidines; Receptors, Dopamine; Receptors, sigma; Stereoisomerism; Tyrosine 3-Monooxygenase

In preparation for expression studies for rat brain sigma-binding sites, Xenopus oocytes were tested for the presence of [3H]di-o-tolylguanidine (DTG)-binding sites. Native oocytes were found to contain two intrinsic [3H]DTG-binding sites, a high-affinity site (Kd = 32 +/- 6 nM, Bmax of 45.7 +/- 19 pmol/mg protein) and a low-affinity binding site (Kd = 1.3 +/- 0.7 microM, Bmax of 3.2 +/- 0.7 nmol/mg protein). In a series of radioligand-binding-displacement studies, the high-affinity binding sites were found to have a binding profile which has a similar Kd to that of the mammalian sigma 2-binding site (32 vs. 38 nM). Comparison of the IC50 values for inhibition of [3H]DTG binding in rat liver and oocytes for DTG, haloperidol (HAL), (-)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ((+)-3-PPP), (+)-pentazocine and Zn2+, showed similarity in rank (r2 = 0.913) but a 7-fold lower potency in oocytes. These results suggest that the high-affinity [3H]DTG-binding site in oocytes represents a sigma 2-like binding site.

Topics: Animals; Binding Sites; Binding, Competitive; Carbazoles; Dextromethorphan; Female; Guanidines; Haloperidol; Liver; Mazindol; Oocytes; Pentazocine; Phenazocine; Piperazines; Piperidines; Radioligand Assay; Rats; Receptors, sigma; Xenopus laevis; Zinc

The ability of the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N-n-propylpiperidine) to modify the extracellular concentration of dopamine (DA) in the caudate-putamen and the nucleus accumbens of awake rats was assessed using intracranial microdialysis. The enantiomers and the racemate were directly infused at 3 incremental concentrations (1-100 microM) or systematically administered by subcutaneous injection (10 mg/kg). Both systemic administration and direct infusion of (-)3-PPP at the highest concentration (100 microM) significantly increased extracellular DA in both brain regions. This increase was also seen in the presence of higher extracellular DA levels following reuptake inhibition by nomifensine (10 microM). In contrast to the effects of (-)3-PPP, systemic administration of both (+)3-PPP and (+/-)3-PPP decreased DA levels. Infusion of (+/-)3-PPP led to slight increases in DA levels in both brain regions at the highest concentration (100 microM), while (+)3-PPP at 100 microM also produced a significant increase in the caudate-putamen, but not in the nucleus accumbens. However, in the presence of nomifensine-induced elevations in extracellular DA, (+)3-PPP produced a significant decrease in DA concentrations in both brain regions. These results support previous findings that the enantiomers of 3-PPP show unique profiles in their in vivo effects on DA terminal functions. Furthermore, these effects are dependent on the mode of 3-PPP administration, the brain region in which DA overflow is measured, and the level of basal extracellular DA.

Topics: Animals; Caudate Nucleus; Dopamine; Dopamine Agonists; Extracellular Space; Female; Nomifensine; Nucleus Accumbens; Piperidines; Putamen; Rats; Rats, Sprague-Dawley

Ditolyguanidine (DTG) induced a dose-dependent emetic response in pigeons, with 100% of the birds vomiting after 5.6 mg/kg. Retching and vomiting originally induced by DTG could be conditioned to the test situation. Both the unconditioned and conditioned emetic responses were dose-dependently blocked by 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) and LY228729, agonists at the 5-HT1A subtype of serotonin receptor, but not by the 5-HT3, antagonist tropisetron. Higher doses (0.25-0.5 mg/kg) of tropisetron exhibited intrinsic emetic activity which could also be prevented by 8-OH-DPAT. NAN-190, a putative 5-HT1A partial agonist, produced both an antiemetic response when administered before DTG and also attenuated the antiemetic effects of 8-OH-DPAT. Pentobarbital blocked the conditioned, but not the unconditioned DTG-induced emesis. These results support the possibility that 5-HT1A agonists exhibit antiemetic activity against a broad range of emetic stimuli, including conditioned vomiting which is usually resistant to pharmacological attenuation.

Topics: Animals; Anticonvulsants; Antiemetics; Columbidae; Conditioning, Classical; Dopamine Agonists; Dose-Response Relationship, Drug; Emetics; Guanidines; Male; Pentobarbital; Piperidines; Serotonin Receptor Agonists

Previous studies used either racemic 3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+/-)-3-PPP] or lower doses of the mixed dopamine (DA) D1/D2 agonist apomorphine (APO) to conclude that brain DA D2 autoreceptors are not behaviorally functional until 28 days of age. The purpose of this study was to provide behavioral evidence for functional D2 autoreceptors before 28 days of age using DA agonists with greater selectivity for D2 autoreceptors. The locomotor activity of 10-, 21-, 35-day-old and adult rats was monitored after injection of a D2 autoreceptor agonist. There were significant decreases in the locomotor activity of 21-, 35-day-old, and adult rats injected with (-)-3-PPP, SND 919, or PD 128483. Lower doses of APO significantly decreased the activity of adult and 35-day-old rats but not younger rats. The only significant effect on the locomotor activity of 10-day-old rats was an increase in activity after injection of APO, 0.01 mg/kg or higher, or B-HT 920, 0.01 mg/kg. The results suggest that brain DA D2 autoreceptors are behaviorally functional at 21, but not 10, days of age.

Topics: Aging; Aminoquinolines; Animals; Apomorphine; Azepines; Behavior, Animal; Benzothiazoles; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Motor Activity; Piperidines; Pramipexole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Thiazoles

In an in vitro model for mitogenic activity in cloned Chinese hamster ovary (CHO) cells expressing rat dopamine D2 or D3 receptors, the EC50D2/EC50D3 ratios for the agonists, apomorphine, (+)-3-hydroxy-N-n-propyl-phenylpiperidine ((+)-3-PPP), quinpirole, R-(+)-7-hydroxy-2-(di-n-propylamino)tetralin (R-(+)-7-OH-DPAT) and pramipexole (SND919) were found to be 0.36, 0.41, 1.3, 3.7 and 7.0, respectively. In locomotor activity experiments with actively exploring rats, the more dopamine D3 preferring agonists, R-(+)-7-OH-DPAT and pramipexole, were most efficacious to reduce locomotion. The hypoactivity was also observed at doses that did not affect brain dopamine synthesis rate (DOPA accumulation) or release (measured in in vivo dialysis experiments). In contrast, for apomorphine, (+)-3-PPP and quinpirole there was a closer correlation between doses that reduced exploratory activity and doses that reduced brain dopamine release and synthesis. The present data support the hypothesis that the functional dopamine D3 receptor is a postsynaptic receptor inhibitory on rat locomotion.

Topics: Analysis of Variance; Animals; Apomorphine; Benzothiazoles; CHO Cells; Cricetinae; Cricetulus; Dihydroxyphenylalanine; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Male; Microdialysis; Mitogens; Motor Activity; Piperidines; Pramipexole; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydronaphthalenes; Thiazoles; Transfection

The electrophysiological responses of rat cerebellar Purkinje neurons to selective sigma ligands applied iontophoretically was examined in urethane anesthetized male Sprague-Dawley rats. 1,3-Di-o-tolylguanidine (DTG), dextrallorphan (DEX), (+)-pentazocine((+)-PENT), (+)-3-(3-Hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), and the novel diamine BD1008, were ejected from multibarrel pipettes onto individual Purkinje cells. In some neurons, cell firing was inhibited following ejections of all compounds. These inhibitory effects were dose dependent and occurred without changes in spike amplitude or duration, thus ruling out local anesthetic effects as a mechanism. (+)-3-PPP and DEX increased firing rate in 27% and 14% (n = 15, n = 14, respectively) of cells studied. The results of this study indicate that sigma ligands significantly alter the spontaneous firing of Purkinje neurons, consistent with previous work suggesting motor effects of sigma ligands via the rubro-cerebellar circuitry.

Topics: Animals; Ethylamines; Guanidines; Iontophoresis; Levallorphan; Male; Pentazocine; Piperidines; Purkinje Cells; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

The interaction of a novel series of heterocyclic amino alcohols with the sigma receptor site was assessed using radioligand binding and computerized molecular modelling. All heterocyclic amino alcohols, like the structurally related ifenprodil, fully inhibited the specific binding of [3H]R(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]3-PPP) to rat cerebral cortical membranes. All compounds recognised two populations of binding sites labelled by [3H]3-PPP and the proportion of sites in the high affinity state was 60-80% of the total sites. Some of the heterocyclic amino alcohols also displayed similar affinity for alpha 1-adrenoceptors labelled by [3H]prazosin, where the pattern of inhibition appears to be stereospecific, unlike that seen with the binding of [3H]3-PPP. The amino alcohols had negligible affinity for sites labelled by the N-methyl-D-aspartate channel ligand, [3H]-(N-1-[thienyl]cyclohexyl)piperidine. Quantitative conformational analyses indicated that the heterocyclic amino alcohols and ifenprodil fitted well to a sigma receptor site model; low energy conformers could be superimposed like other potent sigma receptor ligands with confidence to the sigma receptor model. Our results define a new class of sigma receptor ligands and extend the understanding of the molecular requirements for drugs active at the sigma receptor.

Topics: Adrenergic alpha-Antagonists; Amino Alcohols; Animals; Binding, Competitive; Cerebral Cortex; Crystallization; Dopamine Agonists; Heterocyclic Compounds; In Vitro Techniques; Ligands; Models, Molecular; Molecular Conformation; Piperidines; Propanolamines; Rats; Receptors, Adrenergic, alpha-1; Receptors, sigma

The present study was undertaken to characterize [3H]ifenprodil binding in rat brain. [3H]Ifenprodil showed saturable, high-affinity binding at 4 degrees C. Specific binding, defined with 10 microM ifenprodil as a competitor, was inhibited biphasically by the s receptor ligands, GBR 12909, 1,3-di-o-tolylguanidine (DTG), and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP). At 4 degrees C, 3 microM GBR 12909, which inhibited about 50% of specific binding of [3H]ifenprodil was used to mask sigma receptors. Under these conditions, specific binding of [3H]ifenprodil was inhibited potently by ifenprodil, SL 82.0715, poly(L-arginine), poly(L-lysine), neomycin, ruthenium red, spermine, arcaine and spermidine. In the presence of 3 microM GBR 12909, Zn2+ and Mg2+ partially inhibited specific binding of [3H]ifenprodil at 4 degrees C. In contrast, in the absence of GBR 12909, at 37 degrees C specific binding of [3H]ifenprodil was partially inhibited by Zn2+, but not by Mg2+. The anatomical distribution of [3H]ifenprodil binding at 4 degrees C (GBR 12909 included) in rat brain closely paralleled that of [3H]MK-801 (dizocilpine) binding (r = 0.971, P < 0.005). Without GBR 12909, specific [3H]ifenprodil binding at 37 degrees C was inhibited potently by sigma ligands. In the presence of 3 microM GBR 12909, [3H]ifenprodil binding at 4 degrees C was highest in synaptosomal and myelin fractions; however, without GBR 12909, [3H]ifenprodil binding at 37 degrees C was highest in microsomal and myelin fractions, consistent with the subcellular distribution of sigma receptors. The results suggest that, in the presence of 3 microM GBR 12909, at 4 degrees C, [3H]ifenprodil binds to sites that are sensitive to polyamines and related compounds; and that without GBR 12909, at 37 degrees C, [3H]ifenprodil interacts with sigma receptors in rat brain.

Topics: Adrenergic alpha-Antagonists; Animals; Binding Sites; Binding, Competitive; Brain; Dizocilpine Maleate; Dopamine Agents; Dose-Response Relationship, Drug; Guanidines; In Vitro Techniques; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Piperidines; Rats; Rats, Inbred F344; Receptors, sigma

(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma ligand, at doses above 3 mg/kg (s.c.) increased the ambulatory activity of rats, while the (-) isomer of 3-PPP with low affinity for sigma receptors, did not significantly modify the ambulatory activity at 10 and 30 mg/kg (s.c.). The ambulation-increasing effect of (+)-3-PPP was prevented by the sigma receptor antagonists BMY 14802 and rimcazole or the sigma/dopamine D2 antagonist haloperidol. The (+)-3-PPP effect was also attenuated by pretreatment with the monoamine depletor reserpine or the tyrosine hydroxylase inhibitor alpha-methyltyrosine, but was not affected by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. Moreover, the (+)-3-PPP effect was antagonized by the dopamine D2 antagonist sulpiride, whereas pretreatment with the 5-HT1A agonist 8-OH-DPAT and the alpha-adrenoceptor antagonist phenoxybenzamine did not exert any significant effect. These results indicate that sigma receptors are involved in the neuronal mechanism(s) of hyperambulation induced by (+)-3-PPP, and the sigma system may exert both a presynaptic action and a dopamine D2 receptor-mediated action to increase the central dopaminergic function.

Topics: Adrenergic alpha-Antagonists; Animals; Dopamine Agents; Dopamine D2 Receptor Antagonists; Ligands; Male; Motor Activity; Piperidines; Rats; Rats, Wistar; Receptors, sigma; Serotonin Receptor Agonists; Stereoisomerism; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

The aim of this work was to investigate the ocular hypotensive activity of some topically administered cAMP-phosphodiesterase inhibitors alone and in combination with dopaminergic compounds. Experiments were performed with ocular normotensive rabbits and during transitory induced ocular hyper- or hypotension. An ocular hypotensive effect was observed after instillation of aminophylline, dyphylline, pentoxifylline, caffeine, and iso-caffeine, but not following topical hydroxypropyl-1,3-dimethylxanthine. Dopaminergic compounds were also studied in order to be combined with phosphodiesterase inhibitors as ocular anti-hypertensive treatment. Significant ocular hypotensive activity was observed after topical application of trifluperidol, fluphenazine, thiothixene, and the S(-) enantiomer of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP). Of the cAMP-phosphodiesterase inhibitors that were tested, pentoxifylline was the most interesting compound, with good ocular tolerance, significant reduction in intra-ocular pressure, and potential retinal microvascular benefits. After allowing adequate time for pentoxifylline to reach its maximal activity, trifluperidol or S(-)-3-PPP was also instilled. A more pronounced ocular hypotensive effect was then observed. The findings of this study may suggest that administration of eye-drops combining drugs acting by separate ways on second messengers involved in the regulation of intra-ocular pressure (e.g. cyclic AMP) could be used to reduce intra-ocular pressure during glaucoma.

Topics: Administration, Topical; Animals; Dopamine Agents; Glucose; Male; Ocular Hypotension; Ophthalmic Solutions; Pentoxifylline; Phosphodiesterase Inhibitors; Piperidines; Rabbits; Stereoisomerism; Trifluperidol; Xanthines

Recent findings have suggested a relationship between 5-hydroxytryptamine (5-HT)4 receptors and sigma binding sites. To test this idea, the affinity of 5-HT4 receptor ligands for sigma binding sites was examined. In contrast to the 5-HT4 receptor ligands BIMU-1 [endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3- dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride] and BIMU-8 [endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3- yl)-2,3-dihydro-(1-methyl)ethyl-2-oxo-1H-benzamidazole-1-carbox ami de hydrochloride], DAU 6215 ]N-(endo-8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride], 5-HT and 5-methoxytryptamine had low affinity for sigma binding sites (pKi < 6). Conversely, the sigma ligands haloperidol and pentazocine had low affinity for 5-HT4 receptors. Thus, no relationship was found between the affinity of ligands at 5-HT4 receptors and sigma binding sites. However, one potent 5-HT4 receptor antagonist, RS-23597-190 [3-(piperidine-1-yl)propyl-4-amino-5-chloro-2-methoxybenzoate hydrochloride], had high affinity for sigma-1 (pKi = 8.4) but not sigma-2 (pKi = 6.2) binding sites. [3H]RS-23597-190 bound to a saturable site with the pharmacology of a sigma-1 binding site: (pIC50) haloperidol (9.0) > (+)-pentazocine (8.8) > (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine (8.2) > 1,3-di-o-tolyl-guanidine (8.0) > (-)-pentazocine (7.8) = (+)-SKF 10,047 [N-allylnormetazocine] > (-)-SKF 10,047 (6.2) > BIMU-1 (5.3) > 5-HT and 5-methoxytryptamine. The distribution of [3H]RS-23597-190 binding sites was similar to that described for other sigma radioligands, with the greatest binding densities in cranial nerve nuclei, the tegmental nucleus and in the mamillary nucleus. In contrast to (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine, [3H]RS-23597-190 binding was not allosterically modulated by phenytoin. These studies do not support the notion of an obvious relationship between sigma and 5-HT4 receptors, but they provide additional insight into the structure/affinity relationship of ligands at specific sigma binding sites, and they uncover a novel sigma-1 receptor ligand whose binding is insensitive to the action of phenytoin.

Topics: Aminobenzoates; Animals; Binding Sites; Brain; Guinea Pigs; Male; para-Aminobenzoates; Piperidines; Receptors, Serotonin; Receptors, sigma; Serotonin Antagonists

This study investigated the effects of sigma receptor ligands on the release of endogenous amino acid neurotransmitters from rat striatal slices. The effect of haloperidol on release in slices prepared from 6-hydroxydopamine lesioned animals was also tested. Haloperidol, the (+/-) reduced metabolite of haloperidol, rimcazole and ifenprodil specifically reduced potassium-stimulated release of glutamate with IC50 values between 20-60 microM. The release of aspartate, gamma-aminobutyric acid (GABA) and glycine was not affected. Haloperidol also reduced glutamate release from slices prepared from lesioned animals. The neuroleptic drug alpha-flupenthixol and the putative sigma receptor ligand R(+)3-(3-hydroxyphenyl)-N-(n-propyl) piperidine (3-PPP) had no effect on release. These effects of the sigma ligands show that the inhibition of glutamate release is specific to this amino acid and also that it is not due to dopamine receptor blockade as those ligands which have low affinity for dopamine receptors were also effective in reducing release. A presynaptic location for sigma receptor sites, possibly associated with ion channels, could account for the effects of these ligands on transmitter release.

Topics: Animals; Corpus Striatum; Female; Glutamic Acid; Haloperidol; In Vitro Techniques; Ligands; Neuropeptide Y; Piperidines; Potassium; Rats; Rats, Wistar; Receptors, sigma

Three sigma receptor ligands were examined for their ameliorating effects on p-chloroamphetamine-induced amnesia in mice. p-Chloroamphetamine was administered intraperitoneally 30 min before the training session of the passive avoidance response. Each sigma receptor ligand was administered 60 min before or immediately after the training session, or 60 min before the retention test. (+)-N-Allylnormetazocine ((+)-SKF-10,047), a prototype benzomorphan sigma receptor ligand, significantly reduced the p-chloroamphetamine-induced amnesia in these three administration schedules, as do acetylcholinesterase inhibitors. On the contrary, the significant anti-amnesic effects elicited by non-benzomorphan sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) or (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperizine ((+)-3-PPP), were observed depending upon the timing of their administration. In addition, the ameliorating effect of (+)-SKF-10,047 against the p-chloroamphetamine-induced amnesia was superior to that of (-)-SKF-10,047. The (+)-SKF-10,047-induced anti-amnesic effect was significantly antagonized by the concurrent administration of either scopolamine, a muscarinic receptor antagonist, or hemicholinium-3, an inhibitor of the Na(+)-dependent high-affinity choline uptake site. These findings indicated that sigma receptor ligands had anti-amnesic effects against drug-induced memory impairment. In addition, the anti-amnesic effect of (+)-SKF-10,047 was superior to those of other sigma receptor ligands, and was mediated by both the sigma receptor and the central acetylcholinergic system.

Topics: Acetylcholine; Amnesia; Animals; Anticonvulsants; Avoidance Learning; Brain; Cholinesterase Inhibitors; Dopamine Agonists; Electroshock; Guanidines; Ligands; Male; Memory; Mice; Mice, Inbred Strains; p-Chloroamphetamine; Phenazocine; Piperidines; Receptors, sigma; Serotonin Antagonists

The s.c. administration of a single dose of 0.1 mg/kg of reduced haloperidol to guinea pigs produced a marked inhibition of the binding of [3H]dextromethorphan and [3H]3-(3-hydroxyphenyl)-N-(n-propyl)piperidine ([3H](+)-3-PPP) to brain. The inhibition was still evident 10 days later, and it was accompanied by residual brain levels of reduced haloperidol, and much lower levels of haloperidol. Scatchard and computer-assisted analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. In the rat, haloperidol and reduced haloperidol also produced a rapid inhibition of binding to sigma sites. Interestingly, the brain of the reduced haloperidol-treated rats contained both haloperidol and reduced haloperidol, but the levels of reduced haloperidol in the haloperidol-treated rats were undetectable. However, the inhibition observed was of comparable magnitude, indicating that the haloperidol remaining in the brain is also inhibitory. In vitro experiments showed that the inhibition produced by haloperidol and reduced haloperidol was apparently competitive, but when brain membranes were preincubated with either drug, the inhibition was noncompetitive. By contrast, the inhibition produced by dextromethorphan was always competitive. Moreover, the inhibition produced by haloperidol and reduced haloperidol could not be reversed by washing. This investigation strongly suggests that the inhibition observed after the administration of haloperidol or reduced haloperidol is not a classic agonist-induced receptor down-regulation. The results indicated that the inhibition produced is a complex phenomenon, and suggest the formation of a slowly reversible or irreversible complex with reduced haloperidol or haloperidol.

Topics: Animals; Binding Sites; Brain; Dextromethorphan; Guinea Pigs; Haloperidol; Male; Oxidation-Reduction; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

Specific binding of [3H]-1,3-di-o-tolylguanidine (DTG) and (+)-[3H]-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] to membranes of cultured cardiac myocytes from neonatal rats revealed the presence of sigma receptors on these cells. Exposure of cultured cardiomyocytes to nanomolar concentrations of (+)-3-PPP, (+)-pentazocine and haloperidol induced specific patterns of changes in contractility of electrically paced cultures. The amplitude of systolic cell-motion (ASM) decreased by 10 to 25% 1 to 2 min after drug addition, then transiently increased (3-10 min) and finally decreased to about 75% of control level. Fluorescence measurements on indo-1 loaded cardiomyocytes revealed drug-induced changes in the size of the concentration of free cytosolic calcium ([Ca++]i)-transients, similar to the changes observed in ASM. These changes appear to be mediated by corresponding changes in the rates of 45Ca++ influx which increased 2 to 7 min after the addition of (+)-3-PPP and decrease to 50% of the control level thereafter. Preincubation with thapsigargin, which depletes the sarcoplasmic reticulum-Ca++ stores, did not affect the pattern of changes in ASM, induced by the subsequent addition of (+)-3-PPP. This indicates that the changes in [Ca++]i are not mediated by sarcoplasmic reticulum-Ca++ transport systems. Exposure to sigma ligands did not affect the apparent sensitivity of the myofilaments to Ca++, as indicated by the relationships between changes in ASM and in [Ca++]i-transients. Cultures which were not paced, contracted spontaneously at a constant rhythm. Sigma receptor ligands caused changes in beating frequencies which were followed by irregular contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Cells, Cultured; GTP-Binding Proteins; Guanidines; Haloperidol; Heart Rate; Myocardial Contraction; Pentazocine; Piperidines; Rats; Receptors, sigma; Sarcoplasmic Reticulum

A study was undertaken to structurally define and functionally assess sigma receptors on splenocytes using the highly selective sigma ligand (+)-azidophenazocine. Radioreceptor assays under reduced lighting show (+)-azidophenazocine can effectively block the binding of sigma ligands [3H]haloperidol (IC50 = 30 nM, Ki = 19.0 nM) and [3H](+)-pentazocine (IC50 = 40 nM, Ki = 350 nM), but not the dopamine (D2) ligand [3H]spiperone (IC50 > 5 microM) to splenic lymphocytes. [3H](+)-1-Propyl-3-(3-hydroxyphenyl)piperidine ([3H](+)-PPP) sites (Kd = 40.8 nM, Bmax = 2.32 pmol/mg) were also present on these lymphocytes. Additional studies using [3H](+)-azidophenazocine indicated the presence of saturable sites (Kd = 29.7 nM, Bmax = 760 fmol/mg) on splenic lymphocytes. There are no significant differences in affinity between sites found on T-enriched (Kd = 59 +/- 47 nM) and B-enriched lymphocytes (Kd = 23 +/- 5 nM). Photoaffinity labeling studies of splenocyte membranes with [3H](+)-azidophenazocine revealed a protein migrating at an apparent m.w. of 57 kDa under reducing and nonreducing conditions on SDS-PAGE. The labeling was specific because pretreatment with unlabeled haloperidol, (+)-PPP, 1,3 di(2-tolyl)guanidine, (+)-pentazocine, and (+)-azidophenazocine before cross-linking competed away > 75% of the radioactivity associated with the protein, whereas (-)-pentazocine and naloxone were significantly less effective. This data together with the observation that both (+)-azidophenazocine or haloperidol inhibit Con A-induced production of IFN by splenocytes, indicates that lymphocytes possess a biologically relevant sigma receptor.

Topics: Affinity Labels; Animals; Binding Sites; Binding, Competitive; Female; Haloperidol; Interferons; Lymphocytes; Mice; Mice, Inbred C57BL; Phenazocine; Piperidines; Receptors, sigma; Spleen

The sigma 2 receptor subtype was studied in rat cerebral cortex and in C6 glioma cells homogenates using various compounds including class III antiarrhythmic drugs. The characteristics of (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-[3H]-3-PPP) binding were assessed in competition experiments with different displacers which revealed the presence of sigma 2 receptors. Various class III antiarrhythmic drugs inhibited (+)-[3H]-3-PPP binding with high affinity and their binding affinity was found to correlate with the potency of these compounds to increase the duration of action potentials measured in Purkinje fibers in electrophysiological studies. Since class III antiarrhythmic drugs are known to interact with voltage-dependent K+ channels, the present results provide evidence that the (+)-[3H]-3-PPP binding sites in rat brain possess the characteristics of K+ channels of class III antiarrhythmic drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Binding, Competitive; Cerebral Cortex; Dopamine Agents; Electrophysiology; Glioma; Guinea Pigs; In Vitro Techniques; Male; Piperidines; Potassium Channels; Purkinje Fibers; Rats; Rats, Wistar; Receptors, sigma; Tumor Cells, Cultured

This work compares the sensitivities of high-yawning (HY) and low-yawning (LY) sublines of Sprague-Dawley rats to dopaminergic and cholinergic yawning-inducing drugs. HY animals are significantly more sensitive to apomorphine and (-)3PPP than LY animals. Physostigmine is a less effective yawning-inducer in HY than in LY rats. With pilocarpine no differences were detected between both sublines in regard to its yawning-inducing activity. Since yawning behavior is subject to dopaminergic (inhibitory) and cholinergic (excitatory) influences, it is suggested that the genetic differences between these sublines affect the dopaminergic pathways that normally regulate yawning frequency.

Topics: Animals; Apomorphine; Dopamine Agents; Dose-Response Relationship, Drug; Male; Parasympathomimetics; Physostigmine; Pilocarpine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Cholinergic; Receptors, Dopamine; Species Specificity; Yawning

The effect of repeated haloperidol administration on sigma binding sites in brain membranes was assessed using [3H](+)-3-(3-hydroxyphenyl)-N-(1- propyl)piperidine ((+)-3-PPP) and [3H]1,3-di-o-tolylguanidine (DTG). Administration of haloperidol (1 mg/kg, i.p.) to guinea pigs for 14 consecutive days followed by a 4 day drug-free period prior to sacrifice resulted in 75% and 6% decreases in the specific binding of [3H](+)-3-(3-hydroxyphenyl)-N-(1- propyl)piperidine and [3H]1,3-di-o-tolylguanidine, respectively, when measured using a single concentration (2 nM) of radioligand. Scatchard analysis revealed a reduction in both the maximum number of [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites and the affinity of these sites for the radioligand; the potency of 1,3-di-o-tolylguanidine to inhibit [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding was also reduced. In parallel studies, the potency of 1,3-di-o-tolylguanidine to inhibit [3H]1,3-di-o-tolylguanidine binding was unaffected by haloperidol treatment, but the potency of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine against [3H]1,3-di-o-tolylguanidine was reduced 3-fold. Phenytoin, which increased (10-fold) the potency of dextromethorphan to inhibit [3H]1,3-di-o-tolylguanidine binding in control membranes, had no effect in membranes obtained from haloperidol-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antipsychotic Agents; Binding Sites; Brain; Dopamine Agents; Drug Administration Schedule; Guanidines; Guinea Pigs; Haloperidol; Male; Phenytoin; Piperidines; Receptors, sigma

In male rats, a high dose of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 30 mg/kg s.c., 24 h) caused a reduction of pituitary dopamine D2 receptor density by 27% as measured by means of in vivo radioligand binding (using a single dose of the ligand [3H]spiperone). The same dose of EEDQ reduced the potency, but not the maximal response, of the dopamine D2 receptor agonists R-(-)-N-n-propylnorapomorphine (NPA), (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP), and 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5]azepine (B-HT 920) with respect to suppression of prolactin release after pretreatment with gamma-butyrolactone. The measured reduction in dopamine D2 receptor density after EEDQ was of the same magnitude as the reduction in receptor number predicted from the EEDQ induced shift in the dose-response curve of the full dopamine D2 receptor agonist NPA. The findings are discussed in relation to our previous observation that a somewhat lower dose of EEDQ (20 mg/kg s.c., 24 h) effectively reduces the efficacy of partial dopamine D2 receptor agonists while affecting neither the prolactin response to full dopamine D2 receptor agonists nor the density of pituitary dopamine D2 receptors.

Topics: Animals; Azepines; Dopamine Agents; Male; Piperidines; Pituitary Gland; Prolactin; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

The effect of 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol monohydrochloride (FH-510) on the binding of sigma ligands such as [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) and [3H]1,3-di-o-tolylguanidine ([3H]DTG) to rat brain membranes was studied. The inhibitory effect of FH-510 on [3H](+)-3-PPP binding to membranes of rat brain was 260 times more potent than that on [3H]DTG binding. Scatchard plot analysis showed that FH-510 inhibited [3H](+)-3-PPP binding in a competitive manner, while the inhibitory effect of FH-510 on [3H]DTG binding was noncompetitive. These results suggest that (+)-3-PPP sites could be discriminated from DTG sites, and that FH-510 binds preferentially to (+)-3-PPP recognition sites in rat brain.

Topics: Animals; Anticonvulsants; Binding Sites; Brain; Carbazoles; Dopamine Agents; Guanidines; In Vitro Techniques; Male; Piperidines; Propylamines; Radioligand Assay; Rats; Rats, Wistar

Further evaluation of the effects of BMY 14802 on dopamine (DA) neuronal activity in the rat substantia nigra pars compacta (A9) was conducted with single-unit recording and microiontophoresis in anesthetized rats. Microiontophoretic administration of BMY 14802 (sigma, serotonin (5-HT)-1A and alpha-1 adrenoceptor ligand) had no effect on DA neurons. Microiontophoretic administration of (+)-3-PPP (weak D2 agonist with high affinity for sigma receptors) and quinpirole (D2/D3 agonist) inhibited A9 DA neuronal activity. Co-iontophoresis or i.v. pretreatment with BMY 14802 had no effect on the current-response curves for the effects of microiontophoretic (+)-3-PPP or quinpirole on A9 DA neurons. Co-iontophoretic administration of (-)-sulpiride, a selective D2 antagonist, blocked the inhibitory effects of microiontophoretic (+)-3-PPP. The effects of BMY 14802 (0.25-8 mg/kg, i.v.) on DA neurons (increased firing rate, increased burst-firing, reduced regularity of firing pattern) were not altered by acute brain hemitransection, but were blocked by pretreatment with NAN-190, an antagonist of 5-HT-1A and alpha-1 receptors. The alpha-1 receptor antagonist, prazosin, did not block these effects of BMY 14802. In conclusion, the effects of BMY 14802 on DA neuronal firing rate and firing pattern are indirect, perhaps due in part to the occupation of 5-HT-1A receptors.

Topics: Adrenergic alpha-Antagonists; Animals; Dopamine; Dopamine Agents; Ergolines; Injections, Intravenous; Iontophoresis; Male; Neurons; Piperidines; Pyrimidines; Quinpirole; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Stereoisomerism; Sulpiride

p-Dimethoxyaryl analogs of certain potent catechol-derived dopaminergic agonists show dopaminergic properties for which no structure-activity relationship has yet been defined. (S)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine (1, S-"3-PPP") is a dopaminergic autoreceptor agonist, and at high doses it also exhibits postsynaptic antagonism. (R)-1 is a postsynaptic agonist. In a continuation of studies of effects of the p-dimethoxy moiety at dopamine receptors, synthesis and resolution of the 2,5-dimethoxy analog 3 of 3-PPP was undertaken. The two enantiomers and the racemic modification showed cardiovascular effects consistent with actions at DA-2 receptors. The potency of all three compounds was much lower than that of 3-PPP, although they displayed approximately the same duration of action. Absolute configuration does not seem to be a major determinant of these compounds' ability to interact with DA-2 receptors.

Topics: Animals; Bradycardia; Dopamine Agents; Hypotension; Piperidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.

Topics: Administration, Oral; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzothiazoles; Cebus; Disease Models, Animal; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Haloperidol; Lisuride; Male; Piperidines; Pramipexole; Quinpirole; Raclopride; Salicylamides; Thiazoles

We examined the characteristics of the binding of radiolabeled 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol monohydrochloride ([3H]FH-510), a highly potent and selective sigma ligand, to guinea-pig brain membranes. [3H]FH-510 showed saturable and reversible binding to sigma binding sites. The association rate constant (k+1) and dissociation rate constant (k-1) of [3H]FH-510 were 0.023 min-1.nM-1 and 0.081 min-1, respectively. Scatchard plot analysis showed a dissociation constant (Kd) and maximal number of binding sites (Bmax) of 6.0 +/- 0.63 nM and 1763.3 +/- 177.4 fmol/mg protein (n = 7), respectively. The rank order of potency (Ki) of several structurally dissimilar sigma ligands obtained for the displacement of [3H]FH-510 binding was highly correlated with that determined for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) binding. The binding of [3H]FH-510 was not influenced by histaminergic, dopaminergic, adrenergic, serotonergic or cholinergic agents at 10(-7) M. Higher [3H]FH-510 binding to brain regions was observed in the cerebellum and pons-plus-medulla. Except for the nuclear fraction, the highest level of [3H]FH-510 and [3H](+)-3-PPP binding to subcellular fractions was observed in the microsomal fraction. From these results, it is suggested that FH-510 selectively binds with high affinity to sigma binding sites in guinea-pig membranes.

Topics: Animals; Anti-Anxiety Agents; Binding Sites; Binding, Competitive; Brain; Carbazoles; Dopamine Agents; Guinea Pigs; Histamine; In Vitro Techniques; Kinetics; Male; Microsomes; Phenazocine; Piperidines; Propylamines; Pyrimidines; Radioligand Assay; Receptors, sigma; Serotonin

The binding of [3H]endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)- 2,3-dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride ([3H]BIMU-1) a benzimidazolone with high affinity for 5-hydroxytryptamine (5-HT)3 and 4 5-HT3 and 5-HT4 receptors, was characterized in NG-108 cells and guinea pig hippocampus. Specific, heat-sensitive, binding of [3H]BIMU-1 was detected in both NG-108 cells and guinea pig hippocampus. In NG-108 cell membranes, a portion of the specific binding was displaced by 5-HT3 receptor ligands with affinities and specificity consistent with the labeling of 5-HT3 receptors. The residual specific binding was insensitive to serotonin (Ki > 1 mM) but was displaced by haloperidol (Ki of 50 nM). In guinea pig hippocampal membranes [3H]BIMU-1 binding was insensitive to serotonin but was displaced by haloperidol, and 1,3-di-o-tolyl-guanidine with affinities appropriate for the labeling of a sigma binding site (Ki of 6.3 and 31 nM, respectively). The affinity profile of ligands displacing [3H] BIMU-1 binding in guinea pig hippocampus was consistent with the selective labeling of a sigma-2 binding site because the sigma-1 selective benzomorphans, (+)-pentazocine and (+)-N-allylnormetazocine, only weakly displaced the binding (Ki greater than 1 microM). The affinity of BIMU-1 for sigma-2 binding sites (Ki = 32 nM) was 200-fold greater than that for sigma-1 binding sites (Ki = 6.3 microM), dopamine (D1 and D2), other serotonin (5-HT1A, 5-HT2A, 5-HT2C) and muscarinic (M1, M2, M3 and M4) receptors (Ki > 10 microM). The distribution of haloperidol-sensitive [3H]BIMU-1 binding was also consistent with the labeling of sigma-2 binding sites. These data suggest that [3H]BIMU-1 selectively labels sigma-2 binding sites in guinea pig hippocampus. [3H]BIMU-1, under appropriate experimental conditions, is thus the first sigma-2 binding site radioligand to be characterized.

Topics: Animals; Autoradiography; Benzimidazoles; Binding Sites; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Guinea Pigs; Hippocampus; Male; Membranes; Mice; Neuroblastoma; Piperidines; Rats; Receptors, Serotonin; Receptors, sigma; Sensitivity and Specificity; Tritium; Tumor Cells, Cultured

Substrates for cytochrome P450-2D1 exhibit a high affinity for sigma binding sites suggesting that sigma sites may be associated with the cytochrome P450-2D1 isozyme. In contrast to Sprague-Dawley, Dark Agouti rat liver does not express the P450-2D1 gene product. Therefore, if a subpopulation of sigma sites is associated with the P450-2D1 enzyme, then the number (Bmax) of sigma sites is predicted to be decreased in Dark Agouti brain and liver compared to Sprague-Dawley tissues. In the present study, binding of [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)3-PPP) in brain and liver from Dark Agouti, Sprague-Dawley, Long Evans and Wistar rat strains was examined. Results demonstrate marked variation in Bmax among the strains, with a consistently lower value for Dark Agouti tissues. However, the absolute difference in sigma binding between brain and liver for each strain was not consistent with reported differences in the activity or levels of P450-2D1. Additionally, the percentage decrease in Bmax for Dark Agouti liver was found to be similar to that for Dark Agouti brain. Taken together these results suggest that P450-2D1 does not account for the strain-related difference in sigma binding; but rather, other genetic factor(s) may be responsible for the decrease in the number of sigma sites in the Dark Agouti strain compared to the other rat strains examined.

Topics: Analysis of Variance; Animals; Binding Sites; Brain; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Liver; Mixed Function Oxygenases; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, sigma; Sex Factors; Species Specificity

Specific binding of [3H]1,3-di-o-tolylguanidine (DTG) was found not only in synaptic membrane fractions but also in subcellular fractions enriched of microsomes, nuclei and mitochondria/myelins, with different sensitivities to displacement by the antipsychotic haloperidol. The highest binding was detected in microsomal fractions followed by, in order of decreasing binding, fractions enriched in nuclei, synaptic membranes, mitochondria/myelins and homogenates. [3H]DTG binding was completely abolished by prior treatment of the synaptic membranes with a low concentration of Triton X-100. [3H]DTG binding reached a plateau within 30 min of the incubation at 2 degree C, whereas raising the incubation temperature to 30 degrees C resulted in marked shortening of the time required to attain equilibrium, without altering the binding at equilibrium. The binding was inhibited by haloperidol in a concentration-dependent manner over a concentration range of 1 nM to 0.1 mM but with a potency more than 100 times weaker than the value reported in the literature, irrespective of the termination method employed and the external proton concentrations. [3H]DTG binding was markedly displaced by a variety of compounds including sigma ligands, benzomorphan opiates and noncompetitive antagonists at the N-methyl-D-aspartate (NMDA) receptor in synaptic membranes of the cortex, hippocampus and cerebellum. However, sigma ligands such as haloperidol, DTG and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine were more potent in displacing [3H]DTG binding in cortical membranes than in hippocampal and cerebellar membranes, while the potencies of the NMDA antagonists were not significantly different from each other among these 3 different central structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding Sites; Brain; Guanidines; Haloperidol; Male; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

Previous studies indicate that the discriminative stimulus effects of cocaine are mediated predominantly by indirect activation of dopamine (DA) D2 postsynaptic receptors, although DA D1 receptors may also be involved. In the present study, full or partial D2 agonists and D2 antagonists were tested for their ability to substitute for, potentiate or antagonize the stimulus effects of cocaine in rats (n = 15) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced task. The full D2 agonists bromocriptine (1.25-20 mg/kg) and quinpirole (0.013-0.2 mg/kg) engendered substantial cocaine-lever responding (> 80% drug-lever responding), whereas the partial D2 agonists preclamol (2.5-10 mg/kg) and terguride (0.313-1.25 mg/kg) produced less than 50% cocaine-lever responding. Co-administration of a threshold dose of cocaine (1.25 mg/kg) with low doses of bromocriptine (1.25-5 mg/kg) or quinpirole (0.025-0.1 mg/kg) induced higher percentages of cocaine-lever responding as compared with occasions when these D2 agonists were given alone. However, co-administration of this dose of cocaine with preclamol (2.5-10 mg/kg) or terguride (0.313-1.25 mg/kg) did not alter the percentage of cocaine-lever responding observed when these partial D2 agonists were administered alone. Pretreatment with the D2 antagonists bromuride (0.25-1 mg/kg) and haloperidol (0.125-0.5 mg/kg) significantly reduced the percentage of cocaine-lever responding. Preclamol (0.625-10 mg/kg) and terguride (0.019-5 mg/kg), but not bromocriptine (2.5-20 mg/kg) or quinpirole (0.01-0.08 mg/kg), significantly reduced the percentage of cocaine-lever responding. These results suggest that full D2 agonists substitute completely for cocaine, whereas partial D2 agonists do not produce cocaine-like responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bromocriptine; Cocaine; Discrimination Learning; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Haloperidol; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclo[b]indoles substituted at the 5 and/or 11 positions was synthesized from tropinone. Affinity for sigma binding sites was determined using [3H]-N,N'-di-o-tolylguanidine ([3H]DTG) and [3H]-(+)-3-(3-hydroxyphenyl)-N-1-propylpiperidine ([3H]-(+)-3-PPP) and for the dopamine D2 receptor labeled with [3H]sulpiride. Nearly all compounds studied in this series possessed a higher affinity for [3H]DTG than [3H]-(+)-PPP-labeled sigma sites, suggesting that [3H]DTG and [3H]-(+)-3-PPP radioligands label pharmacologically distinct sigma binding sites, as reported previously. Substitution at the 11 position with side chains containing a four-carbon tether resulted in compounds having the highest affinity for the [3H]DTG-labeled sigma site. The most potent and selective member of this series was 11-[4-(2-furanyl)butyl]-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept [b] indole (40). Enantioselectivity was investigated by preparing the (+)- and (-)-isomers of 40. These studies revealed that (+)-40 was more potent at the [3H]-DTG-labeled sigma site whereas (-)-40 had a higher affinity at sigma sites labeled with [3H]-(+)-PPP. Racemic 40 was observed to possess a higher affinity than either of its respective enantiomers at both the [3H]DTG- and [3H]-(+)-3-PPP-labeled sites, suggesting an allosteric interaction.

Topics: Animals; Binding, Competitive; Brain; Carbolines; Guanidines; Guinea Pigs; In Vitro Techniques; Piperidines; Radioligand Assay; Rats; Receptors, Dopamine D2; Receptors, sigma; Stereoisomerism; Structure-Activity Relationship; Sulpiride; X-Ray Diffraction

Pigeons were trained to discriminate between 3 mg/kg cocaine and saline. Tests with cocaine and amphetamine were conducted at different intervals after administration to compare the time course of the discriminative stimulus (DS) effects. Tests were of two kinds: a) separate, that is, only one dose and interval were examined on each separate test day; and b) repeated, that is, all three intervals were assessed after a single administration of the drug dose during 1 test day. Separate and repeated determinations of the time course yielded similar estimates. The duration of the DS effects of amphetamine were longer than those of cocaine. No apparent difference, either with regard to duration of effect or potency, existed between (+)- and (-)-amphetamine. The potency of cocaine was similar to that of the amphetamine isomers. The dopamine autoreceptor blockers (+)- and (-)-3-(hydroxyphenyl)-N-n-propylpiperidine (3-PPP) (1-10 mg/kg) engendered less than 44% cocaine-associated responding for the repeatedly examined intervals (15, 60, and 120 min after administration). The results of this study encourage the use of repeated testing methodology to assess the duration of action of the DS effects of drugs.

Topics: Amphetamine; Animals; Cocaine; Columbidae; Discrimination Learning; Dopamine Antagonists; Male; Piperidines; Time Factors

The effects of sigma receptor ligands on the neurogenic twitch contraction in the ddY mouse vas deferens were studied. In functional studies, (+)-N-allylnormetazocine ((+)-SKF-10,047) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) potentiated neurogenic twitch contractions in a concentration-dependent manner. The potentiation by each (+) enantiomer was significantly more potent than that by the respective (-) enantiomer. In addition, haloperidol and (+/-)-pentazocine also potentiated neurogenic twitch contractions. The order of potentiating ability was: haloperidol > (+/-)-pentazocine > (+)-3-PPP > (-)-3-PPP > (+)-SKF-10,047 > (-)-SKF-10,047. In contrast, other sigma receptor ligands, 1,3-di(2-tolyl)guanidine (DTG) and rimcazole, suppressed this twitch contraction. In addition, rimcazole significantly antagonized the (+)-SKF-10,047-induced potentiation at concentrations which did not affect contractions per se. Furthermore, binding studies showed that the kinetic parameters and the inhibitory potencies of sigma receptor ligands for the binding of [3H](+)-SKF-10,047 in the mouse vas deferens were similar to those in the guinea pig brain. The order of potency of sigma receptor ligands to potentiate the neurogenic twitch contraction in the mouse vas deferens was significantly correlated with the potency to inhibit [3H](+)-SKF-10,047 binding in both mouse vas deferens and guinea pig brain. These results indicate that sigma receptor ligands regulate the neurogenic twitch contraction, which is mediated by rimcazole-sensitive benzomorphan-type sigma receptors.

Topics: Animals; Antiparkinson Agents; Brain; Drug Synergism; Guinea Pigs; Haloperidol; Ligands; Male; Mice; Phenazocine; Piperidines; Receptors, sigma; Spasm; Vas Deferens

The allosteric modulation of sigma recognition sites by phenytoin (diphenylhydantoin) has been demonstrated by the ability of phenytoin to stimulate binding of various [3H] sigma ligands, as well as to slow dissociation from sigma sites and to shift sigma sites from a low- to a high-affinity state. Phenytoin stimulated the binding of the sigma 1- selective ligand [3H](+)pentazocine in a dose-dependent manner. Stimulation of binding at a final concentration of 250 microM phenytoin was associated with a decrease in the KD. The affinities of the sigma reference compounds caramiphen, dextromethorphan, dextrophan, (+)3-PPP and (+)SKF-10,047 were three- to eight-fold higher, while the affinities of benzetimide, BMY-14802, carbetapentane, DTG and haloperidol were unchanged in the presence of 250 microM phenytoin. The relative sensitivity of sigma compounds to allosteric modulation by phenytoin is not a property of all sigma ligands, and may provide an in vitro basis for distinguishing actions of sigma compounds and predicting sigma effects in vivo.

Topics: Allosteric Regulation; Animals; Binding Sites; Cyclopentanes; Dextromethorphan; Dextrorphan; Guinea Pigs; Ligands; Male; Pentazocine; Phenazocine; Phenytoin; Piperidines; Radioligand Assay; Receptors, sigma; Tritium

Dextromethorphan (DM) binds to high- and low-affinity sites in the rat brain. The high-affinity DM binding is inhibited by nonnarcotic antitussives, opipramol and sigma ligands with nanomolar affinities. Computer-assisted modeling of homologous and heterologous competition studies between DM and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] were performed at pH 8.4. These experiments confirmed the existence of the common high-affinity DM1/sigma 1 site (R1) for which DM and (+)-3-PPP have Kd values of 20 and 10 nM, respectively. DM also binds to a second high-affinity site (R2, Kd, 20 nM) for which (+)-3-PPP has only micromolar affinity. Similarly, (+)-3-PPP binds to another high-affinity site (R3, Kd, 60 nM) for which DM has micromolar affinity. The common high-affinity DM1/sigma 1 site is allosterically modulated by the anticonvulsant ropizine, and is (+)-pentazocine sensitive, as is the homologous site in the guinea pig. However, in the rat the common DM1/sigma 1 site is 10 times smaller than in the guinea pig. This explains the apparently different effects of the allosteric modifiers in both species. The multiplicity of binding sites for DM and (+)-3-PPP resolved in this investigation will help to establish the physiological role and the pharmacological potential of the different sites. Meanwhile, the pharmacological effects of DM and sigma ligands cannot be summarily attributed to any particular binding site or receptor. This investigation also demonstrates that the use of multiple labeled and unlabeled ligands, combined with computer-assisted modeling, is essential to resolve multiple binding sites with similar affinities and to characterize the complex effects of allosteric modifiers.

Topics: Allosteric Regulation; Animals; Antitussive Agents; Binding Sites; Brain; Computer Simulation; Dextromethorphan; Guinea Pigs; Hydrogen-Ion Concentration; Male; Pentazocine; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

High-affinity binding sites (apparent KD 2.87 nM) for [3H]desmethylimipramine ([3H]DMI), have been demonstrated and characterized in membrane preparations of bovine adrenal medulla. The binding of [3H]DMI improved upon pretreatment of the membrane with KCl and was saturable, sodium dependent, and potently inhibited by nisoxetine and imipramine. [3H]DMI binding was also inhibited by various phencyclidine (PCP)- and (or) sigma-receptor ligands, with the following order of potency: haloperidol > rimcazole > (-)-butaclamol > dextromethorphan > MK-801 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) > PCP > N-(2-thienyl)cyclohexyl-3,4-piperidine (TCP) > (+)-SKF-10047 > (-)-SKF-10047. The inhibition produced by sigma ligands was not attributed to stimulation of either sigma 1- or sigma 2-receptors, owing to inactivity of the selective sigma-receptor ligands (+)-pentazocine and 1,3-di(2-tolyl)guanidine (DTG). The inhibition of [3H]DMI binding by sigma- and PCP-receptor ligands was not attributed to PCP1- or PCP2-receptor stimulation, owing to the decreased potency (100-fold) of these ligands in [3H]DMI assays compared with the affinity for brain PCP1 sites, and the ineffectiveness of the PCP2-ligand N-(1-(2-benzo(b)thiophenyl)cyclohexyl)piperidine (BTCP). Scatchard analysis of the inhibition by the sigma-ligands haloperidol and (+)-3-PPP, as well as the PCP1 receptor ligand MK-801, demonstrated noncompetitive interaction with the site bound by [3H]DMI. These studies indicate that bovine adrenomedullary membranes possess a specific receptor for the noradrenaline uptake inhibitor [3H]DMI, which is sensitive to allosteric modulation produced by PCP and sigma-ligands.

Topics: Adrenal Medulla; Animals; Binding Sites; Cattle; Desipramine; Dextromethorphan; Dizocilpine Maleate; Phenazocine; Phencyclidine; Piperidines; Potassium Chloride; Receptors, Opioid, delta; Receptors, Phencyclidine; Tranquilizing Agents

In saturation binding experiments, (+)pentazocine, (+)3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), haloperidol and rimcazole did not inhibit the binding of [3H]DTG in a purely competitive fashion. Although Scatchard analysis indicated that [3H]DTG bound to a single site, the inhibition curves of some, but not all, reference compounds exhibited Hill coefficients of less than 0.8. The Scatchard data were consistent with a model of hyperbolic competitive inhibition of binding to the [3H]DTG-defined sigma site, although other possibilities such as negative cooperativity or binding to two sites cannot be definitively excluded. Compounds from numerous pharmacological and structural classes inhibited the binding of [3H]DTG, suggesting that interactions of [3H]DTG with other receptors may have confounded the Scatchard analysis of the binding of [3H]DTG to sigma recognition sites.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Carbazoles; Dopamine Agents; Guanidines; Guinea Pigs; Haloperidol; In Vitro Techniques; Kinetics; Male; Pentazocine; Piperidines; Radioligand Assay; Receptors, Opioid; Receptors, sigma

Pigeons were fed a fixed amount of grain-based feed and behavior was observed after administration of doses of ditolyguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP], dextromethorphan, haloperidol, (+)-N-allylnormetazocine (NANM), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol (BMY-14802) apomorphine, pentobarbital, propranolol, and MK-801. Of the drugs tested, DTG, dextromethorphan, and (+)-3-PPP each produced dose-related increases in the percentage of pigeons exhibiting an emetic response. The emetic response produced by DTG was antagonized by haloperidol and BMY-14802 but not by propranolol. These observations suggest that the emetic response in the pigeon may be mediated by sigma sites and is unlikely to be mediated by phencyclidine receptors.

Topics: Animals; Apomorphine; Columbidae; Dextromethorphan; Dizocilpine Maleate; Dopamine Agents; Guanidines; Haloperidol; Male; Pentobarbital; Phenazocine; Piperidines; Propranolol; Psychotropic Drugs; Pyrimidines; Receptors, Opioid; Receptors, sigma; Vomiting

Functional changes in sigma receptors were examined after behavioral sensitization induced by repeated methamphetamine treatment. Rats received either saline or 4 mg/kg methamphetamine for 14 days. (+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma receptor agonist, was given as challenge after various periods of abstinence. (+)-3-PPP at doses greater than 6 mg/kg stimulated several forms of behavior in naive rats. (+)-3-PPP at 12 and 24 mg/kg produced more frequent rearing and more intense stereotyped sniffing and repetitive head movements in rats previously sensitized with methamphetamine than in saline-pretreated rats. The augmented response to (+)-3-PPP in methamphetamine-treated rats was maintained for at least one month. The augmented response to (+)-3-PPP was reversed by the combined administration of 100 mg/kg (+/-)-sulpiride, a D2 dopamine receptor antagonist, and 30 mg/kg BMY 14802, a sigma receptor antagonist. These results suggest that repeated methamphetamine treatment induces persistent supersensitivity in sigma receptors and that it may subsequently activate the dopamine system.

Topics: Animals; Behavior, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Drug Tolerance; Male; Methamphetamine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

After s.c. administration of 3-(3-hydroxyphenyl)-N-n-propylpiperidine HCl (3-PPP) to rats, plasma and brain levels were monitored in relation to the amount of spontaneous locomotor activity. Based on time-course relationships, concentration-effect curves were elaborated after administration of (-)3-PPP and (+)3-PPP in the dose range of 1 to 256 mumol.kg-1. Both enantiomers were readily absorbed and distributed, as evidenced by a close correlation between brain and plasma levels, brain levels being 7 to 9 times higher than those found in plasma. Plasma half-lives were 25 and 32 min for (-)3-PPP and (+)3-PPP, respectively. Plotting brain concentrations of (-)3-PPP against locomotor activity resulted in a good fit to a declining two-phase curve, in all probability reflecting preferential actions at pre- and postsynaptic dopamine receptors, respectively. These two underlying mechanisms could also be identified from the biphasic effects produced by (+)3-PPP on locomotor activity: suppression followed by stimulation, respectively. Together, these observations provide further support for the contention that at low doses, both enantiomers have sedative actions due to stimulation of inhibitory autoreceptors. With increasing doses, however, a postsynaptic receptor blockade will predominate for a partial agonist like (-)3-PPP, producing suppression of locomotion, whereas the full agonist, (+)3-PPP, will produce behavioral activation due to stimulation of postsynaptic receptors.

Topics: Animals; Brain; Dopamine Agents; Dose-Response Relationship, Drug; Half-Life; Injections, Subcutaneous; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Stereoisomerism; Tissue Distribution

We examined the mechanism of the muscle relaxant action of eperisone, using Straub tail and binding studies. In vivo, eperisone (50 and 100 mg/kg i.p.) produced a dose-dependent inhibition of the Straub tail in mice and this inhibitory effect was significantly reversed by haloperidol (0.5 mg/kg i.p.). This drug in itself had no effect on the Straub tail. Sulpiride (50 mg/kg i.p.) failed to reverse the inhibitory effect of eperisone. In vitro, (+)-3-(3-[3H]hydroxyphenyl)-N-(1-propylpiperidine) ((+)-[3H]3-PPP) specific binding, in rat brain membrane, was prevented by eperisone and the IC50 value was 0.43 nM. The muscle relaxant action of eperisone may be modulated by sigma receptors.

Topics: Animals; Behavior, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Haloperidol; In Vitro Techniques; Mice; Mice, Inbred ICR; Muscle Relaxants, Central; Piperidines; Propiophenones; Receptors, Opioid; Receptors, sigma

We investigated the role of sigma receptors in the expression of behavioral sensitization induced by cocaine. Rats received intraperitoneal injections of either 20 mg/kg cocaine or saline once daily for 14 consecutive days. Cocaine-treated rats became sensitized. After a 5-day abstinence period, a challenge dose of (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine ((+)-3-PPP), a sigma receptor agonist, was administered. (+)-3-PPP at doses of 12 and 24 mg/kg induced significantly more frequent rearing and more potent stereotypy consisting of repetitive head movement and sniffing in cocaine-sensitized rats than in saline-pretreated rats. These enhanced responses to (+)-3-PPP lasted for at least a month. The enhanced responses to (+)-3-PPP were attenuated by 30 mg/kg BMY 14802, a putative sigma antagonist, and also attenuated by 100 mg/kg (+/-)-sulpiride, a D2 dopamine antagonist. These findings show that repeated administration of cocaine produces lasting supersensitivity of simga receptors, which may induce subsequent activation of dopaminergic transmission.

Topics: Animals; Behavior, Animal; Cocaine; Dopamine Agents; Drug Administration Schedule; Injections, Intraperitoneal; Male; Narcotic Antagonists; Piperidines; Psychotropic Drugs; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

The effects of 14 days' treatment of rats with haloperidol, remoxipride or both combined on the sigma binding sites in whole brain and liver were determined. The compounds were given subcutaneously via osmotic minipumps at a dose of 0.25 mg/rat/day (corresponding to about 1 mg/kg body weight/day at start) for haloperidol and 2.5 mg/rat/day (10 mg/kg/day) for remoxipride hydrochloride. The sigma recognition sites were determined after a washout period of 2 days with the radioligand [3H](+)-N-propyl-3-(3-hydroxyphenyl)piperidine ([3H](+)-3-PPP). It was found that the haloperidol treatment but not the remoxipride treatment decreased the density of the sigma sites in the brain, without any effect on the affinities of the ligands. Haloperidol had no effect on the binding of [3H](+)-3-PPP to the sigma recognition sites in the liver.

Topics: Animals; Antipsychotic Agents; Benzamides; Brain; Corpus Striatum; Dopamine Agents; Dopamine Antagonists; Haloperidol; In Vitro Techniques; Liver; Male; Piperidines; Raclopride; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Opioid; Receptors, sigma; Remoxipride; Salicylamides

Some substituted 3-phenylmorpholines (10a-e,j,k) and 3-thienylmorpholines (10f,g), isosteres of 3-(3-hydroxy-phenyl)-N-n-propylpiperidine (3-PPP), were prepared and submitted to binding assays on D-2 dopaminergic and 5-HT1 and 5-HT2 serotonergic receptors, in comparison with 3-PPP and its analogue 3a,b. The results show the loss of D-2 affinity for all morpholines, while a certain activity was still observable for piperidine derivatives. Regarding the serotonergic affinity, only chloro and methoxy derivatives (10a-d) were moderately active on the 5-HT1A receptor, either when the substituent was in the C-2 or C-3 position, whereas no tested compounds showed affinity toward the 5-HT2 receptor.

Topics: Animals; Brain; Dopamine Agents; In Vitro Techniques; Ketanserin; Mice; Oxygen; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Serotonin; Spiperone

The present series of experiments was performed in order to determine the relative role of presynaptic and somato-dendritic autoreceptors for the sedative effects produced by systemically administered dopaminergic agonists. Thus, the effects of intracerebral administration of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), or sulpiride, enantiomers on spontaneous locomotor activity was investigated in rats. It was found that the local application of (-)3-PPP, but not (+)3-PPP, into the nucleus accumbens (1.25-80.0 micrograms, bilaterally) produced a suppression of the locomotor activity, whereas the local application of the two enantiomers into the ventral tegmental area resulted in a suppression of the locomotor activity in the same dose range. Thus, the full dopamine D2 agonist (+)3-PPP produced suppression of locomotor activity only after local application into the somato-dendritic region, suggesting that in terminal areas postsynaptic receptor stimulation effectively counterbalanced the functional consequences of presynaptic receptor stimulation. The sulpiride enantiomers both produced a suppression of locomotor activity after local application into the accumbens (0.2-5.0 micrograms, bilaterally). In the ventral tegmental area, however, (-)sulpiride administration (0.2-5.0 micrograms, bilaterally) resulted in an increased locomotion, whereas the (+)enantiomer produced no effect or, at the highest dose (5.0 micrograms), a suppression of the locomotor activity. These observations indicate that for a dopamine D2 antagonist, the postsynaptic receptor blockade in the terminal region, resulting in behavioral suppression, not only counteract compensatory effects produced via the presynaptic receptor in this region, but also to a great extent overshadow the functional consequences of somatodendritic autoreceptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dopamine Agents; Male; Motor Activity; Nucleus Accumbens; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sulpiride; Tegmentum Mesencephali

Irreversible inactivation of striatal D2 dopamine (DA) autoreceptors with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) or inactivation of striatal guanine nucleotide binding proteins (G proteins) with pertussis toxin (PT) shifted the dose-response curve for N-n-propylnorapomorphine (NPA)-mediated inhibition of gamma-butyrolactone (GBL)-induced elevation of L-3,4-dihydroxyphenylalanine (L-DOPA) to the right, with a decrease in the maximum response. For the partial agonist (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)-3-PPP], in contrast, there was little shift in the ED50, after inactivation of either D2 receptors or G proteins. Completely analogous effects were found at the somatodendritic 5-HT1A autoreceptor in the raphe nuclei, mediating inhibition of the synthesis of serotonin (5-HT); the full agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the partial agonist, buspirone were utilized to inhibit the synthesis of 5-HT, as measured by changes in levels of L-5-hydroxytryptophan (5-HTP). Additionally, in both systems, combined treatment with pertussis toxin, followed by EEDQ, reduced the maximum effect, when compared to either agent alone but had little further effect on the ED50. In systems exhibiting a large receptor reserve for agonists, such as those described above, the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve.

Topics: 5-Hydroxytryptophan; Animals; Apomorphine; Brain; Dopamine Agents; GTP-Binding Proteins; Levodopa; Male; Neurotransmitter Agents; Pertussis Toxin; Piperidines; Quinolines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Serotonin; Ribose; Virulence Factors, Bordetella

1. This work was conducted to provide new data concerning the possible dose-dependent activity of dopamine (DA) after ocular instillation. Experiments were done in rabbits with normal intraocular pressure (IOP), or after transitory induced ocular hypertension in water-loaded animals. 2. In ocular normotensive animals, a biphasic dose-dependent activity is observed, with no significant effect for 0.001% and 0.003% DA, a decrease in IOP after 0.005% and 0.01% DA instillation, then an important increase in IOP at concentrations from 0.05% onwards. 3. During transitory ocular hypertension, this phenomenon was confirmed, with a marked ocular hypotensive activity for 0.01% DA, no effect after 0.005% DA, then an important ocular hypertension with 0.05% and 0.5% DA as compared to the control group (0.9% NaCl). 4. An immediate and similar ocular hypertensive effect with DA could be reproduced by a subsequent instillation at high concentration (1%), while the hypotensive activity induced at low concentration (0.01%) is followed by a long-lasting refractory period (about 18 h). 5. Such a dose-dependent biphasic effect was also observed with N-methyl-dopamine (NMDA) after ocular instillation. The effects of instilled dopaminergic compounds were tested and ocular hypotensive activities of the S(-)enantiomer of the DA analogues 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), and of thiothixene (TIX) were also demonstrated. 6. The possible relationships to DA1 and DA2 receptors of the dual effect is discussed.

Topics: Animals; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Intraocular Pressure; Male; N-Methylaspartate; Ocular Hypertension; Piperidines; Rabbits; Receptors, Dopamine; Thiothixene

Akin to receptor inactivation with phenoxybenzamine (PBZ) (1 microM, 1 hr), treatment of anterior pituitary cells with 17 beta-estradiol (10 nM, 3 days) right-shifted the dose-response curve for inhibition of prolactin (PRL) secretion by the full agonist R-(-)-N-n-propylnorapomorphine (NPA) and reduced the maximal effect [EC50 (pM) and percent maximal effect: control, 25.4 and 81.2; PBZ, 115.3 and 57.9; 17 beta-estradiol, 358 and 58.6]. PBZ treatment of 17 beta-estradiol-pretreated cultures further reduced the maximal response but did not alter the EC50. Plots of receptor occupancy vs. response indicated a large receptor reserve for NPA (approximately 60%) in control cultures but its abolition by 17 beta-estradiol. 17 beta-Estradiol pretreatment elicited identical rightward shifts (4.5-fold) and similar reductions in maximal PRL inhibition by quinpirole and (+)-3-PPP, although these drugs were partial agonists with dissimilar efficacies relative to NPA (0.61 and 0.12, respectively) at presynaptic striatal D2 receptors. However, receptor inactivation experiments with (+)-3-PPP and quinpirole, and subsequent comparison of receptor occupancy vs. response plots, demonstrated that the relative efficacies of quinpirole and (+)-3-PPP were reversed in the striatum and anterior pituitary. In striatum, half-maximal response to quinpirole and (+)-3-PPP required 6.2 and 30% receptor occupancy, respectively, whereas 25.6 and 9.6% occupancy was required in the pituitary. Pertussis toxin treatment (10 ng/ml, 24 hr) produced large shifts in the dose-response curves for all three agonists (8.4-21.9-fold), but was distinguished from the effects of both PBZ and 17 beta-estradiol by a significant (P < .001) decrease in the slope factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Estradiol; GTP-Binding Proteins; Male; Pertussis Toxin; Phenoxybenzamine; Piperidines; Pituitary Gland, Anterior; Prolactin; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Drug; Virulence Factors, Bordetella

The selective sigma compound (+)-pentazocine was radiolabeled and its binding characteristics in guinea pig brain membranes were investigated. [3H](+)-Pentazocine bound to a single high-affinity site with a KD of 2.9 nM and a Bmax of 1998 fmol/mg protein. Saturation was achieved at a ligand concentration of 15 nM. Maximal specific binding was observed at 37 degrees C and was greater than 90% of total binding. Equilibrium was reached by 120 min and dissociation was complete by 420 min, with a t1/2 of 121 min. Li+, Ca2+ and Mg2+ inhibited binding at high concentrations, and binding was insensitive to adenyl and guanyl nucleotides. Stereoselectivity was observed for the inhibition of binding by benzomorphans, 3-(3-hydroxyphenyl)-N-propylpiperidine and butaclamol, and the (+) enantiomers and alpha diastereomers of pentazocine and cyclazocine were more potent than their corresponding (-) enantiomers and beta diastereomers. The rank order of potency for the sigma reference agents to displace [3H](+)-pentazocine binding was similar to that reported using the [3H]sigma ligands dextromethorphan, 1,3-di(2-tolyl)guanidine and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine. Haloperidol, (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-propylpiperidine and rimcazole were competitive inhibitors of binding to the [3H](+)-pentazocine-defined sigma recognition site, suggesting that these different structural classes of compounds all bind to a single molecular entity.

Topics: Animals; Antipsychotic Agents; Binding Sites; Binding, Competitive; Brain; Carbazoles; Dopamine Agents; Guinea Pigs; Haloperidol; Kinetics; Male; Pentazocine; Piperidines; Receptors, sigma

The effect of pretreatment with a high dose of the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (20 mg/kg, 24 h) on the intrinsic activity displayed by a series of full and partial dopamine D2 receptor agonists on prolactin regulating pituitary D2 receptors in male rats was studied. To increase baseline prolactin levels, gamma-butyrolactone in a dose inhibiting brain dopamine neurotransmission was given to all animals. In controls, i.e. rats not given EEDQ, supramaximal doses of all full and partial D2 receptor agonists tested decreased serum prolactin levels with greater than 80%. While the intrinsic activities of the dopamine precursor 1-DOPA and of the full agonists (+)-3-PPP, 5-OH-DPAT, B-HT 920 (talipexole), apomorphine, and NPA (R-(-)-N-n-propylnorapomorphine) were not affected by pretreatment with EEDQ, the effects of supramaximal doses of the partial agonists (-)-HW-165, TDHL (terguride), SDZ208-911, (-)-3-PP) (preclamol), and SDZ 208-912 were reduced to 66%, 74%, 59%, 100%, and 100%, respectively. The effect of EEDQ on the intrinsic activity displayed by the various agonists corresponds inversely to the intrinsic efficacy displayed by the drugs in other models of D2 receptor function with one exception only; thus, the prolactin suppressive effect of (-)-3-PPP was more effectively antagonized by EEDQ than would have been predicted from the intrinsic efficacy usually attributed to the drug. Since the dose of EEDQ used in the present study has previously been shown not to decrease D2 receptor density in the pituitary as measured using in vivo radioligand binding, it is suggested that alkylation of D2 receptors may change the conformation of the individual receptor complexes in a way that decreases the responsiveness to partial but not full agonists.

Topics: 4-Butyrolactone; Adrenergic alpha-Antagonists; Animals; Apomorphine; Dopamine Agents; Ergolines; Levodopa; Male; Piperidines; Prolactin; Quinolines; Rats; Rats, Sprague-Dawley

In order to study the control mechanism of cholecystokinin (CCK) contents of the rat brain mediated by pre-synaptic receptors in dopamine (DA) neurons, R(+) and S(-) compounds of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), which are selective pre-synaptic dopaminergic agents, were administered in rats at low and high doses. CCK-8-like immunoreactivity (CCK-8 LI) was measured in the medial frontal cortex. In another experiment, a neurotoxin, N-methyl-D-aspartic acid (NMDA) was used to degenerate efferent CCK neurons and CCK interneurons of the medial frontal cortex, followed by an intraperitoneal administration of apomorphine hydrochloride (APO) to study the effect on CCK-8 LI via the pre-synaptic DA receptor. According to the results of these experiments, CCK-8 LI was increased in the medial frontal cortex in response to the stimulation of pre-synaptic DA receptor, suggesting a control of CCK-8 release, at least in part, by the pre-synaptic DA receptor.

Topics: Animals; Apomorphine; Behavior, Animal; Cholecystokinin; Dopamine; Dopamine Agents; In Vitro Techniques; Male; Microinjections; N-Methylaspartate; Nerve Degeneration; Neurons; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Dopamine

Intraperitoneal injection of (+)-3-[3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), a sigma receptor agonist, significantly reduced the striatal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) measured by in vivo microdialysis. These reductions were significantly greater at (+)-3PPP doses of 12 and 24 mg/kg than at 1 mg/kg. The levels of 5-hydroxyindoleacetic acid (5HIAA) were increased by the injection of (+)-3PPP in dose of 24 mg/kg, but were not affected at lower doses. BMY-14802, a sigma antagonist, alone at doses of 15 mg/kg and 30 mg/kg did not affect the levels of DA, DOPAC, HVA and 5HIAA. Pretreatment with 30 mg/kg BMY-14802 reversed the reduction of the levels of DA induced by 12 mg/kg (+)-3PPP. Although neither 30 mg/kg BMY-14802 nor 12 mg/kg (+)-3PPP affected the levels of striatal 5HIAA, combined treatment with both produced a significant elevation. These findings clearly demonstrate that sigma receptors may regulate DA release from the striatal presynapse.

Topics: Animals; Corpus Striatum; Dialysis; Dopamine; Dopamine Agents; Male; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stereoisomerism

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Biogenic Amines; Guinea Pigs; Male; Phenazocine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Serotonin; Receptors, sigma; Rotation; Serotonin Antagonists

The in vitro binding properties of 1-(cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'-oxoethyl)pipe ridi ne HBr, [3H]DuP 734, a novel sigma receptor ligand, were examined in homogenates of guinea pig brain. Specific [3H]DuP 734 binding (10 microM haloperidol-displaceable) in cerebellum was dependent on pH, temperature and membrane protein concentration, reversible, saturable and of high affinity (KD = 228 +/- 34 pM; Bmax = 3856 +/- 340 fmol/mg protein). [3H]DuP 734 binding was substantially reduced by treating the membrane with proteases and completely abolished by heat denaturation. [3H]DuP 734 binding was unaffected by the presence of ions or guanine nucleotides. The pharmacological characteristics of [3H]DuP 734 binding in cerebellum displayed the same rank order and stereospecificity as previously reported for sigma receptors in brain. [3H]DuP 734-labeled sigma receptors were heterogeneously distributed throughout the central nervous systems with highest densities present in pons/medulla, hypothalamus, spinal cord and cerebellum. In addition to labeling sigma receptors, a second, lower affinity, haloperidol-insensitive [3H] DuP 734 binding site was observed in the cerebral cortex. This second site could not be positively identified as a neuronal receptor because a series of standard compounds were unable to displace [3H]DuP 734 from the haloperidol-insensitive site; only structural analogs of DuP 734 proved effective in displacing [3H]DuP 734 from the haloperidol-insensitive site. In summary, [3H]DuP 734 is a novel ligand that binds with high affinity to sigma receptors in brain.

Topics: Animals; Antipsychotic Agents; Brain; Guanylyl Imidodiphosphate; Hydrogen-Ion Concentration; In Vitro Techniques; Kinetics; Male; Mice; Phenazocine; Phenytoin; Piperidines; Receptors, sigma; Structure-Activity Relationship; Temperature

1. Evidence is accumulating for multiple sigma (sigma) sites in the mammalian CNS. 2. We have addressed this problem and have examined sigma site - G-protein coupling in guinea-pig and rat brain membranes. 3. Ditolylorthoguanidine (DTG), (+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine (3PPP) and dextromethorphan displaced [3H]-DTG (3.4 nM) with low Hill slopes of 0.5, 0.6 and 0.6, respectively in guinea-pig brain membranes. 4. In the presence of 5'-guanylylimidodiphosphate (Gpp(NH)p; 100 microM), the specific binding of [3H]-DTG was reduced by 36.7%, the Hill slope of 3PPP was increased to near unity, the ability of dextromethorphan to displace DTG was virtually abolished and the Hill slope for DTG remained low (0.7), indicating the presence of at least two binding sites. These data indicate that although Gpp(NH)p removes a dextromethorphan high affinity site, two DTG selective sites remain in the presence of Gpp(NH)p. 5. The present study suggests that DTG binds to at least three sites in guinea-pig brain membranes, at least one of which is G-protein linked. 6. In rat brain membranes, DTG displaced itself (3.4 nM) with a Hill slope near 1. 3PPP displacement of [3H]-DTG was comparable with the guinea-pig (Hill slope 0.5) and displaced from more than 1 site. Dextromethorphan did not displace [3H]-DTG at concentrations below 10 microM. 7. The heterogeneity of sigma sites appears to be less in rat than in guinea-pig brain membranes.

Topics: Animals; Binding, Competitive; Brain Chemistry; Dextromethorphan; Dopamine Agents; GTP-Binding Proteins; Guanidines; Guinea Pigs; In Vitro Techniques; Male; Membranes; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Receptors, Opioid, delta

In the search for an endogenous sigma transmitter, whose existence was previously suggested by release studies, we tested the effects of releasable substances known to be present in the hippocampus, and we determined that ionic zinc may function as an endogenous ligand for the haloperidol-sensitive sigma 2 site. Zn2+ displaced 1,3-di(2-[5-3H]tolyl)guanidine ([3H]DTG) from two binding sites in rat brain membranes, with an IC50 for the high affinity site of 110 +/- 3 microM and for the low affinity site of 20 +/- 4 mM. The sigma 1-selective ligand (+)-[3H]pentazocine was only weakly displaced from rat brain membranes by Zn2+ (IC50 = 1.4 +/- 0.05 mM). These results indicate that the Zn(2+)-sensitive sigma binding site corresponds to the sigma 2 site. The interaction between Zn2+ and the sigma 2 site may have physiological significance, because ionic zinc is present in synaptic vesicles in the brain and may function to regulate binding at the sigma 2 site. To test this hypothesis, we measured the effects of metallothionein peptide 1, a specific zinc chelator, on the actions of the putative endogenous sigma ligand(s) released in the hippocampus by focal electrical stimulation. Release of the endogenous sigma ligand(s) was measured by competition with specific radioligand binding in live hippocampal slices. High frequency, focal, electrical stimulation of the zinc-containing mossy fibers in the hilar region of the hippocampus caused a decrease in the specific binding of [3H]DTG, (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, or (+)-[3H]pentazocine to sigma sites. The decrease in [3H]DTG binding was largely blocked by metallothionein peptide 1, whereas the decrease in (+)-[3H]pentazocine binding was unaffected. These results suggest that Zn2+ may act as an endogenous ligand at sigma 2 sites in the rat hippocampus.

Topics: Animals; Binding, Competitive; Brain; Cations, Divalent; Copper; Electric Stimulation; Guanidines; Haloperidol; Hippocampus; Hydrogen-Ion Concentration; Kinetics; Male; Membranes; Pentazocine; Piperidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sensitivity and Specificity; Tritium; Zinc

The effects of the high affinity sigma (sigma) ligands 1,3-di(2-tolyl)guanidine (DTG), (+)N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1- ethyl-but-3-en-1-yl-amine hydrochloride (JO-1784), (+)3-[3-hydroxyphenyl]-N-(1-propyl)piperidine hydrochloride [(+)3-PPP] and haloperidol were studied on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline (NA) from preloaded hippocampal slices made from Sprague-Dawley rats. The [3H]NA release was evoked once by a 4 min exposure to NMDA, 40 min after the beginning of superfusion with a Mg+(+)-free Krebs' solution. In the absence of any drug, NMDA evoked a concentration-dependent [3H]NA release. Mg++ and EGTA abolished the [3H]NA release induced by NMDA. JO-1784 and (+)3-PPP potentiated in a concentration-dependent manner NMDA-induced [3H]NA release, without affecting the basal outflow. DTG concentration-dependently inhibited the overflow of [3H]NA evoked by NMDA, without affecting the basal efflux. Haloperidol, which did not modify NMDA-evoked [3H]NA release by itself, completely prevented the effects of JO-1784, (+)3-PPP and DTG. In contrast, spiperone, also a potent dopamine receptor antagonist but with low affinity for sigma binding sites, failed to prevent the potentiation of NMDA-evoked release of [3H]NA by JO-1784 and (+)3-PPP. The possible involvement of Gi/o proteins in the modulation by sigma ligands of NMDA-evoked [3H]NA release in the rat hippocampus was also investigated. To this end, Gi/o proteins were inactivated with pertussis toxin (PTX), injected locally 3 to 11 days prior to the experiment or with in vitro preincubation with N-ethylmaleimide (NEM) for 30 min prior the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcium; Cinnamates; Cyclopropanes; Dose-Response Relationship, Drug; Ethylmaleimide; GTP-Binding Proteins; Guanidines; Haloperidol; Hippocampus; In Vitro Techniques; Magnesium; Male; N-Methylaspartate; Norepinephrine; Pertussis Toxin; Piperidines; Rats; Rats, Inbred Strains; Spiperone; Tritium; Virulence Factors, Bordetella

Studies of 1,3-di-(2-[5-3H]tolyl)guanidine ([3H]DTG) binding to rat brain membranes revealed that [3H]DTG binds to a high and a low affinity site with Kd values of 19.8 nM and 1.31 microM (corresponding Bmax values 291 fmol/mg protein and 8.68 pmol/mg protein). The order of potency of competitors for [3H]DTG binding revealed a binding profile typical of sigma site ligands. Several sigma ligands such as the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N- (n-propyl)piperidine) and (+/-)-pentazocine exhibited biphasic competition profiles for [3H]DTG binding, whereas other sigma ligands such as haloperidol displayed monotonic competition curves. Neither phenytoin nor carbamazepine were observed to enhance [3H]DTG binding. These data support the hypothesis that multiple sigma binding sites exist. The lack of phenytoin and carbamazepine modulation of [3H]DTG binding are in agreement with the proposed greater density of sigma site 2 in the rat, since allosteric modulation has been ascribed to the DM1/sigma 1 site.

Topics: Animals; Binding Sites; Binding, Competitive; Carbamazepine; Guanidines; Haloperidol; Male; Pentazocine; Phenytoin; Piperidines; Prosencephalon; Rats; Rats, Wistar; Receptors, sigma; Stereoisomerism

Putative sigma receptors are a current target for antipsychotic drug development. Novel antipsychotic agents which possess selective and high affinity for sigma binding sites may serve as an alternative to the principal neuroleptic drugs currently in clinical use which mediate extrapyramidal side effects and dyskinesias through their blockade of dopamine receptors. We have used in vitro autoradiography to localize putative sigma receptors labelled with (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]-3-PPP] in the brain of the rhesus macaque. The binding characteristics of (+)-[3H]-3-PPP in the primate brain were comparable to those previously described in the rodent. Saturation analysis demonstrated a single class of sites in cerebellar and hippocampal membranes with a Kd value of 28 nM. Sigma receptors labeled with (+)-[3H]-3-PPP in the primate brain displayed the appropriate rank order of potency and stereoselectivity in competition binding assays. Haloperidol displaced (+)-[3H]-3-PPP binding in the low nanomolar range, and the (+) isomer of pentazocine was 50-fold more potent than (-) pentazocine. Computerized densitometric analysis of the autoradiograms demonstrated a striking enrichment of sigma binding sites over the paralimbic belt cortices, including the orbitofrontal, cingulate, insular, parahippocampal, and temporopolar gyri. Peak densities of sigma receptors were seen over the medial and central nuclei of the amygdala and were widely distributed within the hippocampal formation. Sigma binding sites densities were elevated over the suprachiasmatic and supraoptic nuclei of the hypothalamus. Moderate sigma receptor densities were observed over the ventromedial sectors of the caudate and the putamen. Sigma receptors were also elevated over autonomic relay nuclei of the brainstem, including the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. The distribution of sigma receptors in the primate brain suggests that the paralimbic belt cortices, amygdala, hippocampus, hypothalamus, and autonomic relay nuclei of the brainstem may be interrelated by a topographic chemical linkage. The autoradiographic visualization of sigma receptor distributions in the primate brain provides further support for a role of sigma receptor mechanisms in the functions of the limbic system.

Topics: Animals; Autoradiography; Binding Sites; Brain; Cerebral Cortex; Image Processing, Computer-Assisted; Limbic System; Macaca mulatta; Male; Piperidines; Radioligand Assay; Receptors, sigma; Tissue Distribution

The binding of four sigma receptor ligands, 3H-(+)-N-allyl-N-normetazocine (3H-(+)-SKF 10,047), 3H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3H-(+)-3-PPP), 3H-haloperidol and 3H-N,N'-di(o-totyl)guanidine (3H-DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor 3H-1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (3H-GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P-450. In rat brain the density of binding sites was increased in order (+)-SKF 10,047 less than (+)-3-PPP less than DTG much less than GBR 12935. In liver the corresponding order was (+)-SKF 10,047 less than DTG less than haloperidol less than (+)-3-PPP less than GBR 12935. The inhibition pattern of each ligand was similar in brain and liver, indicating that the binding sites were similar in the two tissues. With the exception of 3H-(+)-SKF 10,047 which appears to bind to a homogeneous haloperidol-sensitive site, there were quite marked differences between the ligands studied, suggesting heterogeneous binding sites. For instance, (+)-SKF 10,047 and progesterone were potent inhibitors of the binding of 3H-(+)-SKF 10,047, 3H-(+)-3-PPP and 3H-haloperidol but inhibited only a minor fraction of the binding of 3H-DTG to the brain and liver preparations. Multiple binding sites were also indicated by the low Hill coefficients found for most of the compounds studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Cytochrome P-450 Enzyme System; Guanidines; Haloperidol; Kinetics; Ligands; Liver; Male; Phenazocine; Piperazines; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Subcellular Fractions

Computer-assisted, simultaneous analysis of self- and cross-displacement experiments demonstrated the existence of several binding sites in guinea pig brain for dextromethorphan, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), and 1,3-di-o-tolyl guanidine (DTG). Dextromethorphan binds with high affinity to two sites (R1 Kd 50-83 and R2 Kd 8-19 nM) and with low affinity to two additional sites (R3 and R4). (+)-3-PPP binds to one high-affinity (R1 Kd 24-36 nM), to one intermediate-affinity (R3 Kd 210-320 nM), and to two (R2 and R4) low-affinity sites. DTG binds with almost identical high affinity to two different sites (R1 Kd 22-24 and R3 Kd 13-16 nM). These results confirm that dextromethorphan, (+)-3-PPP, and DTG bind to the common DM1/sigma 1 site (R1). The binding of DTG to two different sites with identical affinities precludes the use of this compound as a specific marker for sigma receptors. Besides, haloperidol displaces labeled ligands from both high-affinity DTG sites (R1 and R3) with high affinity. Thus, haloperidol sensitivity should not be used as the single criterion to identify a putative receptor. The resolution of these novel sites also may provide new insights into the multiple effects of antipsychotic drugs. In addition, this investigation has important implications regarding the methods that must be applied to characterize multiple binding sites and their relations with putative receptors.

Topics: Animals; Binding Sites; Binding, Competitive; Brain; Computer Simulation; Dextromethorphan; Guanidines; Guinea Pigs; Haloperidol; Kinetics; Male; Models, Biological; Piperidines; Receptors, Opioid; Receptors, sigma; Tritium

Previous data indicated that opioid receptors occur in both neural and nonneural human tumors. However, it has recently been shown that some of the putative opioid binding may be attributable to sigma sites. In this study the occurrence of sigma and opioid receptors in nonneural human tumors was assessed. The neoplasms included renal and colon carcinomas and a sarcoma. [3H]1,3-di-o-tolylguanidine was used to assay sigma receptors by homologous competition binding assays, which when analyzed provided dissociation constant and receptor density values. Opioid binding was measured with [3H]-(-)-ethylketocyclazocine, a ligand which interacts with mu, delta, and kappa subtypes. Fresh surgical specimens were obtained from 9 human neoplasms, selected for their large size, and compared with nonmalignant tissues. All 9 tumors contained sigma sites, and dissociation constant values were within the range of 27-83 nM. Occasionally, two-site fit the data better than one-site binding, suggesting the presence of multiple sigma sites. Opioid binding was not detected. Intratumoral variability was evaluated by sampling several locations on the periphery of the mass and one in the center. Each of the samples was bisected, with a portion reserved for histological examination to correlate morphological features with receptor data. Changes in sigma binding were not associated with the extent of fibrosis, viability, or necrosis. Receptor density values displayed moderate intra- and intertumoral variation (coefficients of variation, 8-39 and 27-49%, respectively). More important, sigma binding in tumors was found to be greater than or equal to 2-fold higher than that of control nonmalignant tissue.

Topics: Binding, Competitive; Carcinoma; Colonic Neoplasms; Guanidines; Humans; In Vitro Techniques; Kidney Neoplasms; Neoplasms; Piperidines; Receptors, Opioid; Receptors, sigma; Sarcoma

The sigma binding sites are postulated to be involved in various central nervous system (CNS) disorders. The neuroleptic drug, haloperidol, displays high affinity for these receptor sites in the CNS. In the present study the effect of repeated exposure of rats to haloperidol (4 mg/kg/day for 14 days) on sigma binding sites labeled with (+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [+)-3-PPP) and 1,3-di-o-tolyl-guanidine (DTG) was investigated. In addition, the regulatory effect of guanine nucleotides on the binding of these two ligands to brain membranes derived from saline and haloperidol-treated rats was examined. Repeated administration of haloperidol induced down-regulation of (+)[3H]-3-PPP binding sites (75% decrease in the number of binding sites compared to control) which persisted for at least 7 days after termination of the haloperidol-treatment. The down-regulation of (+)-3-PPP binding sites was accompanied by reduced responsiveness to guanine nucleotides (i.e. 5-guanylylimidodiphosphate (Gpp(NH)p) compared to the sensitivity of (+)-3-PPP binding sites to the nucleotides tested in control membranes. However, at the 28th day after termination of the haloperidol-treatment, a complete recovery in the total number of (+)[3H]-3-PPP binding sites was observed, and the sensitivity to guanine nucleotides was regained. These findings suggest a marked plasticity in (+)-3-PPP/sigma receptor binding activity. In contrast, [3H]DTG binding sites expressed neither sensitivity to the repeated exposure to haloperidol nor to guanine nucleotides, suggesting a distinction between DTG and (+)-3-PPP binding sites in rat brain.

Topics: Adenosine Triphosphate; Animals; Brain; Cell Membrane; Down-Regulation; Guanidines; Guanine Nucleotides; Guanylyl Imidodiphosphate; Haloperidol; Kinetics; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Reference Values

The effects of pretreatment with the irreversible inactivator of brain D2 receptors N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the suppression of prolactin (PRL) release induced by the two partial D2 agonists (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(+)-3-PPP, (-)-3-PPP] were investigated in gamma-butyrolactone (GBL) treated male rats. Pretreatment with a high dose of EEDQ (20 mg/kg, 24 h) did not influence the PRL response to (+)-3-PPP. In contrast, the effect of (-)-3-PPP was dose-dependently antagonized by EEDQ administration; thus, while pretreatment with EEDQ 2 mg/kg (24 h) failed to influence the efficacy of (-)-3-PPP, a complete antagonism of the PRL suppressive effect of the (-) enantiomer was obtained by administration of EEDQ 16 or 20 mg/kg (24 h). Moreover, in EEDQ (20 mg/kg, 24 h) treated rats (-)-3-PPP effectively antagonized the PRL inhibiting effect of the (+) enantiomer. Also, in EEDQ (20 mg/kg, 24 h) treated animals not receiving GBL (-)-3-PPP induced a dose-dependent increase in plasma levels of PRL. The data indicate that higher doses of EEDQ are required in order to reduce the responsiveness of lactotroph D2 receptors than that of various populations of brain D2 receptors. Also, the data lend support for the assumption that an altered receptor responsiveness may dramatically modify the response to a partial agonist with low intrinsic efficacy without affecting the response to a partial agonist with higher intrinsic efficacy.

Topics: 4-Butyrolactone; Animals; Brain; Dopamine Agents; Male; Piperidines; Prolactin; Quinolines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Reference Values

1. Fast cyclic voltammetry at carbon fibre microelectrodes was used in rats anaesthetized with chloral hydrate to monitor dopamine release in the caudate and nucleus accumbens evoked by electrical stimulation of the median forebrain bundle. Stimulation trains (50 Hz sinusoidal current, 100 +/- 10 microA r.m.s., 2s duration) were repeated every 5 min throughout the experiment. 2. The actions of the dopamine agonists quinpirole, pergolide, SKF 38393, bromocriptine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3PPP) and (-)-3PPP were compared in the two nuclei. 3. Bromocriptine (10 mg kg-1, i.p.) did not affect release in either nucleus while SKF 38393 caused a fleeting decrease in limbic but not striatal dopamine release at a high dose (20 mg kg-1, i.p.). 4. Quinpirole and pergolide (both 1 mg kg-1, i.p.) decreased stimulated dopamine release in the nucleus accumbens while in the caudate the drugs each caused a transient, though not quite significant, elevation of stimulated dopamine release followed by decrease in release of the same magnitude as that seen in the nucleus accumbens. 5. The (-)-enantiomer of 3PPP (20 mg kg-1, i.p.), a partial agonist at the dopamine autoreceptor, increased stimulated dopamine release in both nuclei although the action in the caudate was larger and more prolonged. (+)-3PPP (20 mg kg-1, i.p.), a full agonist, decreased release in the nucleus accumbens. A small, transient and not significant increase in the caudate was followed by decreased release. 6. The results are interpreted as being evidence for differences in the dopamine autoreceptor in the two nuclei, possibly in the affinity state of the receptor in each nucleus.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Bromocriptine; Corpus Striatum; Dopamine; Dopamine Agents; Electrochemistry; Electrophysiology; Ergolines; In Vitro Techniques; Limbic System; Male; Microelectrodes; Nucleus Accumbens; Pergolide; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Stereotaxic Techniques

The interaction of various compounds with sigma binding sites was examined in membranes prepared from whole guinea pig brain. Whereas [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine labeled a single population of binding sites exhibiting a Kd of 43 nM, [3H]1,3-di-o-tolylguanidine bound to two sites having Kds of 35 and 212 nM, and to a greater maximum number of sites than [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. Haloperidol, 1,3-di-o-tolylguanidine, BMY 14802, and (-)-pentazocine each displayed nearly equal affinity for binding sites labeled by [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H]1,3-di-o-tolylguanidine, whereas (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine was 3 times more potent in inhibiting [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding. In contrast, (+)-SKF 10,047, (+)-cyclazocine and (+)-pentazocine exhibited more than 9-fold higher affinity for [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine binding sites. Dextromethorphan was 15-fold more potent against [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine than [3H]1,3-di-o-tolylguanidine, inhibited [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine binding in a biphasic manner, and inhibited [3H]haloperidol and [3H](+)-SKF 10,047 binding with potencies similar to those obtained against [3H]1,3-di-o-tolylguanidine and [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, respectively. Phenytoin increased [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and [3H](+)-SKF 10,047 binding, but did not enhance [3H]1,3-di-o-tolylguanidine or [3H]haloperidol binding. However, the potency of dextromethorphan to inhibit [3H]1,3-di-o-tolylguanidine binding was increased in the presence of phenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Binding, Competitive; Brain; Dextromethorphan; Dopamine Agents; Guanidines; Guinea Pigs; Haloperidol; In Vitro Techniques; Kinetics; Membranes; Phenazocine; Phenytoin; Piperidines; Receptors, Opioid; Receptors, sigma

JO 1784 ((+)-N-Cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride), has been recently described as a selective ligand for the sigma receptor with an IC50 of 39 +/- 8 nM28. In the present study the effects of JO 1784 on experimental induced amnesia were investigated using one trial passive avoidance task in rats. Amnesia was produced by injecting scopolamine (1 mg/kg i.p.) 30 min before the second session (T2) on day 2 of the passive avoidance task. The anti-amnesic effect of JO 1784 was compared with other typical and atypical psychotropic drugs which interact at the sigma and or the phencyclidine site. JO 1784 was studied at 5 doses; 0.0625, 0.25, 1.0, 4.0 and 16.0 mg/kg i.p. ((+)-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine ((+)-3-PPP). Rimcazole, (+)-N-allylnormetazocine ((+)-NANM), 1,3-di(2-tolyl) guanidine (DTG) were studied at 4 doses; 0.25, 1.0, 4.0 and 8.0 mg/kg i.p. All drugs were administered 60 min before the test (T2) on day 2 i.e. 30 min before scopolamine. Piracetam (1000 mg/kg p.o.) administered in the same test conditions was used as a reference compound in each experiment. Of the drugs investigated JO 1784 (0.25, 1.0, 4.0 and 16.0 mg/kg i.p.), (+)-3-PPP (0.25, 1.0 and 4.0 mg/kg i.p.), DTG (1.0, 4.0 and 8.0 mg/kg) and piracetam significantly reversed scopolamine induced amnesia on day 3 (T3). At the lower dose, JO 1784 (0.0625 mg/kg) failed to reverse the amnesic effects of scopolamine on day 3. These results suggest that JO 1784 the selective sigma ligand, may be beneficial in amnesic status.

Topics: Amnesia; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Carbazoles; Cinnamates; Cyclopropanes; Dopamine Agents; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Scopolamine

Previous work in this laboratory, as well as observations reported in the literature, indicate that the adrenal medulla contains dopamine (DA) receptors of the D-2 subtype, which among other things are capable of controlling the DA level in rat adrenal glands. To further characterize the DA receptors involved in the control of the adrenal DA level, the effects of 9 DA receptor agonists with various intrinsic activities were compared. After various periods of drug administration the rats were killed by decapitation and the DA content of the adrenal glands and the DOPAC content of the forebrain were measured by high-performance liquid chromatography with electrochemical detection. All the investigated DA receptors agonists caused an increase in adrenal DA level, although statistical significance was not reached in one case [(-)-HW 165]. Domperidone, a DA D-2 receptor antagonist which does not readily cross the blood brain barrier, blocked the DA-elevating effects of apomorphine, quinpirole, B-HT 920 and both enantiomers of 3-PPP. For the two ergolines terguride and SDZ 208-920 the blockade by domperidone was not complete, suggesting that their effects are mediated not only through DA, but also through other receptor systems. The dose of domperidone used (3 mg/kg) had but a marginal influence on brain DOPAC levels, supporting the almost exclusively peripheral effect of this agent. Our data indicate that the DA D-2 receptors which control the DA level in the adrenal medulla in rats, have characteristics similar to, though not identical with the autoreceptors in the forebrain.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenal Medulla; Animals; Apomorphine; Azepines; Diencephalon; Domperidone; Dopamine; Dopamine Agents; Epinephrine; Ergolines; Lisuride; Male; Norepinephrine; Phenanthrenes; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Telencephalon

Focal electrical stimulation of selected excitatory pathways in the hippocampal slice caused a decrease in the binding of [3H]-1,3-di(2-tolyl)guanidine (DTG) or [3H]-(+)-3-[hydroxyphenyl]-N-(1-propyl)piperidine [( 3H )-(+)3-PPP) to haloperidol-sensitive sigma binding sites in the slice. Activation of the mossy fibers or perforant path by high frequency electrical stimulation caused the reduction in [3H]-DTG binding; whereas activation of fibers in the strata radiatum, lacunosum-moleculare, alveus, or oriens did not affect [3H]-DTG binding. The decrease in binding observed was calcium-dependent and tetrodotoxin sensitive and varied with the frequency, intensity, and duration of stimulation. Although haloperidol-sensitive [3H]-DTG binding sites are distributed throughout the hippocampus, stimulation of the perforant path or mossy fibers resulted in a significant reduction in binding only in the dentate region of the slice. The decrease in binding following perforant path stimulation was blocked by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); whereas the decrease in binding caused by mossy fiber stimulation was not affected by CNQX or DL-APV. The results obtained support the hypothesis that activation of the granule cells in the hippocampal slice caused the release of an endogenous ligand which acts at the haloperidol-sensitive sigma binding site in the dentate gyrus.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Calcium; Electric Stimulation; Guanidines; Haloperidol; Hippocampus; Male; Piperidines; Quinoxalines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

The ability of low doses of the dopamine (DA) agonists quinpirole and (+)-3-PPP to reduce the discriminative stimulus properties and locomotor hyperactivity produced by d-amphetamine (0.5 mg/kg) was assessed in two groups of rats. Quinpirole (0.0125-0.05 mg/kg) and (+)-3-PPP (1.0-2.0 mg/kg) completely antagonized d-amphetamine-induced locomotor hyperactivity. In contrast, only single doses of quinpirole (0.025 mg/kg) and (+)-3-PPP (2.0 mg/kg) were effective in the drug discrimination paradigm; the antagonisms were small (18-47%), but significant. The inhibitory effects of quinpirole and (+)-3-PPP in these behavioural models are probably due to their ability to selectively stimulate DA autoreceptors in the nucleus accumbens and reduce the increase in DA release produced by d-amphetamine. It is suggested that the much weaker effects of the drugs in the discrimination paradigm are due to changes produced by the long-term periodic administration of d-amphetamine to these animals, such as a down-regulation in the sensitivity of DA autoreceptors.

Topics: Animals; Conditioning, Operant; Cues; Dextroamphetamine; Discrimination, Psychological; Dopamine Agents; Ergolines; Male; Motor Activity; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine

1,3-di(2-[5-3H]tolyl)Guanidine ([3H]DTG) was found to bind to a single saturable population of binding sites in human cerebral cortex and NCB20 cells, a second low-affinity site was apparent in guinea pig brain. Displacement studies were performed to determine the pharmacology of the [3H]DTG binding site in these 3 membrane preparations. In human cortical tissue and NCB20 cell membranes the (+)-stereoisomers of benzomorphans displaced binding with Hill coefficients close to one, displayed similar affinity and did not give the biphasic displacement curve characteristic of guinea pig membranes. The pIC50 of the low-affinity component of the sigma binding site in guinea pig brain correlates best with the affinity of drugs for the binding site in human cortex.

Topics: Animals; Brain Chemistry; Cells, Cultured; Cerebral Cortex; Cricetinae; Cricetulus; Dopamine Agents; Guanidines; Guinea Pigs; Humans; Kinetics; Male; Mice; Neuroblastoma; Pentazocine; Phenazocine; Piperidines; Radioligand Assay; Receptors, Opioid; Receptors, sigma; Stereoisomerism; Tumor Cells, Cultured

In the present investigation, the effects of sigma ligands [WY-47384 [8-fluoro-2,3,4,5-tetrahydro-2[3-(3-pyridinyl)propyl)1H- pyrido(4,3b)indole], (+)-pentazocine, (+)-SFK 10,047 (N-allylnormetazocine), mafoprazine, opipramol, dextromethorphan, dextrorphan, (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine], (-)-butaclamol, DTG [1,3-di(2-tolyl)guanidine], rimcazole, ifenprodil and BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoropyrimidinyl)-1-piperazine butanol]] on harmaline-, pentylenetetrazol (PTZ)-, methamphetamine (MA)- and D-serine-induced increases in mouse cerebellar levels of cGMP were determined. Ifenprodil, BMY-14802, dextromethorphan, dextrorphan, (+)-SKF 10,047, opipramol and mafoprazine reversed harmaline-, PTZ-, MA- and D-serine-induced increases in levels of cGMP. Rimcazole reversed only the harmaline-induced response. WY-47384 reversed harmaline-, MA-, D-serine-, but not PTZ- or quisqualate-induced increases in levels of cGMP. (+)-Pentazocine attenuated harmaline- and D-serine-, but not PTZ- and MA-induced cGMP responses. Haloperidol did not affect harmaline- and D-serine-induced cGMP responses. (+)-3-PPP and (-)-butaclamol did not affect any of the responses studied. Furthermore, (+)-3-PPP-induced increases in levels of cGMP were reversed by the competitive N-methyl-D-aspartate (NMDA) antagonist, CPP]3-(2-carboxypiperazin-4-yl)propyl- 1-phosphonic acid, the non-competitive NMDA antagonist, (+)-MK-801 (dizocilipine maleate), the NMDA-associated glycine receptor antagonist, HA-966 (3-amino-1-hydroxypyrrolidin-2-one), the partial glycine agonist, DCS (D-cycloserine) as well as by the sigma ligands, ifenprodil, WY-47384, (+)-pentazocine, (+)-SKF 10,047, dextromethorphan and dextrorphan but not by rimcazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cerebellum; Cyclic GMP; Dopamine Agents; Harmaline; Ligands; Male; Methamphetamine; Mice; Pentylenetetrazole; Piperidines; Quisqualic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, sigma; Serine

Using extracellular single unit recording techniques, we analyzed the significance of sigma-receptors in the neuronal control of dopamine (DA) neurons in the zona compacta of the substantia nigra. Administration of racemic trans-9-methoxy-4-benzyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (HW 173), a drug displaying high and specific affinity for sigma-receptors, was not associated with any change in the firing rate of DA neurons. Furthermore, pretreatment with the drug did not affect the dose-response curve for the inhibitory effects of the DA receptor agonist apomorphine or the mixed DA agonist/sigma-receptor ligand (+)-3-(3-hydroxyphenyl)-N-1-propyl)piperidine ((+)-3-PPP). In contrast to the effects of HW 173 on the DA cell firing rate, the firing pattern of the DA cells was significantly changed by the drug. The data suggest that sigma-receptors do not play a pivotal role in the control of the firing rate of DA neurons in the substantia nigra. Rather, they may have a function in the regulation of the firing pattern of these neurons.

Topics: Animals; Apomorphine; Binding, Competitive; Dizocilpine Maleate; Dopamine; Dopamine Agents; Male; Neurons; Piperidines; Quinolines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Stereotaxic Techniques; Substantia Nigra

Yawning was recorded from five rhesus monkeys restrained in a chair after i.m. injection of dopaminergic compounds: apomorphine (0.03 mg/kg), quinpirole (0.01 mg/kg), and (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (1 mg/kg). SKF 38393 or physostigmine produced no yawning. Yawning from apomorphine was blocked by chlorpromazine or SCH 23390 (0.03 mg/kg). Sulpiride (10 mg/kg) was ineffective. The difference between rats and monkeys in their yawning response to dopaminergic compounds is discussed.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Apomorphine; Benzazepines; Dopamine; Dopamine Agents; Dopamine Antagonists; Ergolines; Macaca mulatta; Male; Physostigmine; Piperidines; Quinpirole; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Yawning

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kg d-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blocked d-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208-911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced by d-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208-911. The profiles of SDZ 208-912 and terguride were intermediary to those of SDZ 208-911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kg d-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dose d-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208-911, preclamol and terguride was accompanied only by the low dose d-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208-912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased by d-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced by d-amphetamine.

Topics: Animals; Dextroamphetamine; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Lisuride; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Stereotyped Behavior

The effects of sigma ligands, (+)3PPP 3-[3-hydroxyphenyl-N(1-propyl) piperidine] and (-)butaclamol, were evaluated in vivo on the metabolism of dopamine (DA) and in the striatum release of adrenocorticotrophic hormone (ACTH) and prolactin in the rat and changes in levels of cyclic guanosine monophosphate (cGMP) in the cerebellum of the mouse and compared with the effects of (+)NANM (N-allyl-normetazocine, SKF 10,047) and (+)pentazocine. Both (+)3PPP and (-) butaclamol decreased the release of prolactin and did not affect the metabolism of DA. N-Allyl-normetazocine and (+)pentazocine increased release of prolactin and have been shown previously to increase the metabolism of DA. All four ligands increased release of ACTH; however, only the increases caused by (+)NANM and (+)pentazocine were reversed by pretreatment with CPP, a N-methyl-D-aspartate (NMDA) receptor antagonist. (+)Pentazocine and (+)NANM inhibited the NMDA receptor-mediated changes in levels of cGMP in the cerebellum of the mouse, while (+)3PPP and (-)butaclamol did not attenuate the response to NMDA. In addition to further confirming a functional interaction between sigma receptors and NMDA receptors, these studies divide the observed effects of putative sigma ligands into two groups, characterized by benzomorphan compounds and non-benzomorphan compounds, suggesting the possibility of subtypes at sigma receptor in vivo.

Topics: Adrenocorticotropic Hormone; Animals; Brain; Butaclamol; Cerebellum; Corpus Striatum; Cyclic GMP; Dopamine; Dopamine Agents; Male; Mice; Pentazocine; Phenazocine; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, sigma

The interaction of several sigma and PCP receptor ligands with the norepinephrine uptake carrier was investigated in the rat tail artery and brain. These ligands include haloperidol; (+)- and (-) 3-(3-hydroxy- phenyl)-N-(1-propyl)piperidine (3-PPP), (+/-)-BMY 14802, [(+/-) alpha-(4-fluoro- phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; (+)-SKF 10047, [(+/-)-N-allyl-N-normetazocine]; 1,3-di-ortho-tolyl-guanidine; rimcazole (BW 234U), [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl] carbazole dihydrochloride]; and MK 801, [(+)-5-methyl-10,1 1-dihydro-5H-dibenzo[a, d]cyclohepten-5, 10-imine maleate]. Our results show that all ligands used, except 1,3-di-ortho-tolyl-guanidine, inhibit both neuronal [3H]norepinephrine accumulation in the rat tail artery and specific [3H] desmethylimipramine binding in the rat brain. Except for (+)-SKF 10047, the order of potency of the ligands used for inhibiting neuronal [3H]norepinephrine accumulation in the rat tail artery was similar to that measured for inhibition of specific [3H]desmethylimipramine binding in the rat brain. Despite these similarities, our results also suggest that haloperidol, (+)- and (-)3-PPP, MK 801, rimcazole and cocaine interact with the [3H]norepinephrine site in the rat tail artery and with the [3H]desmethylimipramine binding site in the rat brain in a complex fashion. These studies demonstrate an important action on the norepinephrine carrier by these sigma and PCP ligands in the rat tail artery and brain.

Topics: Animals; Biological Transport; Brain; Desipramine; Dizocilpine Maleate; Male; Norepinephrine; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Tail; Vasoconstriction

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like symptoms in humans, nonhuman primates, and mice. Several studies suggest that MPTP is metabolized by monoamine oxidase (MAO) type B to yield N-methyl-4-phenyl-pyridinium (MPP+), which is responsible for the neurotoxic effects of the drug. In the present study, the pharmacological properties of [3H]MPTP binding sites in C57BL/6 mouse brain membranes were investigated, and a possible relationship to the sigma binding sites was examined. Both equilibrium binding experiments and kinetic assays indicate that [3H]MPTP labels two distinct binding sites in C57BL/6 mouse brain. The high affinity [3H]MPTP binding sites (Kd = 13 nM) are selectively blocked by the MAO type A inhibitor clorgyline, and the residual low affinity [3H]MPTP sites (Kd = 1100 nM) display the pharmacological specificity of MAO-B binding sites. In contrast, the low affinity [3H]MPTP binding sites are blocked by the selective MAO-B inhibitor (-)-deprenyl, and the drug-specificity profile of the remaining high affinity sites is consistent with the properties of MAO-A binding sites. The affinities of several MAO inhibitors tested and of MPTP for the high affinity MPTP/MAO-A binding sites correlate well (r = 0.96) with their affinities for the sigma binding sites labeled with [(+)-[3H]-3-PPP]. The sigma receptor ligand (+)-3-PPP displays moderately high affinity for the MPTP/MAO-A binding sites but negligible affinity for MPTP/MAO-B sites. Moreover, (+)-3-PPP alters the dissociation kinetics of MPTP from the high affinity MPTP/MAO-A sites. The finding that [3H]MPTP labels MAO-B sites supports the hypothesis that the drug is a substrate for these enzyme binding sites. However, the finding that the high affinity sites, labeled by [3H] MPTP, are particularly sensitive to MAO-A inhibitors, which also display high affinity for the sigma binding sites, may suggest a possible relationship between MAO-A and sigma binding sites. In turn, the kinetic experiments imply that sigma ligands [i.e., (+)-3-PPP] may allosterically modulate the binding to MAO-A binding sites.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Cell Membrane; Clorgyline; Kinetics; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperidines; Receptors, Opioid; Receptors, sigma; Selegiline

Our preliminary studies indicated that certain monoamine oxidase (MAO) inhibitors display high affinity for the sigma-binding sites labeled with (+)[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)[3H]-3-PPP] in C57BL/6 mouse brain (Itzhak, Y., and Kassim, C. D.: Eur. J. Pharmacol. 176: 107-108, 1990). In the present study, the drug specificity and the subcellular distribution of (+)[3H]-3-PPP, (+)[3H]-N-allylnormetazocine [(+)[3H]SKF 10047] and [3H]1,3-di-o-tolyl-guanidine ([3H]DTG) binding sites in C57BL/6 mouse brain were investigated, and the properties of clorgyline interaction with the (+)-3-PPP/sigma-binding site(s) were examined. (+)[3H]-3-PPP binding, but not [3H]DTG binding, is inhibited by low concentrations (nM) of the dextrorotatory (+)-isomers of SKF 10047, 3-PPP and deprenyl and the type A MAO inhibitor, clorgyline. The haloperidol-sensitive/(+)[3H]SKF 10047 binding sites display virtually identical sensitivity towards the MAO inhibitors as (+)-3-PPP binding sites. These observations suggest a distinction between [3H]DTG and (+)[3H]-3-PPP/(+)[3H]SKF 10047 binding sites in the mouse brain. Clorgyline interaction with (+)-3-PPP/sigma-sites is competitive and reversible unlike the interaction of clorgyline with MAO-A. The sigma-ligands tested do not inhibit MAO activity and bind to sites that are apparently distinct from the MAO binding sites labeled with [3H]-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, the mitochondrial fraction of the mouse brain that expresses MAO activity and high density of [3H]-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine binding sites also comprises high density of (+)-3-PPP/(+)SKF 10047 binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Binding Sites; Brain; Guanidines; In Vitro Techniques; Ligands; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Phenazocine; Piperidines; Receptors, Opioid; Receptors, sigma

Whole cell voltage clamp studies were performed on NCB-20 cells to examine physiological responses to drugs possessing affinities for sigma receptors. Those drugs [haloperidol, alpha-(4-fluoro-phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutano l (BMY-14802), pentazocine, N-allylnormetazocine (SKF-10047), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP), phencyclidine, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine maleate (MK-801)] caused an apparent inward current, which was due to blockade of a tonic, outward potassium current. The rank order of drug potencies in producing this effect generally resembled the rank orders of sigma-receptor affinities for the drugs, except that a reverse stereoselectivity was observed for several drugs. [3H](+)-SKF-10047 labeled two sites in intact NCB-20 cells (Kd = 49 nM, Bmax = 1.0 pmol/mg protein and Kd = 9.6 microM, Bmax = 69 pmol/mg protein). The high affinity site was similar pharmacologically to the sigma receptor assayed in membrane fragments from NCB-20 cells. However, the low affinity site showed a slightly different profile, highlighted by a reverse stereoselectivity. The rank order of drug potencies was as follows at the low affinity site: haloperidol greater than BMY-14802 greater than (-)-pentazocine greater than (+)-pentazocine greater than (-)-SKF-10047 greater than (-)-3-PPP greater than (+)-SKF-10047 greater than (+)-3-PPP greater than phencyclidine greater than TCP greater than MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cricetinae; Cricetulus; Hybrid Cells; Ligands; Mice; Neuroblastoma; Phenazocine; Piperidines; Potassium Channels; Receptors, Opioid; Receptors, sigma; Stereoisomerism; Tumor Cells, Cultured

The effects of the enantiomers of 3-hydroxyphenyl-N-n-propylpiperidine (3-PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)-3-PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (-)-3-PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)- and (-)-3-PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0 microns, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 microM). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine-pretreated rats and was blocked by the selective D2 DA antagonist (-)-sulpiride. This suggests that 3-PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)-3-PPP. However, the stimulation of DA autoreceptors by (-)-3-PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (-)-3-PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (-)-3-PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biogenic Monoamines; Cerebral Cortex; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Electrochemistry; Ergolines; In Vitro Techniques; Lisuride; Male; Nerve Tissue Proteins; Nucleus Accumbens; Piperidines; Potassium; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

The exposure to bright light of dark-adapted (DKA) mouse retinas incubated in the dark (DI) in IBMX-containing medium causes a marked loss of cyclic AMP. This light response also occurs if the medium contains 10 mM aspartate or cobaltous ion, agents believed to confine the effects of light to photoreceptors. Thus, the action of light in the presence of either of these agents defines a light-sensitive pool of cyclic AMP in photoreceptors. This pool could also be reduced or eliminated in DKA-DI retinas by nanomolar to micromolar levels of dopamine (if the medium contained SCH23390, a potent antagonist of D1 receptors), thus indicating an agonistic action of dopamine at D2 receptors. The D2 agonists LY171555 (EC50 10 nM) or (+)-3-PPP also reduced the cyclic AMP level in the dark. Of the D2 antagonists tested, the butyrophenone spiperone (in the presence of the 5HT-2 blocker ketanserin) countered the action of the D2 agonists but substituted benzamides were ineffective. Consistently, the D2 agonists had no effect on cyclic AMP levels of mutant retinas lacking photoreceptors (rd/rd), but reduced cyclic AMP in DKA-DI glutamate-modified retinas which exhibit a major loss of inner retinal neurons without apparent loss of photoreceptors. The D1 antagonist SCH23390 only reduced cyclic AMP levels of DKA-DI retinas when cyclic AMP levels had been elevated by adding dopamine to the incubation medium.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Benzazepines; Cyclic AMP; Dark Adaptation; Dopamine; Dopamine Agents; Ergolines; Ligands; Light; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Photoreceptor Cells; Piperidines; Quinpirole; Receptors, Dopamine

Opipramol, a tricyclic antidepressant drug, potently interacted with sigma recognition sites labelled by [3H](+)-3-hydroxyphenyl)N-(1-propyl)piperidine [( 3H](+)-3-PPP) with a Ki value of 50 +/- 8 nM and with minimal affinity for phencyclidine receptors (Ki greater than 30,000 nM). Opipramol potently increased the metabolism of dopamine in the striatum, olfactory tubercle and pyriform cortex of the rat and increased the release of dopamine from the striatum of the mouse, as measured by increases in the levels of 3-methoxytyramine in vivo. Opipramol increased plasma prolactin in the rat, only at a dose as large as 50 mg/kg dose. Irreversible inactivation of dopamine receptors by EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) did not affect the opipramol-induced increases in levels of dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat, indicating a predominant role of activation of sigma receptors in the dopaminergic effects of opipramol. However, pretreatment with the putative sigma ligand, rimcazole, markedly potentiated the ability of opipramol to increase the metabolism of release of DA in the striatum of the mouse in vivo. These results suggest that rimcazole and opipramol interact at two distinct receptors, the pharmacological significance of which is yet to be elucidated.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain; Corpus Striatum; Dopamine; Haloperidol; Homovanillic Acid; Ligands; Male; Mice; Opipramol; Organ Specificity; Phencyclidine; Piperidines; Quinolines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Most agents employed for the investigation of sigma (sigma) binding sites display relatively low affinity for these sites, bind both at sigma sites and at either phencyclidine (PCP) sites or dopamine receptors with similar affinity, and/or produce some dopaminergic activity in vivo. We describe a new agent, (-)PPAP or R(-)-N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane hydrochloride, that binds with high affinity and selectivity at sigma (IC50 = 24 nM) versus either PCP sites (IC50 greater than 75,000 nM) or D1 and D2 dopamine receptors (IC50 greater than 5,000 nM). The sigma affinity of this agent is comparable to that of the standard ligands (+)-3-PPP and DTG. Furthermore, although (-)PPAP is structurally related to amphetamine, it neither produces nor antagonizes amphetamine-like stimulus effect in rats trained to discriminate 1 mg/kg of S(+)amphetamine from saline.

Topics: Animals; Catalysis; Dextroamphetamine; Discrimination, Psychological; Guinea Pigs; Haloperidol; In Vitro Techniques; Male; Piperidines; Propylamines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Topics: Animals; Benzomorphans; Binding, Competitive; Brain; Dynorphins; Female; Haloperidol; In Vitro Techniques; Mice; Morphinans; Peptide Fragments; Phencyclidine; Piperidines; Receptors, Opioid

Pre- and postsynaptic dopaminergic activities of a series of indolizidine and quinolizidine analogues of 3-(3-hydroxyphenyl)-N-(n-propyl)piperidine (3-PPP) have been studied. The pharmacological data have been interpreted in terms of a previously reported model for interactions with dopamine pre- and postsynaptic D2-receptors and molecular mechanics (MM2(85] calculated geometries and conformational energies. The model has been further developed with respect to the receptor topography in the vicinity of the nitrogen binding site. In particular, a novel spatial orientation of the important "propyl cleft" has been proposed. This cleft is suggested to be located mainly above a plane through the receptor-bound substrate. The biologically active agonist and antagonist conformations of the enantiomers of 3-PPP have been reinvestigated.

Topics: 3,4-Dihydroxyphenylacetic Acid; 5-Hydroxytryptophan; Animals; Dopamine Agents; Dopamine Antagonists; Male; Models, Structural; Molecular Conformation; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Structure-Activity Relationship

Medial and lateral neostriatum differ qualitatively in their sources of dopamine (DA) innervation and in their behavioural functions. The present study sought to ascertain whether these differences were reflected in their response to DA autoreceptor drugs. Fast cyclic voltammetry was used to measure stimulated DA release at medial and lateral carbon fibre microelectrodes. Metoclopramide and (+)-3-PPP were used as autoreceptor antagonist and agonist respectively. No differences were observed in the level of DA release evoked by stimulation or in the agonist and antagonist responses at medial or lateral sites. We therefore conclude that differences between medial and lateral striatal DA function are not evident at the autoreceptor level.

Topics: Animals; Corpus Striatum; Dopamine; Dopamine Agents; Dopamine Antagonists; Electrochemistry; Male; Metoclopramide; Piperidines; Rats; Rats, Inbred Strains

The (+) and (-) isomers of 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP) (2-32 mg/kg) were tested for their effects on the acoustic startle response in the rat and these effects were compared with those of apomorphine and haloperidol. Both startle amplitude and startle latency were recorded. (+)-3-PPP produced a dose-dependent prolongation of startle latency. No other significant effects of the 3-PPP isomers were observed. Apomorphine (0.75-3 mg/kg) produced a dose-dependent increase in startle amplitude concurrent with a dose-dependent prolongation of startle latency. Both these effects were blocked by haloperidol. Haloperidol by itself produced a significant decrease in startle amplitude at the highest dose used (1.6 mg/kg). These and other data suggest that activation of both dopamine D-1 and dopamine D-2 receptors is essential for the stimulatory effects of dopamine receptor agonists on the acoustic startle response in the rat.

Topics: Animals; Apomorphine; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Haloperidol; Male; Piperidines; Rats; Rats, Inbred Strains; Reflex, Startle; Stereoisomerism

Haloperidol and (+)-3-PPP, compounds with known affinity for the sigma-receptor, have been examined for their ability to reduce the excitatory actions of N-methyl-DL-aspartate (NMDLA), quisqualate and kainate on rat spinal neurons in-vivo. The actions of (-)-3-PPP were also tested. Haloperidol was injected intravenously whereas the 3-PPP enantiomers were administered by microelectrophoresis. Haloperidol had little effect on excitations evoked by NMDLA, quisqualate or kainate whereas both (+)- and (-)-3-PPP usually enhanced, non-selectively, responses to all three excitatory amino acid analogues. The results support suggestions that phencyclidine (PCP)-like compounds with affinity for both PCP and sigma-receptors reduce neuronal excitations mediated by the N-methyl-D-aspartate (NMDA) receptor via a selective effect at the PCP site.

Topics: Animals; Aspartic Acid; Haloperidol; In Vitro Techniques; Kainic Acid; Ligands; N-Methylaspartate; Neurons; Oxadiazoles; Piperidines; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Spinal Cord; Stereoisomerism

Umespirone (3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraon; KC9172) has been recently described as a potential antipsychotic/anxiolytic. In the present study the interaction of umespirone and several other typical and atypical psychotropics with the sigma and phencyclidine (PCP) receptor subtypes, in rat brain membranes, was investigated. Umespirone, haloperidol, chlorpromazine and buspirone, but not clozapine and diazepam, compete for the binding of the sigma-ligand, (+)[3H]-3-(3-hydroxy-phenyl)-N-1-(propyl) piperidine [(+)]3H-3-PPP]. The compounds do not compete for the binding of PCP-receptor ligands. Umespirone, buspirone and (+)-3-PPP, unlike haloperidol and chlorpromazine, inhibit (+)[3H]-3-PPP binding in a manner indicating the existence of high and low affinity states of the sigma receptor. 5'-Guanylylimidodiphosphate (Gpp(NH)p; 0.1mM) abolishes the high affinity binding component associated with the binding of umespirone, buspirone and (+)-3-PPP, but does not affect the affinities of haloperidol and chlorpromazine for the sigma receptor. These findings suggest that different coupling states of the sigma receptor may be associated with the binding of umespirone and buspirone compared to the binding of haloperidol and chlorpromazine.

Topics: Animals; Antipsychotic Agents; Brain Chemistry; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Chlorpromazine; Guanylyl Imidodiphosphate; Haloperidol; In Vitro Techniques; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Phencyclidine

The actions of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)3-PPP] on sympathetic neurons of the mouse isolated hypogastric ganglion were studied using the current clamp and single electrode voltage clamp techniques. In neurons studied under current clamp (+)3-PPP (10(-5) to 3 x 10(-4) M) evoked a concentration-dependent depolarization, which was fully reversible on washout of the drug. The depolarization was associated with an increase in membrane input resistance. At membrane potentials between -43 and -65 mV the amplitude of the depolarization was inversely related to the membrane potential. (+)3-PPP had no effect on membrane potential at potentials negative to -65 mV. The effect of (+)3-PPP on the M-current was studied in cells voltage clamped at -40 mV and stepped to -60 mV for 300-500 ms. The slow current relaxations seen during and after the voltage step are largely due to the M-current. (+)3-PPP (3 x 10(-5) to 3 x 10(-4) M) inhibited the M-current and produced an inward current in a concentration-dependent manner. (-)3-PPP (3 x 10(-5) M) had similar effects, but was less potent than (+)3-PPP. (+)3-PPP (3 x 10(-5) M) also inhibited the A-current and a calcium-dependent potassium current, but to a lesser degree than the M-current.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atropine; Carbazoles; Dopamine Agents; Evoked Potentials; Ganglia, Sympathetic; In Vitro Techniques; Male; Membrane Potentials; Mice; Mice, Inbred DBA; Neurons; Piperidines; Potassium Channels; Receptors, Opioid; Receptors, sigma; Sulpiride; Tetraethylammonium; Tetraethylammonium Compounds; Tetrodotoxin

We have characterized the actions of several sigma receptor ligands on the electrically evoked, neurogenic contractions of the mouse isolated vas deferens. (-)SKF 10,047 was significantly more potent than (+)SKF 10,047 in potentiating twitch contractions and was equipotent with (+)3-PPP. Rimcazole (1 and 3 microM) antagonised the potentiation induced by 100 microM (+)SKF 10,047 and, to a lesser extent, that induced by 30 microM (-)SKF 10,047 but increased that elicited by (+)3-PPP (30 microM). This apparent contradiction may arise from sigma agonists acting in this tissue at both sigma and non-sigma sites.

Topics: Animals; Antipsychotic Agents; Carbazoles; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; Muscle, Smooth; Phenazocine; Piperidines; Stereoisomerism; Vas Deferens

Topics: Adrenal Medulla; Animals; Biogenic Polyamines; Brain Chemistry; Cattle; Dopamine Agents; Guinea Pigs; In Vitro Techniques; Kinetics; Piperidines; Rats; Receptors, Opioid; Receptors, sigma

The active site of minaprine (3-(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine) was studied by means of receptor binding and its effect on acetylcholine (ACh) release in rat hippocampus. [3H]Minaprine binding to the hippocampal membrane was inhibited by minaprine, 4-aminopyridine (4-AP) and phencyclidine (PCP) dose-dependently, whereas it was not inhibited by L-glutamate (L-Glu), N-methyl-D-aspartate (NMDA), 2-amino-5-phosphonovalerate (APV), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP) or ketamine. [3H]PCP binding was inhibited by PCP and APV in an extensively washed hippocampal membrane. Minaprine, however, failed to inhibit the [3H]PCP binding. [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) binding was inhibited by L-Glu but not by minaprine. NMDA-evoked [3H]ACh release from the rat hippocampal slices was effectively inhibited by PCP. However, minaprine had no effect on the NMDA-evoked [3H]ACh release. Similar results were obtained from the study of [3H]ACh release in the striatum. These results suggest that minaprine exerts its action via the voltage-dependent K+ channel but not via the NMDA receptor-channel complex or sigma receptor.

Topics: 2-Amino-5-phosphonovalerate; Acetylcholine; Animals; Binding Sites; Hippocampus; Ketamine; Male; Membranes; N-Methylaspartate; Phencyclidine; Piperazines; Piperidines; Potassium Channels; Pyridazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

SL 82.0715 and ifenprodil are potent anti-ischemic agents, which are believed to be due to non-competitive antagonism of N-methyl-D-aspartate (NMDA). It has been proposed that SL 82.0715 and ifenprodil non-competitively antagonize the actions of NMDA by interacting as antagonists with a polyamine site associated with the NMDA/phencyclidine (PCP)/glycine complex. The present study demonstrates that the actions of SL 82.0715 and ifenprodil may also be due in part to an interaction with sigma binding sites, a property that is not shared with polyamines.

Topics: Animals; Binding, Competitive; Brain; Dopamine Agents; Kinetics; Male; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Tritium

Increase of serotoninergic system activity and blockade of dopaminergic system activity led to the change of T- and B-lymphocyte distribution in immunocompetent organs of non-immunized animals. Increase of suppressor cel number with Lyt2.2 phenotype was found in bone marrow of C57Bl/6 mice under activation of serotoninergic system (blockade of serotonin reuptake by sertraline) as well as under blockade of dopaminergic system by administration of dopamine autoreceptor agonist--3-PPP. Role of bone marrow in neuro-immunomodulation is discussed.

Topics: 1-Naphthylamine; Animals; Bone Marrow; Bone Marrow Cells; Dopamine Agents; Leukocyte Count; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neuroimmunomodulation; Neurotransmitter Agents; Piperidines; Serotonin Antagonists; Sertraline; T-Lymphocytes, Regulatory

Fluspirilene and GBR-12909, two compounds structurally similar to BMY-14802 and haloperidol, were assessed for their ability to interact with sigma receptors. Fluspirilene, an antipsychotic agent that interacts potently with dopamine receptors, inhibited the binding of [3H]-(+) 3-PPP (IC50 = 380 nM) more potently than rimcazole, a putative sigma antagonist that was tested clinically for antipsychotic activity. GBR-12909, a potent dopamine uptake blocker, also inhibited the binding of [3H]-(+) 3-PPP with an IC50 of 48 nM. However, other compounds that block the re-uptake of catecholamines, such as nomifensine, desipramine, imipramine, xylamine, benztropine and cocaine, were much weaker than GBR-12909 as sigma ligands. Thus, GBR-12909 and fluspirilene, compounds structurally similar to BMY-14802, are potent sigma ligands.

Topics: Animals; Antipsychotic Agents; Brain; Dopamine Agents; Fluspirilene; Male; Neurotransmitter Uptake Inhibitors; Piperazines; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

SKF 10,047 (N-allylnormetazocine) was found to be neuroprotective against glutamate-induced excitotoxicity in our model system of energy-stressed neurons which rapidly succumb to glutamate via N-methyl-D-aspartate (NMDA) receptor-mediated events. The 50% protective concentration (PC50) of the (+) and (-) enantiomers was 3.3 microM and 9 microM, respectively, against the toxic action of 100 microM glutamate. Protection by SKF 10,047 seemed to be mediated by the lower-affinity phencyclidine (PCP) binding site rather than the higher-affinity sigma-site since the potent sigma-ligand (+)-3-(3-hydroxyphenyl-N-1-propyl)piperidine [+)-3-PPP) did not protect at concentrations up to 2 mM. A reversed stereoselectivity was apparent for neuroprotection since (-)-3-PPP was weakly protective with a PC50 of 1.5 mM. These data suggest that energy-stressed rat cerebellar granule cells are a useful model for identifying neuroprotective agents, as shown by SKF 10,047.

Topics: Animals; Cell Survival; Cells, Cultured; Cerebellum; Dopamine Agents; Glutamates; Glutamic Acid; Neurons; Neurotoxins; Phenazocine; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine

Features of amnesia trace reactivation by activation of different links of dopaminergic system synaptic apparatus following the change of benzodiazepine, GABAA and GABAB receptors activity are found in experiments in mice. Diazepam pretreatment increases bupropion effectiveness, prolongs duration of enhanced passive avoidance response retrieval during D-1 and D-2 receptors activation by (+)3-PPP and decreases both characteristics under selective D-2 receptor activation by quinpirole. Activation of GABAA and GABAB receptors induces the attenuation of quinpirole effect and the duration of (+)3-PPP action.

Topics: Animals; Avoidance Learning; Bupropion; Diazepam; Dopamine Agents; Ergolines; Male; Mice; Mice, Inbred BALB C; Piperidines; Propiophenones; Quinpirole; Receptors, GABA-A

Topics: Animals; Binding Sites; Dextromethorphan; Guinea Pigs; Hallucinogens; Haloperidol; In Vitro Techniques; Kinetics; Levorphanol; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Topics: Animals; Binding, Competitive; Brain; Guinea Pigs; In Vitro Techniques; Kinetics; Pentazocine; Phenazocine; Piperidines; Receptors, Opioid; Receptors, sigma

Topics: Adrenal Medulla; Animals; Binding Sites; Binding, Competitive; Cattle; In Vitro Techniques; Membranes; Phencyclidine; Piperidines; Receptors, Opioid; Receptors, sigma

Topics: Animals; Brain; Guinea Pigs; In Vitro Techniques; Kinetics; Piperidines; Receptors, Opioid; Receptors, Opioid, delta

Haloperidol bound with equal affinity to sigma and dopamine D-2 receptors (KI = 2.8 nM). Compared to haloperidol, its carbonyl-reduced metabolite bound to sigma receptors with nearly equal affinity. However, reduced haloperidol bound to dopamine receptors with 85-fold lower affinity compared to haloperidol (KI = 239 nM). The chlorophenyl-hydroxy-piperidine metabolite of haloperidol lacked affinity for dopamine receptors, but bound with moderate affinity to sigma receptors (KI = 326 nM). The carboxylic acid metabolite lacked affinity for either receptor. Like haloperidol, (+)-pentazocine, and 1,3-di-o-tolylguanidine, reduced haloperidol potently inhibited the phosphoinositide response to muscarinic agonists in rat brain synaptoneurosomes, an assay which monitors sigma agonist activity. This metabolite also produced a dystonic alteration of head position in rats when microinjected into the red nucleus. However, unlike observations with haloperidol and other sigma ligands, this effect was associated with pathological changes in the red nucleus. Therefore, it cannot be attributed to sigma receptor interactions with certainty. These findings suggest that administration of haloperidol results initially in effects mediated through both dopamine and sigma receptors, but as metabolism proceeds the sigma actions would be expected to decline at a significantly slower rate than the dopaminergic actions.

Topics: Animals; Brain; Haloperidol; In Vitro Techniques; Male; Motor Activity; Parasympathetic Nervous System; Pentazocine; Phosphatidylinositols; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Opioid; Receptors, sigma

Phencyclidine (PCP) binds with high affinity to two receptors in rat brain--the PCP receptor and the Sigma receptor. Although both receptors are present prenatally, and their number increases postnatally, their rate of increase, compared to the increase in brain protein, is quite different, yielding distinct ontogenic profiles. Thus, PCP receptors are present on prenatal day 2 and show a further 15-fold increase by postnatal day 28. In contrast, Sigma receptors are present at their highest density during the perinatal period, and decline thereafter. The Kd of the PCP receptor for TCP remains constant throughout development, whereas the Kd of the Sigma receptor for (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine decreases 40% postnatally. On postnatal day 6, both PCP and Sigma receptors display a pharmacological profile similar to that observed in adult animals.

Topics: Aging; Animals; Brain; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

The functional effects of sigma and PCP receptor ligands were examined in the perfused rat tail artery. The following ligands were studied: haloperidol; (+)-3-PPP [(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine]; (+-)-BMY 14802 [(+-)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol]; DTG [1,3-di-orthotolyl-guanidine]; rimcazole (BW 234U) [cis-9-[3-(3,5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride]; (+)-SKF 10047 [(+)-N-allyl-N-normetazocine]; TCP, [1-[1-(2-thienyl)cyclohexyl] piperidine]; and MK 801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]. (+)-3-PPP, (+)-SKF 10047, MK 801 and TCP potentiated contractile responses to norepinephrine, an effect which was blocked by cocaine implying an action of these agents on monoamine uptake. In the presence of cocaine an additional postjunctional inhibitory action of (+)-3-PPP and (+)SKF 10047 on norepinephrine-induced contractile responses was unveiled. In contrast, haloperidol, (+/-)-BMY 14802, rimcazole and DTG inhibited contractile responses to norepinephrine. Haloperidol, (+/-)-BMY 14802 and (+)-SKF 10047 (+ uptake blockade) also inhibited contractile responses to serotonin. The order of potency for inhibition of norepinephrine-induced contractions was haloperidol greater than (+/-)-BMY 14802 greater than (+)-3-PPP greater than rimcazole greater than (+)-SKF 10047 (+ uptake blockade) greater than DTG. These studies demonstrate the lack of selectivity of many sigma and PCP ligands, significant effects on norepinephrine uptake, as well as the potential utility of the rat tail artery to explore the functional properties of these ligands.

Topics: Animals; Cocaine; Desoxycorticosterone; Haloperidol; Male; Norepinephrine; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Serotonin; Vasoconstriction

Three (+)-benzomorphans that bind to sigma receptors produced dystonia in a dose-related manner when microinjected into the red nucleus of rats. Two lines of evidence suggest that these effects were related to the sigma-binding properties of the compounds. First, the behavioral potency of the (+)-benzomorphans and other active sigma compounds correlated highly with their affinities for [3H]1,3-di-o-tolylguanidine-labelled sigma receptors in the rat brain (r = .94). Second, similar intrarubral injections of non-sigma ligands were without effect: various vehicles, a structurally related (+)-opiate with no affinity for sigma receptors, and selective dopaminergic and serotonergic compounds failed to significantly alter the normal posture of rats. The only ligand in this study that binds with high affinity to sigma receptors, but failed to elicit torsional head movements was (+)-[3-(3-hydroxyphenyl)-N-(1-propyl)piperidine] [(+)-3PPP], a ligand with mixed activity at sigma and dopamine receptors. Since (+)-3PPP failed to produce an effect on its own and also failed to attenuate the dystonia produced by another sigma ligand (DTG), it may interact with a non-sigma mechanism or with a different sigma receptor type from the other compounds.

Topics: Animals; Benzomorphans; Drug Interactions; Dystonia; Male; Microinjections; Morphinans; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Red Nucleus

Several phencyclidine (PCP) and sigma receptor ligands were examined for their effects on a single trial passive avoidance test in rats. Rats were administered the PCP receptor ligands (+)-5-methyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-im ine maleate (MK-801), PCP, ketamine or the sigma receptor ligands (+)-N-allylnormetazocine ((+)-NANM), (+)-pentazocine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP) or 1,3-Di(2-[5-3H]tolyl)guanidine (DTG) subcutaneously prior to acquisition of the passive avoidance response, and tested 24 h later for retention. MK-801 (0.1-0.3 mg/kg), PCP (0.54-1.7 mg/kg), ketamine (10.0-17.2 mg/kg) and (+)-N-allylnormetazocine (5.4-10.0 mg/kg) produced significant memory deficits. (+)-Pentazocine (54 mg/kg) and (+)-3-PPP (30 mg/kg) also produced retention deficits, but at significantly higher doses. DTG (0.3-3.0 mg/kg s.c.) had no effect on retention. There was a positive correlation between production of retention deficits and the compounds' PCP receptor binding affinity. The results suggest that the sigma receptor is not involved in learning the passive avoidance response.

Topics: Animals; Avoidance Learning; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ketamine; Ligands; Male; Memory; Pentazocine; Phenazocine; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Phencyclidine; Retention, Psychology

Computer-assisted analysis of self- and cross-displacement studies between dextromethorphan (DM) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine ((+)-3-PPP) demonstrated in the rat brain the existence of two high-affinity and one low-affinity binding site for each ligand. One high-affinity site is the common DM1/sigma 1 site, the affinity of which is allosterically increased 4 to 5-fold by 10 microM ropizine. The Kd values of the DM1/sigma 1 for DM and (+)-3-PPP are 17 and 11 nM respectively. DM binds to the second high-affinity site (R2) with a Kd of 15 nM; this site has low affinity for (+)-3-PPP. Conversely, (+)-3-PPP binds with high affinity (Kd 53 nM) to another site (R3), that has low-affinity for DM. The Bmax of the common DM1/sigma 1 site in the rat is about ten times smaller than that in the guinea pig. Thus, extreme caution should be exercised in extrapolating from one species to another. Since DM and most sigma ligands bind to more than one site, not all of which are shared, it is important not to attribute the complex pharmacological effects of these ligands to a single hypothetical receptor.

Topics: Allosteric Site; Animals; Binding, Competitive; Brain; Dextromethorphan; Electronic Data Processing; In Vitro Techniques; Kinetics; Models, Biological; Pentazocine; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Tritium

Functional effects of the sigma ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), were explored in perfused rat tail and rabbit ear arteries in vitro. In the rat tail artery (+)-3PPP inhibited contractile responses to adrenergic nerve stimulation, an effect which was reversed to potentiation by the dopamine D2 receptor antagonist sulpiride. In the rabbit ear artery, however, (+)-3PPP potentiated contractile responses to nerve stimulation, an effect which was unchanged by sulpiride. In the rat tail artery, blockade of norepinephrine uptake by cocaine and deoxycorticosterone in the presence of sulpiride revealed two additional actions of (+)-3PPP. First, an inhibitory action on the monoamine uptake site was confirmed by direct measurement of [3H]norepinephrine accumulation. Second, at higher concentrations, an action to inhibit contractile responses to adrenergic nerve stimulation was manifested at a still unidentified site. These studies demonstrate that the observed functional effect of (+)-3PPP results from its combined actions on three individual sites with the net effect dependent on the relative densities of these different receptor sites in each type of vessel.

Topics: Animals; Arteries; Cocaine; Desoxycorticosterone; Ear; Male; Muscle Contraction; Muscle, Smooth, Vascular; Neuromuscular Junction; Norepinephrine; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Stimulation, Chemical; Sulpiride; Tail

Topics: Allosteric Regulation; Animals; Autoradiography; Binding Sites; Brain; Dextromethorphan; Guinea Pigs; In Vitro Techniques; Levorphanol; Piperazines; Piperidines; Tissue Distribution

Equilibrium binding analysis demonstrated that (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]3-PPP] binds in guinea pig brain homogenates to high and low affinity sites with Kd values of 25 nM and 0.9 microM, respectively. Competition studies with dextromethorphan (DM) site ligands and other drugs against (+)-[3H]3-PPP demonstrated that their Ki values and rank order of potency are identical to those found previously against [3H] DM. Most significant, ropizine produced a concentration-dependent increase in the binding of (+)-[3H]3-PPP, with an inhibitory component at high concentrations, as described previously for [3H]DM. Similarly, phenytoin increased the binding of (+)-[3H]3-PPP in the same fashion as that of [3H]DM. Computer-assisted analysis of equilibrium binding of (+)-[3H]3-PPP in the presence of 10 microM ropizine demonstrated that the binding increase produced is due to a 3-fold increase in the affinity for (+)-[3H]3-PPP. These results, and our previous finding that sigma ligands inhibit [3H] DM binding with a rank order of potency similar to that for sites labeled with (+)-[3H]3-PPP or (+)-[3H]SKF10,047 strongly suggest that sigma ligands bind to the high affinity DM site. These findings, and the inability of DM and other antitussives to produce psychotomimetic side effects, suggest that the high affinity DM sites can mediate only the nonpsychotomimetic effects of sigma ligands. However, further studies are necessary to determine the physiological role and therapeutic potential of the DM high affinity sites.

Topics: Allosteric Regulation; Animals; Binding Sites; Binding, Competitive; Dextromethorphan; Guinea Pigs; In Vitro Techniques; Levorphanol; Phenytoin; Piperazines; Piperidines; Receptors, Opioid; Receptors, sigma

We have used a variety of selective radioligands to identify and localize sigma- and phencyclidine (PCP)-binding sites in rat endocrine organs. [3H]Haloperidol-labeled sigma-receptors were identified in membrane homogenates of rat pituitary, adrenal, testis, and ovary which had kinetic and pharmacological characteristics similar to those of the well characterized sigma-receptors in rat cerebellum. The highest density of sigma-receptors was present in the ovary, with progressively lower densities present in the testis, pituitary, adrenal, and cerebellum, respectively. In autoradiographic studies, sigma-receptors [labeled with d-3-(3-hydroxyphenyl)N-(1-propyl-2,3-[3H]piperidine or [3H]1,3-di-(2-tolyl)guanidine] were discretely localized within the endocrine tissues. In the pituitary, the highest density of sigma-receptors was found in the anterior lobe. In the adrenal, sigma-receptors were localized primarily in the cortex. In the testis, sigma-receptors were present in highest concentrations in the ductuli efferentes and ductus epididymis; lower densities of binding sites were present in the seminiferous tubules, and no binding was seen in the interstitial tissue. In the ovary, sigma-receptors were localized in high density in the maturing follicles, and lower densities were present in resting follicles. After hypophysectomy, there were relative increases in the densities of sigma receptors in the remaining tissue in the adrenal gland and testis. In contrast, hypophysectomy resulted in a marked depletion of sigma-binding sites in the ovary. The data from hypophysectomized rats indicate that the highest densities of sigma-receptors in the ovary are localized to (LH-dependent) maturing follicles, while sigma-binding sites in adrenal and testis are localized to cells that are not dependent on trophic maintenance by the pituitary. In contrast, high affinity PCP receptors were not detected in pituitary, adrenal, testis, or ovary either by homogenate binding studies with 3,4-[3H]N-[1-(2-thienyl)cyclohexyl]piperidine or in vitro autoradiography using 3,4-[3H]N-[1-(2-thienyl)cyclohexyl]piperidine and d-[3H]5-methyl-10,11-dihydro-5H-dibenzo-[a,d] + cyclohepten-5,10-imine. In summary, the data suggest that the reported endocrine effects of PCP and the prototypic sigma-receptor agonist N-allylnormetazocine are probably mediated either through direct action on sigma-receptors in the pituitary and/or target endocrine organs or by actions on sigma- and/or PCP receptors

Topics: Adrenal Glands; Animals; Autoradiography; Brain Chemistry; Cell Membrane; Dibenzocycloheptenes; Dizocilpine Maleate; Female; Haloperidol; Hypophysectomy; Male; Ovary; Phencyclidine; Piperidines; Pituitary Gland; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Testis; Tissue Distribution

Pretreatment of guinea pig brain membranes with 1-[1-(3-isothiocyanatophenyl)cyclohexyl]piperidine (Metaphit) caused irreversible and differential inhibition of ligand binding to sigma (sigma) receptors. The concentration of Metaphit required to produce 50% inhibition of binding of [3H]1,3-di-o-tolylguanidine ([3H]DTG), [3H](+)-3-(3-hydroxy-phenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP), and [3H](+)-N-allylnormetazocine ([3H](+)-SKF 10,047) to sigma receptors was 2, 10 and 50 microM, respectively. This compares to a value of 10 microM for inhibition of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) binding to phencyclidine (PCP) receptors. While Metaphit was an irreversible, non-competitive inhibitor at PCP receptors, this compound produced irreversible, competitive inhibition at sigma receptors.

Topics: Acylation; Animals; Behavior, Animal; Brain Chemistry; Electrophysiology; Guinea Pigs; In Vitro Techniques; Membranes; Phencyclidine; Piperidines; Rats; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Phencyclidine

Irradiation of rat brain membranes with light of 254 nm, a treatment which modifies ultra-violet absorbing residues in proteins, decreased binding of both [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([ 3H](+)-3-PPP) and [3H]1,3-di-o-tolylguanidine ([3H]DTG) to sigma receptors. For [3H](+)-3-PPP, this was due to a decreased Bmax. In contrast, irradiation markedly increased binding of [3H](+)-N-allylnormetazocine ([3H](+)-SKF 10,047) due to a decrease in the Kd. Both unlabeled DTG and haloperidol were competitive inhibitors of [3H](+)-3-PPP binding to untreated membranes, causing an increase in the Kd and no change in the Bmax. The benzomorphans, (+)-SKF 10,047 and (+)-pentazocine, were uncompetitive inhibitors, causing a decrease in both the Kd and Bmax for [3H](+)-3-PPP. Finally, the ability of DTG and (+)-3-PPP to inhibit binding of [3H](+)-SKF 10,047 was markedly reduced by ultra-violet irradiation, whereas irradiation had little effect on the potency of unlabeled (+)-SKF 10,047 and (+)-pentazocine. These data suggest that sigma-related (+)-benzomorphans and non-benzomorphans interact either with distinct, allosterically coupled sites on the same sigma receptor macromolecule or with different populations of sigma receptor types.

Topics: Animals; Brain; In Vitro Techniques; Male; Membranes; Models, Biological; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Synaptosomes; Ultraviolet Rays

Long-term (24 h) pretreatment of cultured rat vascular smooth muscle cells with 100 nM angiotensin and 1 microM vasopressin induced a marked reduction of the maximal binding capacity of atrial natriuretic peptide (ANP) receptors in a fashion similar to that induced by phorbol ester. The down-regulation of the receptors induced by vasoconstrictors and phorbol ester was concomitantly associated with an attenuation of ANP-stimulated cGMP accumulation. These data suggest that vasoconstrictor-induced activation of protein kinase C is involved in the mechanism of heterologous down-regulation of vascular ANP receptors.

Topics: Angiotensin II; Animals; Arginine Vasopressin; Cyclic GMP; Humans; In Vitro Techniques; Iodine Radioisotopes; Muscle, Smooth, Vascular; Piperidines; Rats; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Tetradecanoylphorbol Acetate; Vasoconstrictor Agents

These experiments were designed to compare phencyclidine (PCP) and sigma (sigma) receptor binding sites in the rat spinal cord by using receptor binding and autoradiographic techniques. Binding sites for 3H-TCP (3H-1-[1-(2-thienyl)cyclohexy]piperidine), a PCP receptor agonist, and (+)3H-3-PPP (3H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine), a sigma receptor agonist, in the rat spinal cord were shown to represent two populations of recognition sites. Inhibition studies revealed that ligands with high affinity for the PCP receptor (MK-801 and PCP) were potent competitors at 3H-TCP binding sites whereas the putative sigma receptor ligands (+/-)pentazocine and haloperidol were potent competitors at (+)3H-3-PPP binding sites. The autoradiographic distribution of 3H-TCP and (+)3H-3-PPP binding sites in adjacent sections of rat spinal cord demonstrated the occurrence of two distinct populations of binding sites. 3H-TCP binding sites were localized primarily in laminae I and II in cervical and thoracic spinal segments. Binding sites in lamina I decreased in density along a rostral to caudal gradient in the spinal cord. The highest density of (+)3H-3-PPP binding sites was found in the ventral horn (lamina VIII and IX) and over perikarya in dorsal root ganglia. Significantly elevated densities of (+)3H-3-PPP binding sites were also found in lamina X within thoracic and lumbar segments and in the intermediolateral cell column. The results of the present study show that PCP and sigma receptor binding sites are differentially localized in the rat spinal cord and suggest that separate binding sites exist for PCP and sigma agonists.

Topics: Animals; Autoradiography; Binding, Competitive; Ganglia, Spinal; Male; Narcotic Antagonists; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Spinal Cord

Topics: 1-Naphthylamine; Animals; Binding, Competitive; Brain Chemistry; In Vitro Techniques; Naphthalenes; Piperidines; Rats; Receptors, Opioid; Receptors, Opioid, delta; Serotonin Antagonists; Sertraline

The effects of 1) the phencyclidine receptor ligand TCP, 2) sigma receptor ligands (+)3-PPP and DTG, and 3) N-methyl-D-aspartate receptor blockers MK-801 and dextrorphan were determined on a brainstem mechanism which controls the termination of the inspiratory phase of the breathing cycle. Inspiratory bursts were recorded from the phrenic nerve in decerebrate paralyzed cats ventilated by means of a phrenic driven servoventilator. The central mechanism which terminates inspiration was tested by withholding lung inflation, thus suppressing the contribution of the vagal feedback from the lungs to inspiratory termination. TCP increased the duration of test inspiration (tTi) by 17% at 0.03 mg/kg and by 14-fold (from 1.6 to 23 s) at 1 mg/kg. With dextrorphan, tTi was significantly increased at 3 mg/kg. In contrast, (+)3-PPP and DTG did not increase tTi at doses up to 10 mg/kg, although MK-801 (0.03 mg/kg), given after the sigma ligands, increased tTi by 59-90%. It is concluded that phencyclidine but not sigma receptor ligands block the central mechanism which terminates inspiration and that the likely site of action is the NMDA receptor complex.

Topics: Animals; Brain Stem; Cats; Decerebrate State; Dextrorphan; Dibenzocycloheptenes; Dizocilpine Maleate; Guanidines; Phencyclidine; Phrenic Nerve; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Respiration

The sigma receptor, which is labeled with (+)-[3H]3-(3-hydroxyphenyl)-N- 1-(propyl)piperidine [(+)-[3H]3-PPP], is a site that binds several psychotomimetic opiate benzomorphans and certain antipsychotics, such as haloperidol. In order to elucidate the mechanisms involved in sigma receptor ligand binding, equilibrium binding analysis and kinetics of association and dissociation of the relatively selective sigma receptor ligand (+)-[3H]3-PPP were determined in rat brain membranes in the absence and presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. In the absence of Gpp(NH)p, (+)-3-PPP, cyclazocine, pentazocine, and (+)-SKF 10047 bind to high and low affinity sites (KH = 1.3-7.5 nM; KL = 84-500 nM), as determined by computer assisted analysis of the inhibition of (+)-[3H]3-PPP binding by the sigma ligands. The antipsychotics haloperidol and chlorpromazine inhibit (+)-[3H]3-PPP binding in a manner indicating interaction with a single state of the receptor. Gpp(NH)p (0.1 mM) abolished the high affinity binding component of the sigma agonist-like compounds tested but had no effect on the affinities of the antipsychotics for the receptor. Gpp(NH)p decreased the association rate of (+)-[3H]3-PPP binding 5-fold and also converted the biexponential dissociation kinetics of the ligand, observed in the absence of Gpp(NH)p, to a rapid monophasic dissociation process. Pretreatment of membranes with N-ethylmaleimide and pertussis toxin inhibited (+)-[3H]3-PPP binding and abolished the effect of Gpp(NH)p on the sigma ligand binding. These findings indicate of the sigma receptor is capable of existing in two discrete states, having high and low affinity for sigma agonist-like drugs. The regulation of the high affinity binding state by GTP-binding protein-modifying agents suggests its coupling to GTP-binding protein(s).

Topics: Animals; Binding, Competitive; Chlorpromazine; Ethylmaleimide; GTP-Binding Proteins; Guanylyl Imidodiphosphate; In Vitro Techniques; Kinetics; Pentazocine; Pertussis Toxin; Piperidines; Rats; Receptors, Opioid; Receptors, sigma; Virulence Factors, Bordetella

1. The effects of several ligands which interact with the sigma-binding site were studied on the electrically-evoked (0.1 Hz) neurogenic twitch contractions of the mouse isolated vas deferens. 2. (+)-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine [+)-3-PPP) (10(-8) - 10(-5) M), inhibited the neurogenic twitch contractions. This inhibitory action was unaffected by naloxone (10(-6)M), idazoxan (10(-6)M), cocaine (10(-6)M) or tyramine (10(-4)-3 x 10(-4)M), but was abolished by the dopamine D2-antagonist, sulpiride (10(-6)M). Therefore, in order to study the potentiating actions of sigma ligands, sulpiride (10(-6)M) was used to prevent any inhibitory actions mediated via dopamine D2-receptors. 3. In the presence of sulpiride (10(-6)M), haloperidol (10(-6)-10(-5)M), (+)-3-PPP (10(-6)-3 x 10(-4) M) and (+)-N-allyl-N-normetazocine [+)-SKF 10,047) (10(-5)-10(-4)M) each reversibly potentiated the neurogenic twitch contractions in a concentration-dependent manner. The rank order of potency was haloperidol greater than (+)-3-PPP greater than (+)-SKF 10,047. 4. The stereoisomers of 3-PPP displayed stereoselectivity with (+)-3-PPP being more potent than (-)-3-PPP. 5. At a concentration that did not potentiate the twitch contractions, (3 x 10(-7)M), haloperidol did not antagonize the potentiating action of (+)-3-PPP (3 x 10(-5)M). 6. 1,3-Di-O-tolyguanidine (DTG) (10(-8)-10(-5)M) had no effect on the amplitude of twitch contractions and did not affect the potentiating action of (+)-3-PPP (10(-5)-3 x 10(-5)M). 7. It is concluded that a-ligands potentiate neurogenic twitch contractions of the mouse isolated vas deferens via a site that is different from the central sigma-binding site.

Topics: Animals; Clonidine; Electric Stimulation; In Vitro Techniques; Male; Mice; Mice, Inbred DBA; Muscle Contraction; Muscle, Smooth; Naloxone; Piperidines; Receptors, Opioid; Receptors, sigma; Vas Deferens

Binding of i.v. administered (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H]3-PPP) in the brain of intact mice is antagonized dose responsively by sigma receptor ligands. The correlation of potencies for inhibition of binding in vivo and in vitro indicates that sigma receptors in mouse brain are labeled in vivo by i.v. [3H]3-PPP. 3-PPPP, the N-phenylpropyl derivative of norpropyl-3-PPP exhibits very high affinity for sigma receptors in vitro and in vivo.

Topics: Animals; Brain Chemistry; Dopamine Agents; Dose-Response Relationship, Drug; Mice; Piperidines; Rats; Receptors, Opioid; Receptors, Opioid, delta; Time Factors

Extracellular recording techniques were used to study the effects of the selective sigma receptor agonist (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and selective sigma receptor antagonist BMY 14802 on dopamine (DA) neurons of the substantia nigra. Intravenous administration of (+)-3-PPP produced a dose-dependent inhibition of DA neuron firing rate. Complete inhibition of DA neurons produced by (+)-3-PPP could be completely reversed by administration of BMY 14802. Also, pretreatment with BMY 14802 shifted the (+)-3-PPP dose response curve to the right. These data demonstrate a relationship of the sigma receptor with the dopamine system and further suggest a model system to study agonist/antagonist interactions of sigma ligands.

Topics: Animals; Antipsychotic Agents; Dopamine; In Vitro Techniques; Male; Membranes; Microelectrodes; Narcotic Antagonists; Narcotics; Neurons; Piperidines; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Spiperone

Tritium-labeled (+)-pentazocine ([3H]-1b) of specific activity 26.6 Ci/mmol was synthesized in 3 steps starting with (+)-normetazocine (2) of defined optical purity. [3H]-1b has been characterized as a highly selective ligand for labeling of sigma receptors. Competition data revealed that [3H]-1b could be displaced from guinea pig brain membrane preparations with a number of commonly used sigma receptor ligands. [3H]-1b exhibited saturable, enantioselective binding with a Kd of 5.13 +/- 0.97 nM and a Bmax of 1146 +/- 122 fmol/mg protein. Phencyclidine (PCP) displaced [3H]-1b with low affinity while MK-801 was inactive, thus indicating insignificant activity at the PCP-binding site; apomorphine failed to displace [3H]-1b indicating lack of dopamine receptor cross-reactivity. Since the affinity of [3H]-1b is about 6 times that of the two commonly employed sigma ligands ((+)-3-[3H]PPP and [3H]DTG) and since it is more selective for sigma receptors than the benzomorphan [3H]SKF-10,047, it represents the first example of a highly selective benzomorphan based sigma receptor ligand. [3H]-1b should prove useful for further study of the structure and function of sigma receptors.

Topics: Animals; Apomorphine; Binding, Competitive; Brain; Cell Membrane; Chemical Phenomena; Chemistry; Dopamine Agents; Guanidines; Guinea Pigs; Hydroxides; Molecular Structure; Pentazocine; Phencyclidine; Piperidines; Potassium; Potassium Compounds; Receptors, Dopamine; Receptors, Opioid; Receptors, sigma; Tritium

The effects exerted by the partial dopamine (DA) receptor agonists (--)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(--)-3-PPP] and transdihydrolisuride (TDHL) on prolactin secretion were compared in male and female rats. Both agents were found to increase prolactin release more than tenfold in female rats. In male rats, in contrast, (--)-3-PPP and TDHL were either without effect or decreased prolactin secretion. It is suggested that this sexually differentiated prolactin response to partial DA agonists reflects a lower responsiveness of lactotroph DA receptors in female than in male rats.

Topics: Animals; Dopamine Agents; Dose-Response Relationship, Drug; Female; Male; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Sex Factors

Phencyclidine binds with high affinity to both PCP and sigma receptors. We investigated whether the clonal cell line PC12 expressed either of these receptors, and found that these cells contain a haloperidol-sensitive (+)-[3H]3-PPP binding site with a KD of 56 nM, but no PCP binding sites. The (+)3-PPP binding sites in PC12 cells displayed a reversed stereoselectivity for the benzomorphan opiates compared to CNS sigma receptors. Neither nerve growth factor nor sodium butyrate treatment affected the expression of either (+)-3-PPP or TCP binding sites in PC12 cells.

Topics: Adrenal Gland Neoplasms; Animals; Cell Line; Cell Membrane; Dopamine Agents; Humans; Pheochromocytoma; Piperidines; Radioligand Assay; Receptors, Drug

Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic L-amino acid decarboxylase by means of NSD-1015, 100 mg kg-1 intraperitoneally. In animals treated with reserpine, 5 mg kg-1 subcutaneously -18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT1A receptor agonist 8-OH-DPAT, 0.15-2.4 mumol kg-1, whereas the partial dopamine D2 receptor agonist (-)3-PPP, 2.5-10.0 mumol kg-1, or the full dopamine D2 receptor agonist quinpirole, 0.05-0.8 mumol kg-1, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mumol kg-1, but not by (-)pindolol, 8 mumol kg-1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (-)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Corpus Striatum; Depression, Chemical; Dihydroxyphenylalanine; Dopamine; Ergolines; Hydrazines; Limbic System; Male; Naphthalenes; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Reserpine; Serotonin; Tetrahydronaphthalenes; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase

Extracellular single unit recording techniques were used to study the effects of selective sigma-receptor agonist [(+)-3-PPP, (+)-pentazocine, and DTG] and selective sigma-receptor antagonists (BMY 14802 and Rimcazole) on dopamine neurons of the substantia nigra. Intravenous (IV) administration of sigma agonists decreased, whereas IV administration of the sigma antagonist BMY-14802 increased the firing rate of dopamine neurons. The other sigma antagonist Rimcazole produced inconsistent changes in dopamine unit activity. These data, in conjunction with anatomic data suggesting sigma receptor localization on dopamine neurons in the substantia nigra (Gundlach et al: J Neurosci 6:1757-1770, 1986; Graybiel et al: Soc Neurosci Abstr 13:28, 1987) demonstrate a relationship of the sigma receptor with the dopamine system and further suggest a model system to study agonist-antagonist interactions of sigma ligands. The selective phencyclidine (PCP) agonist MK-801 was equipotent to PCP in regard to stimulatory properties on dopamine neurons. However, the relative potencies do not correspond to their relative binding affinities, suggesting that non-PCP-receptor properties may mediate this effect.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Antipsychotic Agents; Carbazoles; Cell Membrane; Dibenzocycloheptenes; Dizocilpine Maleate; Dopamine; Dopamine Agents; Male; Neurons; Pentazocine; Phencyclidine; Piperidines; Pyrimidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Substantia Nigra

SND 919 [S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole) is expected to have a potent and selective dopamine D2-receptor agonistic activity. From this information, the present study was performed to investigate effects of SND 919 on yawning behavior and prolactin secretion in rats. Subcutaneous injections of SND 919 (25-500 micrograms/kg, s.c.) elicited yawning responses. Its dose-response curve was bell-shaped with maximal effects at a dose of 100 micrograms/kg. Yawning behavior was also evoked by the putative dopamine autoreceptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]azepine) (B-HT 920) (5-100 micrograms/kg, s.c.) and (+)-3-PPP ((+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine) (5-15 mg/kg, s.c.). The yawning induced by SND 919 (100 micrograms/kg, s.c.) as well as talipexole (25 micrograms/kg, s.c.) was inhibited by pretreatment with dopamine D2-receptor antagonists such as spiperone (0.5 mg/kg, i.p.) and YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-met hylamino- benzamide) (0.1 mg/kg, i.p.), or the muscarinic receptor antagonist, scopolamine (0.5 mg/kg, i.p.). However, the yawning was not affected by the dopamine D1-receptor antagonist, SCH 23390 (R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o l) (0.5 mg/kg, i.p.). Stereotypy such as licking and biting was not observed following the administration of SND 919, talipexole and (+)-3-PPP. Administration of SND 919, talipexole or (+)-3-PPP in respective yawn-inducing doses caused a reduction in both the basal prolactin levels and the alpha-methyl-p-tyrosine-induced hyperprolactinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: alpha-Methyltyrosine; Animals; Azepines; Behavior, Animal; Benzothiazoles; Dopamine Agents; Male; Methyltyrosines; Piperidines; Pramipexole; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Thiazoles; Yawning

The present study was conducted to determine whether or not two behavioral characteristics of individually-housed mice, hyperactivity in a novel environment and intermale fighting, are attenuated by the dopamine (DA) agonists, apomorphine, (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP). Autoreceptor-activating doses of these drugs which reduced spontaneous activity in a novel environment did not inhibit spontaneous fighting with conspecific olfactory bulbectomized males. Individually-housed mice were more active in a novel environment and showed a significant reduction of activity at lower doses of apomorphine, (+)- and (-)-3-PPP than group-housed mice. However, the ED50's for the inhibition of spontaneous activity in a novel environment in group- and individually-housed mice were similar: apomorphine, 0.02 vs. 0.012 mg/kg, SC; (+)-3-PPP, 0.50 vs. 0.51 mg/kg, SC; and (-)-3-PPP, 1.0 vs. 0.56 mg/kg, SC, for group- and individually-housed mice respectively. A significant proportion of individually-housed mice, but not group-housed mice, displayed catalepsy in response to high doses of (-)-3-PPP. These data suggest that DA autoreceptor agonists can modulate the hyperactivity syndrome but not spontaneous fighting behavior in individually-housed mice.

Topics: Aggression; Agonistic Behavior; Animals; Apomorphine; Catalepsy; Dopamine Agents; Dose-Response Relationship, Drug; Housing, Animal; Male; Mice; Motor Activity; Piperidines; Social Isolation; Stereoisomerism

Neuroleptic drugs increase the biosynthesis and release of opioid peptides from the myenteric plexus of guinea-pig ileum. In the present work, the involvement of dopamine receptors or alpha-adrenoceptors in the release of opioids from the myenteric plexus of guinea-pig was investigated. Acute or chronic treatment with prazosin, an alpha 1-blocking drug, produced no changes in the release of these peptides. Release was also unchanged after acute or chronic treatment with the alpha 2-blocking drug yohimbine. However, treatment with domperidone, a selective dopamine receptor antagonist, resulted in an increase in the release of opioids, as did treatment with (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), a dopamine autoreceptor stimulant. It is concluded that the effect of neuroleptics on the release of opioids from myenteric plexus is due to the blockade of dopamine receptors, and that interruption of dopaminergic transmission produces an increase in opioid release at this level.

Topics: Adrenergic alpha-Antagonists; Animals; Domperidone; Dopamine; Endorphins; Female; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle, Smooth; Myenteric Plexus; Naloxone; Norepinephrine; Piperidines; Prazosin; Receptors, Dopamine; Yohimbine

The effects of three compounds with high affinity for the haloperidol-sensitive alpha-binding site were studied with intracellular recordings in the vitro neuronal preparations of the rat locus ceruleus, rat dorsal raphe and the guinea pig submucous plexus. Both (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] and 1,3-di-o-tolylguanidine (DTG) inhibited the hyperpolarization induced by a ligand-activated potassium conductance. In the locus ceruleus, (+)-3-PPP and DTG produced a maximal 40 to 45% inhibition of the [Met5]enkephalin hyperpolarization, and had EC50 values of 6.6 and 2.2 microM, respectively. In the submucous plexus, the two compounds had a similar action on the alpha-2 adrenoceptor agonist UK14304 hyperpolarization, producing a maximal 50% inhibition with EC50 values of 140 and 32 nM, respectively. In addition, DTG inhibited the alpha-2-mediated inhibitory postsynaptic potential in both preparations. In contrast, (+)-3-PPP increased and prolonged the inhibitory postsynaptic potential. This action is qualitatively similar to the actions of cocaine on locus ceruleus and submucous plexus neurons. Haloperidol (1-10 microM) shared none of these actions. It is concluded that DTG and (+)-3-PPP are inhibitors of the opiate and alpha-2-mediated hyperpolarization at a postreceptor site, possibly the potassium channel. In addition, (+)-3-PPP, but not DTG, inhibits norepinephrine reuptake. None of these effects appear to be related to the sigma -binding site, because haloperidol acted as neither an agonist nor an antagonist.

Topics: Animals; Brimonidine Tartrate; Dopamine Agents; Enkephalin, Methionine; Guanidines; Haloperidol; Male; Membrane Potentials; Neurons; Norepinephrine; Piperidines; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Serotonin

The behavioural and ECoG spectrum power effects of agonists at dopamine D2 autoreceptors, both after systemic or intracerebral administration, were studied in rats. It was shown that the bilateral injection of apomorphine or (+) 3PPP (0.1, 0.5 and 1.0 nmol for each compound) into the ventral tegmental area produced behavioural and ECoG sleep, accompanied by a statistically-significant increase in ECoG total spectrum power. These effects were completely antagonized by a pretreatment (24, 48 or 72 hr before) with pertussis toxin (0.34 and 3.4 micrograms), given into the same site. Similarly, behavioural sleep and an increase in ECoG total voltage power, produced by systemic administration of apomorphine (263 nmol/kg i.p.), were abolished by pertussis toxin (3.4 micrograms) injected bilaterally into the ventral tegmental area 24, 48 or 72 hr before. In conclusion, the present results suggest that behavioural and ECoG spectrum power effects, triggered by stimulation of dopamine D2 autoreceptors in the ventral tegmental area of rats, seem to be linked to the inhibition of adenylate cyclase activity through a Gi protein and or to other biochemical events linked to Gi proteins.

Topics: Adenylate Cyclase Toxin; Animals; Apomorphine; Electrocardiography; Male; Pertussis Toxin; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Tegmentum Mesencephali; Time Factors; Virulence Factors, Bordetella

In a previous study we have demonstrated that repeated reserpine treatment markedly enhances the intrinsic activity of the partial dopamine (DA) agonist (-)-3-PPP (preclamol) on pituitary DA receptors in female rats. This effect was attributed to the DA-depleting action of reserpine. However, since reserpine may also decrease oestrogen secretion, and since this hormone is known to affect dopaminergic transmission, experiments with ovariectomized, oestrogen-replaced female rats were undertaken. Ovariectomized rats were administered a depot preparation of oestradiol valerate in a dose that, according to literature data, yields physiological or slightly supraphysiological plasma concentrations of oestrogen. In spite of this treatment, repeated reserpine administration was found to substantially increase the intrinsic activity of (-)-3-PPP, as well as that of the partial DA agonist TDHL (terguride), on female pituitary DA receptors. It was concluded that repeated reserpine treatment increases pituitary DA receptor responsiveness in female rats by depleting DA, rather than by decreasing oestrogen secretion.

Topics: Animals; Estradiol; Estrogens; Female; Lisuride; Ovariectomy; Piperidines; Pituitary Gland, Posterior; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine

Pigeons trained to discriminate between the presence and absence of delta 9-THC (0.56 mg/kg, IM, intramuscularly) were tested with diazepam (5.6-30 mg/kg), administered IG (intragastrically), and were found to generalize the response associated with the THC training to the diazepam treatment only to a limited extent. Two groups of gerbils trained to discriminate between the presence and absence of IP (intraperitoneally) injected benzodiazepine agonists (5.6 mg/kg of diazepam and Ro 11-3128, respectively) generally did not generalize the drug response to IP administered THC (5.6 and 17.5 mg/kg). In addition, substitution testing with the dopamine autoreceptor blocker (+)-3PPP yielded non-drug responding in the pigeons. Hence neither proposed structural similarity between 3-PPP and THC, nor purported anxiolytic activity by 3-PPP (see Introduction) matched the THC-induced stimulus effects. The data are discussed with reference to the specificity of the THC cue or stimulus.

Topics: Animals; Benzodiazepinones; Columbidae; Diazepam; Discrimination, Psychological; Dronabinol; Generalization, Stimulus; Gerbillinae; Male; Piperidines; Receptors, GABA-A

The effect of guanine nucleotides and ions on (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+ )-[3H]3-PPP), (+)-N-[3H]allylnormetazocine ((+)-[3H]SKF 10047) and [3H]1-[1-(3-hydroxyphenyl)-cyclohexyl]piperidine ([3H]PCP-3-OH) specific binding to rat brain membranes was examined. These 3 compounds are proposed as prototypical ligands for the labeling of the sigma- and phencyclidine (PCP)-receptor subtypes. Competition binding experiments of (+)-SKF 10047 with (+)-[3H]3-PPP yielded a biphasic inhibition curve which transformed to a monophasic curve when membranes were incubated in the presence of Gpp(NH)p (0.1 mM). The common (+)-[3H]3-PPP/(+)-SKF 10047 binding component is more susceptible to Gpp(NH)p than the high affinity [3H]PCP-3-OH/(+)-SKF 10047 common binding component. Low affinity [3H]PCP-3-OH binding, which may represent a PCP-selective site, is not affected by GTP and Gpp(NH)p. Mono- and divalent cations markedly inhibit high affinity [3H]PCP-3-OH binding but they had a differential inhibitory effect on the binding of the other radioligands tested. These findings suggest differences in the regulation of multiple psychotomimetic (sigma- and PCP) binding sites by guanine nucleotides and ions.

Topics: Animals; Binding, Competitive; Brain; Cations; Guanine Nucleotides; Male; Phenazocine; Phencyclidine; Piperidines; Rats; Receptors, Neurotransmitter; Receptors, Phencyclidine; Subcellular Fractions

To compare the actions of prototypic drugs which are selective for phencyclidine and sigma receptors, the electrophysiological effects of phencyclidine (PCP),3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [+)3-PPP), and 1,3-di(2-tolyl)guanidine (DTG) on CA1 hippocampal pyramidal neurons were examined. A wide range of concentrations of drug was tested to differentiate specific, receptor-mediated effects from nonselective, anesthetic-like actions. At relatively large concentrations (0.1-1 mM), each compound reversibly increased the threshold of action potentials driven by Schaffer collaterals, the duration of action potentials and membrane resistance. The low potencies and rank order of potency suggested that phencyclidine, (+)3-PPP, and DTG were not acting through either high affinity sigma or phencyclidine receptors. These compounds did have receptor-mediated effects at smaller concentrations. Since none of the compounds affected evoked excitatory or inhibitory postsynaptic potentials (EPSP or IPSP) or driven action potentials at subanesthetic concentrations (less than 100 microM), no evidence was found to support the hypothesis that the actions of phencyclidine result from enhanced release of transmitter, caused by the inhibition of a presynaptic potassium conductance. As observed in other neurons, phencyclidine blocked excitations in CA1 pyramidal cells mediated by N-methyl-D-aspartic acid (NMDA) at behaviorally relevant concentrations (1-10 microM). However, (+)3-PPP (1 microM-1 mM) enhanced the pyramidal cell response to NMDA. Alone, DTG did not effect the NMDA-induced response but did inhibit the enhancement induced by (+)3-PPP. The agonist and antagonist actions of the sigma-selective ligands, (+)3-PPP and DTG, suggests that they modify NMDA-induced responses by acting at the sigma receptor.

Topics: Action Potentials; Animals; Aspartic Acid; Guanidines; Hippocampus; Male; N-Methylaspartate; Neurons; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

The effects of subchronic administration of rimcazole and 1,3-di(2-tolyl)guanidine (DTG) on the central R(+)[3H]-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine (R(+)[3H]-3-PPP) binding site were investigated in the rat. Subchronic treatment with rimcazole was characterized by a 30% increase in the density and a two-fold decrease in the affinity of R(+)[3H]-3-PPP binding sites relative to saline-treated animals. DTG, a more potent sigma ligand, produced a similar alteration to the affinity but a 130% increase in the density of R(+)[3H]-3-PPP binding sites. These data thus provide evidence for the functional involvement of sigma receptors in the central nervous system.

Topics: Animals; Carbazoles; Guanidines; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma

Topics: Brain; Dibenzocycloheptenes; Dizocilpine Maleate; Humans; In Vitro Techniques; Membranes; Phencyclidine; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

The pharmacological specificity of representative psychotomimetic agents such as phencyclidine (PCP) analogs, opiate benzomorphans and several antipsychotic agents was assessed for the sigma and PCP binding sites. In a series of binding experiments, in rat brain membranes, sigma and PCP binding sites were labeled with [3H]-1-[1-(3-hydroxyphenyl)cyclohexyl]piperidine [( 3H]PCP-3-OH), (+) [3H]-N-allylnormetazocine [(+) [3H]SKF 10047] and (+) [3H]-3-[3-hydroxy-phenyl]-N-(1-propyl)piperidine [(+) [3H]-3-PPP]. PCP analogs inhibit potently high affinity [3H]PCP-3-OH binding and (+) [3H]SKF 10047 binding, moderately the low affinity binding component of [3H]PCP-3-OH and very weakly (+) [3H]-3-PPP binding. (+)SKF 10047 and cyclazocine are potent to moderate inhibitors of (+) [3H]SKF 10047, high affinity [3H]PCP-3-OH and (+) [3H]-3-PPP binding, but extremely weak inhibitors of low affinity [3H]PCP-3-OH binding. The antipsychotic agents display high affinity for (+) [3H]-3-PPP binding sites, moderate affinity for (+) [3H]SKF 10047 sites and have no effect on either the high or low affinity [3H]PCP-3-OH binding. The present data further support the existence of multiple sigma and PCP binding sites.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Haloperidol; In Vitro Techniques; Male; Phenazocine; Phencyclidine; Piperidines; Psychotropic Drugs; Rats; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma

Topics: Animals; Apomorphine; Behavior, Animal; Cerebral Cortex; Dopamine Agents; Electric Stimulation; Electroencephalography; Piperidines; Rats; Receptors, Dopamine; Sleep; Tegmentum Mesencephali

1. In freely moving rats the effects on behaviour and electrocortical (ECoG) spectrum power of some dopamine agonists, i.e. apomorphine and (+)-3PPP, given directly into different areas of the rat brain were studied. In particular, dopamine agonists were microinfused in the ventral tegmental area (VTA) and substantia nigra (SN) or into the caudate nucleus, n. accumbens and prefrontal cortex. The ECoG spectrum power effects were continuously analysed by means of a computerized Berg-Fourier analyser as total spectrum power and power in preselected frequency bands. 2. Apomorphine and (+)-3PPP (0.01, 0.1 and 1.0 nmol) given bilaterally into the VTA produced behavioural and ECoG sleep in a dose-dependent fashion. A statistically significant (P less than 0.01) increase in ECoG total spectrum power with a predominant increase in the lower frequency bands (0.25-3, 3-6 and 6-9 Hz) occurred. No behavioural and ECoG changes were evoked by the same doses of apomorphine bilaterally microinfused into the SN or into the caudate nucleus or by (+)-3PPP (1.0 nml) microinjected into the n. accumbens or applied onto the prefrontal cortex. 3. Behavioural and ECoG sleep was also induced in rats after systemic administration of apomorphine (263 nmol kg-1, i.p.). 4. The behavioural and ECoG spectrum power effects of apomorphine (1.0 nmol) bilaterally micro-infused into the VTA were prevented by a previous microinjection into the same site of (-)-sulpiride (9.8 nmol). Similarly, behavioural and ECoG effects evoked by (+)-3PPP (0.1 nmol) given bilaterally into the VTA, were completely antagonized by a previous injection into the same site of haloperidol (16 pmol given 10 min before). In contrast, pretreatment with SCH 23390 (50 pgkg-1, s.c.), a selective antagonist at dopamine Dl-receptors, was unable to antagonize the behavioural and ECoG spectrum power effects of ( +)-3PPP. 5. Soporific effects induced by systemic administration of apomorphine were antagonized by (-)- sulpiride (9.8 nmol) given bilaterally into the VTA 10min before, whereas, yohimbine (1.3 nmol), (an antagonist at alpha 2-adrenoceptors) bilaterally microinfused into the VTA, was ineffective in this respect. 6. The present experiments provide evidence suggesting that stimulation of dopamine D2-receptors located at the cell body level and/or the dendrites of dopaminergic neurones in the VTA may represent the mechanism through which apomorphine or (+)-3PPP exert their soporific effects in rats.

Topics: Animals; Apomorphine; Cerebral Cortex; Electroencephalography; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Sleep; Sulpiride; Tegmentum Mesencephali

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), was synthesized in our laboratories and compared with apomorphine, 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and dopamine antagonists in a series of tests designed to characterize dopamine receptor activation and inhibition. The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392, 3-PPP and apomorphine. Haloperidol antagonized the inhibitory effect of OPC-4392 in both instances. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit 14C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices. In addition, OPC-4392 appears to block postsynaptic D2 receptors since OPC-4392, as well as dopamine antagonists, was able to inhibit stereotyped behavior and climbing behavior induced by apomorphine in mice, displace the 3H-spiroperidol binding to rat synaptosomal membranes in vitro and reverse the inhibitory effect of apomorphine on Ach release in rat striatal slices. These results suggest that OPC-4392 acts as a dopamine agonist at presynaptic autoreceptors related to dopamine synthesis and acts as dopamine antagonist at postsynaptic D2 receptors.

Topics: Animals; Apomorphine; Brain; Corpus Striatum; Diencephalon; Dihydroxyphenylalanine; Frontal Lobe; Hydroxydopamines; Kainic Acid; Kinetics; Male; Mice; Mice, Inbred ICR; Motor Activity; Oxidopamine; Piperazines; Piperidines; Quinolines; Quinolones; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior; Telencephalon

We have compared the central dopamine (DA) autoreceptor-stimulatory properties of the 'atypical' DA agonist, (-)-3-PPP, its (+)-antipode and the reference DA agonist, apomorphine, following a 5 or an 18 h interruption of synaptic dopaminergic transmission by means of reserpine. The results are consistent with the notion that even a relatively short period (18 h) of synaptic DA deprivation results in a functional 'supersensitivity' of central DA synthesis-modulating autoreceptors. Interestingly, the data demonstrate a clearcut and significant enhancement of the intrinsic agonist efficacy of (-)-3-PPP in limbic and striatal parts after an 18 h as compared to a 5 h reserpine-induced impairment of synaptic DA transmission. In addition, there was a tendency towards a reduction in the doses of apomorphine and the 3-PPP enantiomers needed to inhibit DA synthesis in 18 vs. 5 h reserpinized rats in both brain regions. The findings indicate that the adaptive state of the DA autoreceptors had been altered, tentatively as a result of the reduced (endogenous) agonist occupancy. This is consistent with the suggestion that DA autoreceptors are influenced by a certain, albeit presumably low, endogenous dopaminergic tone under in vivo physiological conditions. The data obtained provide further support for the contention that receptor responsiveness is a critical determinant of the intrinsic efficacy displayed by DA receptor agonists such as (-)-3-PPP.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Brain; Brain Chemistry; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Limbic System; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Stereoisomerism; Synapses

Qualitative differences in pharmacological responsiveness to various types of dopamine agonists have been reported in rats that have undergone unilateral 6-hydroxydopamine (6-OHDA)-induced denervation of the nigro-striatal pathway. The present experiments further characterize these differences, pharmacologically and neurochemically. Rats were classified as having high rotational sensitivity (0.03 mg/kg SC apomorphine sufficient to induce more than 100 rotations/20 min) or low sensitivity (0.3 mg/kg SC apomorphine required to meet this criterion). High sensitivity rats showed marked contralateral rotational behavior (approximately 150 rotations/20 min) in response to apomorphine (ED50 = 0.08 mg/kg IP), CGS 15855A (ED50 = 0.07 mg/kg), CGS 15873A (ED50 = 0.43 mg/kg), (+)-3-PPP (ED50 = 2.3 mg/kg), (-)-3-PPP (ED50 = 0.87 mg/kg) and quinpirole (peak effective dose, 0.03 mg/kg). In low sensitivity rats, 3- to 10-fold higher doses of apomorphine induced a maximal rate of rotational behavior, but only partial effects were produced by quinpirole, CGS 15855A, CGS 15873A, (+)-3-PPP, and (-)-3-PPP (40-80 rotations/20 min). Because apomorphine is a nonselective D1 and D2 agonist, it is proposed that activation of either D1 or D2 receptors suffices to induce high rates of rotation in high sensitivity rats, whereas in low sensitivity rats, D1 or D2 agonism alone induces submaximal rotation rates. The ipsilateral rotational behavior induced by d-amphetamine was more pronounced and occurred at lower doses in the high-sensitivity rats. Striatal dopamine depletion on the lesioned side did not differ between the groups, but low sensitivity rats showed two-fold higher DOPAC/DA ratios on the lesioned side than did high-sensitivity rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Apomorphine; Benzopyrans; Brain Chemistry; Corpus Striatum; Dopamine; Ergolines; Hydroxydopamines; Male; Oxidopamine; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Rotation; Stereotyped Behavior; Sympathectomy, Chemical

The effects of intraperitoneal administration of apomorphine, (+)-3-PPP, and (-)-3-PPP on slow-(less than 4 spikes/sec) and fast-(greater than 4 spikes/sec) firing dopaminergic neurons in the substantia nigra zona compacta of rats anesthetized with chloral hydrate were assessed. All compounds completely inhibited slow-firing dopaminergic neurons. When a dose-response was determined by administering each dose in a single bolus injection, apomorphine and (+)-3-PPP produced dose-related inhibitions of fast-firing dopaminergic neurons, with the largest dose of each compound completely inhibiting nearly all cells tested. In contrast, (-)-3-PPP only partially inhibited (50%) fast-firing dopaminergic neurons. Thus, on fast-firing neurons, (-)-3-PPP had the profile of a partial agonist, while apomorphine and (+)-3-PPP demonstrated greater efficacy than (-)-3-PPP. Pretreatment while doses of apomorphine, (+)-3-PPP, or (-)-3-PPP that partially inhibited the activity of dopaminergic neurons antagonized the complete inhibitory effects of a dose of apomorphine that normally produced complete inhibition of neuronal firing. In addition, pretreatment with doses of (+)-3-PPP that partially inhibited the activity of cells antagonized the complete inhibitory effects of a dose of (+)-3-PPP that, normally produced complete inhibition of neuronal firing. From the antagonism studies alone, it was not clear if tachyphylaxis or partial agonist activity accounted for the observed antagonisms. However, since apomorphine and (+)-3-PPP completely inhibited the activity of fast-firing DA neurons, it is proposed that they antagonize by inducing a dose- and time-dependent tachyphylaxis. In contrast, (-)-3-PPP is proposed to antagonize by virtue of its partial agonist activity.

Topics: Action Potentials; Animals; Apomorphine; Drug Tolerance; Injections, Intraperitoneal; Injections, Intravenous; Male; Neurons; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Substantia Nigra

Effects of the enantiomers of the dopamine (DA) autoreceptor agonist 3-PPP (0.5-8.0 mg/kg body weight, i.m.) were studied in three Cebus apella monkeys with persistent abnormal movements induced by prior long-term treatment with fluphenazine enanthate. In 2 of the animals, (-)-3-PPP abolished the abnormal movements while producing only negligible acute motor effects (trembling and stereotypy). (+)-3-PPP, administered to one of these monkeys, also produced a dose-dependent suppression of the persistent abnormal movements, along with the appearance of acute motor signs including tongue protrusions, hyperkinesia, and stereotypy; at the highest dose, there was a biphasic effect. In the first phase, there were pronounced acute motor signs but no persistent abnormal movements. In the second phase, there were neither acute nor persistent abnormal movements. One monkey was unaffected by (-)-3-PPP or low doses of (+)-3-PPP; a higher dose (4 mg/kg) produced hyperkinesia and increased persistent abnormal movements in one experimental setting. The suppression of neuroleptic-induced persistent abnormal movements by 3-PPP enantiomers may be related to their ability to act as autoreceptor agonists, while the acute motor signs produced by higher doses of (+)-3-PPP may be due to activation of postsynaptic DA receptors. The present findings suggest that (-)-3-PPP and drugs with a similar pharmacological profile might be effective as symptomatic treatments for tardive dyskinesia, with little chance of inducing acute extrapyramidal side-effects.

Topics: Animals; Cebus; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Fluphenazine; Piperidines; Stereoisomerism; Time Factors

Using the technique of brain dialysis in freely moving rats we have investigated the effect of various dopamine (DA) receptor agonists on the release and metabolism of DA in two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of various DA receptor agonists such as apomorphine (12-100 micrograms/kg s.c.), LY 171555 (5-50 micrograms/kg s.c.), pergolide (5-25 micrograms/kg s.c.), (+)-3PPP (0.5-2.5 mg/kg s.c.) and BHT 920 (10-250 micrograms/kg s.c.) reduce DA release and elicit hypomotility. The potency of the drugs and their effectiveness is similar in the two areas. Inhibition of DA release appears related to the ability of the various agonists to stimulate D-2 rather than D-1 receptors. Thus, the reportedly selective D-1 agonist, SKF 38393, was inactive on DA release and metabolism even at doses fully active in eliciting D-1-mediated effects (grooming); on the other hand apomorphine, a D-1/D-2 agonist, and pergolide, a D-2 agonist with rather weak D-1 activity, reduced DA release in a manner which was related to their agonist activity at D-2 receptors; finally LY 171555, (+)-3PPP and BHT 920, which selectively stimulate D-2 receptors, were fully active at reducing DA release in vivo. Apomorphine, pergolide, LY 171555 and (+)-3PPP given at higher doses elicited behavioral stimulation. In contrast, BHT 920 failed to do so. In further contrast (-)-3PPP (0.1-10 mg/kg s.c.), which failed to reduce DA release at low doses, actually stimulated it at high doses (10 mg/kg s.c.) and elicited hypomotility, thus resembling DA receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 3,4-Dihydroxyphenylacetic Acid; Animals; Apomorphine; Azepines; Behavior, Animal; Benzazepines; Brain; Dialysis; Dopamine; Ergolines; Homovanillic Acid; Isomerism; Male; Motor Activity; Neurons; Pergolide; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Time Factors

The present investigation was aimed at comparing the influence of the partial dopamine (DA) receptor agonist (-)-3-PPP (preclamol) on prolactin release in acutely hyperprolactinemic but otherwise intact female rats and female rats subjected to chronic DA depletion. One group of animals received daily vehicle injections (controls) and another group daily reserpine (1 mg/kg) injections for a period of seven days. On the eighth day all animals were administered 10 mg/kg of reserpine in order to eliminate endogenous DA and elevate serum prolactin levels. In the control group (-)-3-PPP lowered serum prolactin levels only moderately. In contrast, in the chronically reserpinized female rats, a pronounced reduction of prolactin secretion was observed. It is suggested that this increase in intrinsic activity of (-)-3-PPP following chronic DA depletion reflects an enhanced responsiveness of hypophyseal DA receptors, possibly due to conformational changes in the receptor molecules. Our observations lend further support to the hypothesis that an inverse relationship exists between the intrinsic activity of a mixed agonist/antagonist and the degree of previous receptor occupancy.

Topics: Animals; Dopamine; Female; Hyperprolactinemia; Piperidines; Pituitary Gland; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine

Neuropharmacological evaluation of the R and S isomers of 11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) supports the impression that the 11-OH group in aporphines (analogous to the meta hydroxyl of dopamine, DA) is sufficient to confer high affinity and activity at DA receptors. As in the case of the catechol congeners, (R)-apomorphine (APO) and (R)-N-n-propylnorapomorphine (NPA), (R)-11-OH-NPa is a potent DA agonist while, like (S)-NPA, (S)-11-OH-NPa is a DA antagonist. Thus, (R) and (S)-11-OH-NPa are an additional pair of compounds in which one enantiomer is a DA agonist and the other an antagonist. Other analogous pairs are the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), and cis-1-methyl-5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-MDAT). All contain a meta hydroxyphenyl, an N-n-propyl, and a phenethylamine moiety which can be superimposed in a consistent way to discriminate the DA agonists from the antagonists, with the key feature in this discrimination being the direction of the ammonium hydrogen. An energy penalty must be incurred by 3-PPP to assume the required conformations and it may account for the relatively low potency of the 3-PPP enantiomers. This analysis supports the view that rigid analogs of flexible compounds when "frozen" in their biologically active conformation exhibit higher affinity interactions with the receptor.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aporphines; Dopamine; Molecular Conformation; Naphthalenes; Piperidines; Receptors, Dopamine; Stereoisomerism; Structure-Activity Relationship; Tetrahydronaphthalenes

The structural determinants of sigma receptor affinity have been evaluated by examining a wide range of compounds related to opioids, neuroleptics, and phenylpiperidine dopaminergic structures for affinity at sigma receptor-binding sites labeled with (+)-[3H]3-PPP. Among opioid compounds, requirements for sigma receptor affinity differ strikingly from the determinants of affinity for conventional opiate receptors. Sigma sites display reverse stereoselectivity to classical opiate receptors. Multi-ringed opiate-related compounds such as morphine and naloxone have negligible affinity for sigma sites, with the highest sigma receptor affinity apparent for benzomorphans which lack the C ring of opioids. Highest affinity among opioids and other compounds occurs with more lipophilic N-substituents. This feature is particularly striking among the 3-PPP derivatives as well as the opioids. The butyrophenone haloperidol is the most potent drug at sigma receptors we have detected. Among the series of butyrophenones, receptor affinity is primarily associated with the 4-phenylpiperidine moiety. Conformational calculations for various compounds indicate a fairly wide range of tolerance for distances between the aromatic ring and the amine nitrogen, which may account for the potency at sigma receptors of structures of considerable diversity. Among the wide range of structures that bind to sigma receptor-binding sites, the common pharmacophore associated with high receptor affinity is a phenylpiperidine with a lipophilic N-substituent.

Topics: Animals; Brain; Hydrogen-Ion Concentration; Male; Molecular Conformation; Narcotics; Phenothiazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Stereoisomerism; Structure-Activity Relationship; Tritium

Low doses of BHT 920, LY 171555 and (+)3PPP, three dopamine agonists selective for D-2 receptors, induced yawning in rats. This effect was reduced by the selective D-1 antagonist SCH 23390 but the antagonism did not exceed a 50% reduction from the control values. In contrast, the selective D-2 antagonist (-)sulpiride completely abolished agonist-induced yawning. A 6 h reserpine pretreatment (5 mg/kg i.p.), which depletes brain dopamine (DA) by about 95%, reduced agonist-induced yawning by an extent similar to SCH 23390; in the reserpinized rats, SCH 23390 completely lost the property of blocking agonist-induced yawning while (-)sulpiride retained it. Two 5HT receptor antagonist, ketanserin and metergoline failed to influence agonist-induced yawning. The reportedly selective D-1 agonist, SKF 38393, failed to induce yawning in normal rats as well as in rats pretreated with reserpine 6 or 16 h earlier. If one excludes that SCH 23390 and the D-2 agonists interact with the same DA-receptors, the data are consistent with the possibility that stimulation of D-1 receptors by endogenous DA plays a permissive-facilitatory role for the behavioural expression of D-2 receptor activation.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adrenergic alpha-Agonists; Animals; Azepines; Benzazepines; Brain Chemistry; Dopamine; Ergolines; Kainic Acid; Ketanserin; Male; Metergoline; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Sulpiride; Yawning

Bilateral injection of apomorphine (2.5 micrograms) into the substantia nigra zona reticulata of rats reduced both locomotor activity and striatal HVA and DOPAC concentrations. Bilateral injection of dopamine (10 micrograms) did not affect locomotor activity whereas a higher dose of dopamine (50 micrograms) enhanced locomotor activity. Striatal HVA and DOPAC concentrations were unchanged following injection of dopamine. Bilateral injection of (+/-)-3PPP (0.1 or 2.5 micrograms) into the zona reticulata of the substantia nigra did not alter locomotor activity while a higher dose (10 micrograms) enhanced locomotion. Injection of (+/-)-3PPP (0.1-10 micrograms) into the zona reticulata was without effect on striatal HVA or DOPAC concentrations. The bilateral manipulation of nigral dopaminergic neurotransmission alters motor activity and nigrostriatal dopamine turnover in conscious rats. However, the changes in motor activity are not necessarily related to altered nigrostriatal activity, suggesting the involvement of dopamine receptors located at non-dopaminergic sites within the substantia nigra.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Apomorphine; Corpus Striatum; Dopamine; Female; Homovanillic Acid; Motor Activity; Phenylacetates; Piperidines; Rats; Rats, Inbred Strains; Substantia Nigra; Sucrose

The irreversible dopamine (DA) receptor antagonist N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the extent of receptor reserve at DA autoreceptors regulating in vivo tyrosine hydroxylase activity. Rats were treated with vehicle or EEDQ (1 X 0.5-2 X 6 mg/kg, subcutaneously) and, 24 hr later, dose response curves were generated for DA agonist reversal of gamma-butyrolactone-induced striatal L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation. Double reciprocal plots were obtained of equieffective doses of agonist required to elicit response at several levels of effect before and after partial irreversible receptor inactivation. A pseudo-dissociation constant (pseudo-KA, in units of dose) and the fraction of receptors remaining active (q) were determined; these values were then used to calculate the relationship between receptor occupancy and response. The ED50 (1 microgram/kg) for the full DA receptor agonist N-propylnorapomorphine (NPA) was shifted 2.8, 4.8-, and 11.3-fold to the right after partial irreversible receptor blockade which left the fraction of receptors remaining active (q) at 0.37, 0.17 and 0.058, respectively. Corresponding maximal reversal of L-DOPA accumulation was 100, 77, and 58%, indicating a nonlinear relationship between receptor occupancy and response for NPA and the presence of a large receptor reserve; maximal and half-maximal responses were calculated to require occupancy of 30 and 3.8% of the total receptor pool, respectively. Dose response curves were also obtained for the DA autoreceptor-selective agents EMD 23,448 and (+)- and (-)-3-PPP before and after EEDQ treatment. In controls, EMD 23,448 and (+)-3-PPP, like NPA, completely reversed striatal gamma-butyrolactone-induced L-DOPA accumulation, whereas the maximal effect of (-)-3-PPP was 52% reversal. After EEDQ treatment (6 mg/kg), EMD 23,448 and (+)-3-PPP showed relatively small shifts in ED50 values. Furchgott analysis demonstrated that all three atypical agents are partial agonists at the DA autoreceptor with efficacies of 0.19 (EMD 23,448), 0.12 [(+)-3-PPP], and 0.05 [(-)-3-PPP] relative to NPA. The presence of a larger receptor reserve at pre-versus postsynaptic D2 DA receptors and the partial agonist character of drugs such as EMD 23,448 and the enantiomers of 3-PPP may account for their autoreceptor selectivity.

Topics: 4-Butyrolactone; Adrenergic alpha-Antagonists; Animals; Apomorphine; Corpus Striatum; Dihydroxyphenylalanine; Homeostasis; Hydrazines; Levodopa; Male; Piperidines; Quinolines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The caudate spindle in rats was observed following bilateral application of apomorphine (1.5-50 micrograms) and (+/-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 0.3-3 micrograms) into the striatum. The smallest dose (1.5 micrograms) of apomorphine enhanced the spindle whereas with a larger dose (50 micrograms), suppression occurred. The preferential dopamine (DA) autoreceptor (inhibitory-receptor) agonist, (+/-)-3-PPP, enhanced the spindle, in a dose-dependent manner. The enhancing effect of apomorphine (1.5 micrograms) and (+/-)-3-PPP (3 micrograms) was prevented by neuroleptics, such as haloperidol (20 micrograms/kg, i.v.) and sulpiride (2 mg/kg, i.v.) at doses which, per se, did not affect the spindle. Small doses of neuroleptics are thought to block DA autoreceptors, suggesting that the enhancing effects of the DA agonists are mediated by autoreceptors. These results lend further support to the assumption that the development of the caudate spindle involves activation or DA receptors. Enhancement of the spindle, induced by injections of apomorphine into the striatum (small dose) and (+/-)-3-PPP, may be mediated by DA autoreceptors (inhibitory-receptors) located at presynaptic elements of the nigro-striatal DA system, while suppression may be due to stimulation of the postsynaptic DA receptors.

Topics: Animals; Antipsychotic Agents; Apomorphine; Corpus Striatum; Dopamine; Electric Stimulation; Electrophysiology; Injections; Male; Piperidines; Rats; Rats, Inbred Strains

In rats with cannulae permanently implanted into the third cerebral ventricle, the effects of different pharmacological manipulations affecting dopaminergic mechanisms, were studied on behaviour and electrocorticographic (ECoG) activity, continuously quantified in its spectrum power. The intraventricular injection (0.1-1 nmol) of (-)3PPP[3-(3-hydroxyphenyl) N-n-propylpiperidine], a specific agonist at dopamine (DA) autoreceptors, produced dose-dependent behavioural sedation or sleep and an increase in ECoG spectrum power, with a predominant increase in the lower frequency bands. Short episodes of stereotyped movements, wet-dog syndrome, penile grooming and erection were also observed. Similar behavioural and ECoG effects were elicited by the intraventricular injection of R-(+)-8-chloro-2,3,4,5-tetrohydro-3-methyl-5-phenyl-1H-3-benzazepi ne-7-ol (SCH 23390), a selective antagonist at D1 postsynaptic receptors, although these were preceded by a short period of behavioural and sexual stimulation. In addition, the intraventricular administration of some neuroleptics, chloropromazine and haloperidol, produced behavioural and ECoG slow wave sleep. No significant changes were observed with a neuroleptic drug, 1-sulpiride, which is reputed to act selectively as an antagonist at dopamine D2 receptors. In conclusion, the present experiments add new evidence in favour of the idea that dopaminergic mechanisms are involved in mammalian species in the control of arousal and that both post-synaptic D1 and D2 receptors may take part in such a control.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzazepines; Brain; Catheters, Indwelling; Dopamine; Dose-Response Relationship, Drug; Electroencephalography; Electrophysiology; Injections, Intraventricular; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior; Synaptic Transmission

The effects of the two enantiomers of 3-PPP upon alpha 1-adrenergic and muscarinic receptors coupled to the inositol phospholipid (PI) breakdown response have been investigated. 3-PPP(-) and 3-PPP(+) were found to antagonize the noradrenaline (10 microM)-stimulated PI breakdown in rat cerebral cortical miniprisms with IC50 values of 18 and 61 microM, respectively. The dopamine receptor antagonists haloperidol and raclopride were also antagonists, with IC50 values of 0.4 and 25 microM, respectively. 3-PPP(-) and raclopride were found further to act as competitive antagonists, with pA2 values of 6.03 and 5.44, respectively. 3-PPP(-), 3-PPP(+) and haloperidol also antagonized the muscarinic receptor-mediated carbachol (50 microM)-stimulated PI breakdown in cortical miniprisms, albeit at high concentrations (IC50 values of 91, 170 and 28 microM, respectively) whereas raclopride produced only 24% inhibition at the highest concentration tested (100 microM).

Topics: Animals; Antiparkinson Agents; Atropine; Carbachol; Cerebral Cortex; Haloperidol; In Vitro Techniques; Inositol Phosphates; Male; Norepinephrine; Phenoxybenzamine; Piperidines; Prazosin; Raclopride; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Salicylamides; Stereoisomerism; Sugar Phosphates

Topics: Animals; Electric Stimulation; In Vitro Techniques; Male; Mice; Muscle Contraction; Norepinephrine; Phencyclidine; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Vas Deferens

The effect of the (+)- and (-)-enantiomers of 3-PPP [conventional and atypical dopamine (DA)-receptor active agent, respectively] were investigated in a commonly used animal model of anxiety: the Vogel licking-conflict test. Low doses (less than or equal to 0.5 mg/kg SC) of both 3-PPP enantiomers resulted in anti-conflict (= anxiolytic-like) actions in this test. (-)-3-PPP proved to be almost as potent as apomorphine in releasing the punished responding (minimum effective doses; (-)-3-PPP: 0.016, and apomorphine: 0.006 mg/kg SC), whereas (+)-3-PPP was about 10 times less effective than apomorphine. In the higher dose range (greater than or equal to 1.0 mg/kg), both 3-PPP enantiomers instead induced an apparent "pro"-conflict effect; i.e. decreased responding to a level significantly below baseline, thus resulting in a biphasic dose-response curve. Simple alterations in the animals' motivation to drink, in shock threshold or in motor capabilities did not seem to be major explanatory factors either for the anti- or for the "pro"-conflict effects. With regard to the latter, the possibility is discussed of an interaction between the experimental test situation and non conflict-related effects of the drugs, thus interfering with the punished drinking. The findings are interpreted within the concept that low doses of the 3-PPP enantiomers, in particular (-)-3-PPP, may attenuate anxiety-elicited increases in the neurotransmission in certain meso-cortical/limbic DA pathways, i.e. consistent with the previously shown preferentially "limbic" net antidopaminergic profile of action of (-)-3-PPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arousal; Avoidance Learning; Conflict, Psychological; Dose-Response Relationship, Drug; Drinking; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

Topics: Animals; Antiparkinson Agents; Chemical Phenomena; Chemistry; Female; Male; Piperidines; Rats; Rats, Inbred Strains

Microinjection of the dopamine (DA) agonist apomorphine into the paraventricular nucleus of the hypothalamus (PVN) induced penile erection and yawning in rats. A significant effect was elicited by a dose of apomorphine as low as 5 ng. The symptomatology usually began within 5 min after the microinjection, lasted for 30-50 min, and was identical to that induced by the systemic administration of the drug. Stereotypy and hypermotility were never observed after apomorphine microinjection into the PVN, even at the highest dose tested (1 microgram). Microinjections of the same doses of apomorphine into the hypothalamic ventromedial and dorsomedial nucleus, preoptic area, caudate nucleus, nucleus accumbens and substantia nigra, were ineffective. LY 171555, a specific D2 Da receptor agonist, and (+)-3-PPP, but not (-)-3-PPP nor the specific D1 DA receptor agonist SKF 38393, were as effective as apomorphine when injected into the PVN. Apomorphine-induced penile erection and yawning were antagonized by pretreatment with neuroleptic drugs, such as haloperidol, (-)-sulpiride, a specific D2 DA antagonist, and SCH 23390, a specific D1 DA antagonist. The present results suggest that the PVN is the brain area where D2 DA agonists act to induce penile erection and yawning. Moreover, since the PVN contains the cell bodies of a group of incerto-hypothalamic DA neurons, the above results suggest for the first time a possible involvement of the incerto-hypothalamic DA system in the expression of penile erection and yawning.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Benzazepines; Brain; Dopamine; Dopamine Antagonists; Ergolines; Male; Microinjections; Paraventricular Hypothalamic Nucleus; Penile Erection; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Yawning

Raclopride, a new potential antipsychotic agent blocking central dopamine (D2) receptors, was found to suppress exploratory locomotor activity, treadmill locomotion and conditioned avoidance response in rats. The threshold dose for effects in these test situations was about 0.5 mg/kg intraperitoneally. A considerably higher dose, 16 mg/kg intraperitoneally, was needed to produce maximal catalepsy. Maximal effects were obtained within 1-2 hrs and the duration of the effect was 2-8 hrs, depending on the test situation. The behavioural profile of raclopride is different from the classic antipsychotic haloperidol, blocking central dopamine (DA) receptors, as well as from the partial DA agonist preclamol, which inhibits central DA neurotransmission by activating DA autoreceptors. Thus, although similar to haloperidol in other respects, comparatively high doses of raclopride are needed to produce catalepsy, indicating less propensity to produce severe extrapyramidal side effects. Raclopride and preclamol are about equipotent in suppressing exploratory locomotor activity. However, raclopride is more potent than preclamol in suppressing treadmill locomotion, conditioned avoidance behaviour and catalepsy.

Topics: Animals; Avoidance Learning; Behavior, Animal; Catalepsy; Exploratory Behavior; Haloperidol; Male; Motor Activity; Piperidines; Raclopride; Rats; Rats, Inbred Strains; Salicylamides; Scopolamine

In the present report we have investigated the effects of apomorphine, (-)3-PPP, L-DOPA and haloperidol on the elicitation of convulsions induced in mice by exposure to oxygen at high pressure (HBO) (5 ata O2). It was found that the administration of apomorphine (0.025-0.1 mg X kg-1 s.c.), (-)3-PPP (4 mg X kg-1 i.p.) L-DOPA (200-400 mg X kg-1 i.p.) as well as haloperidol (0.25-2.0 mg X kg-1 i.p.) produced a significant protection against HBO-induced convulsions. Haloperidol was the only drug to produce a dose-dependent decrease in respiration, and this effect does probably explain the anticonvulsant effects observed. The low doses at which apomorphine was effective, and the effects produced by (-)3-PPP, indicate an effect mediated via DA autoreceptors. Alternatively, and more likely taking the effects of L-DOPA into account, the DA receptors involved are sensitive enough to disclose postsynaptic agonist properties of apomorphine and (-)3-PPP at the doses employed.

Topics: Animals; Antiparkinson Agents; Apomorphine; Body Temperature; Dose-Response Relationship, Drug; Haloperidol; Hyperbaric Oxygenation; Levodopa; Male; Mice; Mice, Inbred CBA; Piperidines; Reaction Time; Receptors, Dopamine; Respiration; Seizures

Twenty derivatives bearing substituents on the phenolic function of (-)-3-(3-hydroxyphenyl)-N-propylpiperidine [(-)-3-PPP] were synthesized and tested as prodrugs. The carbamate ester derivatives were found to be the most suitable prodrugs, and especially the 4-isopropylphenylcarbamate 20 was capable of escaping the first-pass metabolism and still generating high plasma levels of the parent compound. Four hours after an oral dose of 100 mumol/kg to rats, a plasma level of 2400 nmol/L of (-)-3-PPP was detected by an HPLC method. This was 90 times the level reached after 4 h (27 nmol/L) when (-)-3-PPP itself was given orally at the same dose.

Topics: Animals; Carbamates; Pharmaceutical Preparations; Piperidines; Prodrugs; Rats; Rats, Inbred Strains; Receptors, Dopamine; Structure-Activity Relationship

The effects of six putative dopamine receptor agonists on exploratory behaviour in rats were assessed: pergolide, (+)- and (-)-3-PPP, bromocriptine, mesulergine and CQ 32-084. Behaviour was automatically recorded in a holeboard apparatus and the data were analysed by the novel multivariate statistical method of partial least squares. All six substances suppressed exploratory behaviour at low doses. Pergolide and (+)-3-PPP-induced stereo-typed behaviour at higher doses. The suppression of exploration induced by pergolide was completely antagonised by sulpiride, partly antagonised by metoclopramide and weakly affected by haloperidol pretreatment. The effects of a low dose of (+)-3-PPP, bromocriptine or CQ 32-084, but not (-)-3-PPP or mesulergine, were antagonised by sulpiride. These findings support the hypotheses that pergolide, (+)-3-PPP, bromocriptine and CQ 32-084 inhibit exploration via stimulation of dopamine receptors. The present data do not substantiate the hypothesis that the suppression of exploration induced by (-)-3-PPP is mediated by stimulation of dopamine autoreceptors. A detailed analysis of the dose curves for pergolide and (+)-3-PPP indicates that the latter compound may have effects in addition to those of a dopamine receptor agonist.

Topics: Animals; Bromocriptine; Ergolines; Exploratory Behavior; Habituation, Psychophysiologic; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The abilities of the mixed agonists/antagonists on dopamine (DA) receptors, (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [-)-3-PPP) and transdihydrolisuride (TDHL), to suppress serum prolactin levels in acutely hyperprolactinemic male and female rats were investigated. gamma-Butyrolactone was used to deplete endogenous DA and raise serum prolactin concentrations. Both (-)-3-PPP and TDHL were found to cause sexually differentiated responses: (-)-3-PPP reduced serum prolactin levels dose dependently and effectively in males but caused only a modest decrease of prolactin release in females. Moreover, (-)-3-PPP antagonized the prolactin-suppressing effects induced by the DA receptor agonist (+)-3-PPP in females. Likewise TDHL decreased prolactin secretion markedly in males while it had only slight effects in females. It can be concluded from these results that the intrinsic activities of the partial DA agonists (-)-3-PPP and TDHL are lower in female than in male rats, suggesting a reduced responsiveness of hypophyseal DA receptors in females. Since DA levels in the pituitary portal circulation are higher in female than in male rats, this study gives further support to the hypothesis claiming an inverse relationship between the intrinsic activity of a mixed agonist/antagonist and the degree of previous stimulation of its receptor.

Topics: Animals; Antiparkinson Agents; Ergolines; Female; In Vitro Techniques; Lisuride; Male; Piperidines; Pituitary Gland; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sex Factors; Stereoisomerism

Eight indolizidine and quinolizidine derivatives of 3-PPP were synthesized and tested for possible dopamine (DA) autoreceptor activity. The equatorial indolizidine derivative 19e had the profile of a selective autoreceptor agonist and was half as active as 3-PPP. However, resolution of the compound revealed that the 8R enantiomer was an unselective DA agonist with a profile similar to (+)-3-PPP, while the 8S enantiomer was a weak DA antagonist without any DA agonist activity. The unsaturated quinolizidine derivative 21 also had the profile of a DA antagonist while the axial quinolizidine derivative 18a had an amphetamine-like profile in 6-OHDA-lesioned rats. All other derivatives were inactive. The observed structure-activity relationships were in agreement with existing DA receptor models, although these models are not apparently detailed enough to explain why the 8S enantiomer of 19e is inactive as a DA agonist.

Topics: alpha-Methyltyrosine; Animals; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Methyltyrosines; Molecular Conformation; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Stereotyped Behavior; Structure-Activity Relationship

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.

Topics: Amisulpride; Animals; Antipsychotic Agents; Apomorphine; Disease Models, Animal; Male; Phenothiazines; Pimozide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reinforcement Schedule; Reinforcement, Psychology; Schizophrenia; Schizophrenic Psychology; Sulpiride

The modulation of 3,4-dihydroxyphenylethylamine (dopamine, DA) synthesis and release in rabbit retina in vitro by high K+; adenylate cyclase activators such as forskolin, 2-chloroadenosine, vasoactive intestinal polypeptide (VIP); and the putative DA autoreceptor agonist N-n-propyl-3-(3-hydroxyphenyl) piperidine (3-PPP) has been investigated. Incubation of retinas in 50 mM K+ resulted in the activation of tyrosine hydroxylase (TH). Activation did not require the presence of extracellular Ca2+. K+ 50 mM also induced a Ca2+-dependent release of DA. Forskolin 50 microM stimulated TH but 100 microM 2-chloroadenosine and 650 nM VIP did not. Individually, (+)-3-PPP, (-)-3-PPP, and (+/-)-3-PPP reduced DA synthesis and increased its release. The effects of (+/-)-3-PPP were dose-dependent and did not require the presence of extracellular Ca2+. The activation of TH induced by 50 mM K+, but not that induced by 50 microM forskolin, was abolished by 100 microM (+/-)-3-PPP.

Topics: 2-Chloroadenosine; Adenosine; Adenylyl Cyclases; Animals; Calcium; Colforsin; Dopamine; Enzyme Activation; Female; Male; Piperidines; Potassium; Rabbits; Retina; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

The effects of some dopaminomimetics on VIP levels in peripheral venous blood of conscious dogs were analysed with a radioimmunoassay. The dopamine D2 agonist pergolide, like apomorphine and bromocriptine, increased VIP levels. The putative DA autoreceptor agonist 3PPP, as well as the D1 agonist SK&F 38393 were devoid of action. The D1 antagonist SCH 23390 did not abolish the effect of apomorphine. It is suggested that monitoring of VIP levels could be an interesting screening test for activity at D2 receptors. Amphetamine did not modify VIP levels suggesting that DA neurons are not involved in the mechanism leading to a release of VIP. The VIP response to apomorphine was not suppressed by an infusion of somatostatin. Decreasing blood pressure with nitroglycerin or with the adrenergic antagonist prazosin did not release VIP. The mechanism by which administration of dopaminomimetics lead to a release of VIP is further discussed.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamine; Animals; Apomorphine; Benzazepines; Dogs; Ergolines; Nitroglycerin; Pergolide; Piperidines; Prazosin; Receptors, Dopamine; Somatostatin; Vasoactive Intestinal Peptide

In the first test (exploratory activity), pretreated rats explored a novel environment in the dark. The potential autoreceptor agonists apomorphine HCl, N-n-propylnorapomorphine (NPA), and N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and its enantiomers decreased the total distance travelled while at the same time paradoxically increasing the number of discrete movements. This is a very different pattern from that of the typical antipsychotic drugs haloperidol HCl and chlorpromazine HCl, and the atypical antipsychotic drug clozapine, which also decreased the total distance travelled but decreased the number of movements. Both groups decreased the distance/movement. In the second test, rats were habituated to the monitors in the light and then treated with test drug and stimulant (d-amphetamine sulfate or apomorphine HCl). Apomorphine HCl, NPA, and (+)3-PPP antagonized amphetamine-stimulated locomotor behavior (total distance) without antagonizing apomorphine-stimulated behavior, suggesting a presynaptic dopamine autoreceptor agonism. EMD 23448 gave equivocal activity. On the other hand, haloperidol HCl, chlorpromazine HCl, and clozapine decreased both amphetamine- and apomorphine-stimulated behavior, suggesting a postsynaptic dopamine antagonism. 3-PPP and (-)3-PPP showed neither pattern in this test.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Drug Evaluation, Preclinical; Exploratory Behavior; Indoles; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

Brain sigma-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of sigma receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2-[5-3H]tolyl)guanidine ([3H]Tol2Gdn), that binds with high affinity to a single population of binding sites in guinea pig brain membrane preparations. The [3H]Tol2Gdn binding site displays stereoselectivity for dextrorotatory optical isomers of benzomorphan opiates known to have sigma-type behavioral effects. Furthermore, the [3H]Tol2Gdn binding site has a high affinity for haloperidol and for phenothiazine antipsychotics, which have antihallucinatory properties in humans. The drug-selectivity profile of [3H]Tol2Gdn binding closely correlates with the drug-selectivity profile of tritiated (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [+)-[3H]3-PPP) binding to guinea pig brain membrane receptors. (+)-[3H]3-PPP has been proposed to be a selective sigma-receptor ligand [Largent, B. L., Gundlach, A. L. & Snyder, S. H. (1984) Proc. Natl. Acad. Sci. USA 82, 4983-4987]. Receptor autoradiography using [3H]Tol2Gdn on slide-mounted rat and guinea pig brain sections reveals a heterogeneous distribution pattern of enriched binding in limbic and sensorimotor structures of the brain. These results indicate that [3H]Tol2Gdn is a selective ligand for the sigma-site. Availability of this sigma-receptor probe should greatly facilitate the physiological, biochemical, and pharmacological characterization of sigma receptors in brain.

Topics: Animals; Antipsychotic Agents; Benzomorphans; Binding Sites; Brain; Guanidines; Guinea Pigs; Hallucinogens; In Vitro Techniques; Ligands; Male; Morphinans; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Tritium

Animals (rats and pigeons) were trained to discriminate between the presence and absence of delta 9-THC; the training doses were, respectively: 0.56 mg/kg (pigeons) and 3.0 mg/kg (rats). Once the drug discrimination was mastered, the pigeons were tested repeatedly after a single intramuscular (i.m.) injection of delta 9-THC (0.56 mg/kg) at the following intervals 0.5, 1.5, 4.5 and 9 hr after the injection. These results were compared with data from a separate procedure, i.e. where the various intervals after injection were examined only once per injection and both procedures yielded essentially the same outcome. Thus, less than 50% appropriate responding to THC was observed at 0.5 and 9 hr after injection, whereas greater than 90% responding to THC occurred at 1.5 and 4.5 hr. The two procedures have previously been compared in rats (Järbe, Swedberg and Mechoulam, 1981). The repeated tests procedure was then used to evaluate combinations of delta 9-THC and cannabidiol in both species. Cannabidiol prolonged the cue effects of 1 mg/kg of delta 9-THC (intraperitoneal route of administration) in rats but did not change the time-effect curve for delta 9-THC in pigeons (dose range examined: 0.10--0.56 mg/kg); the challenge doses of cannabidiol were, respectively: 30.0 mg/kg (i.p.) and 17.5 mg/kg (i.m.). The rate of responding did not differ in tests with combinations of delta 9-THC and cannabidiol as compared to delta 9-THC given alone in pigeons. Subcutaneously administered 3-PPP, a dopamine pre-synaptic blocker, did not induce responding appropriate for delta 9-THC in rats.

Topics: Animals; Cannabidiol; Cannabinoids; Columbidae; Discrimination Learning; Discrimination, Psychological; Dronabinol; Male; Piperidines; Rats; Rats, Inbred Strains; Species Specificity; Time Factors

(+)3H-3-PPP [(+)3H-3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine] binds with high affinity to brain membranes with a pharmacological profile consistent with that of sigma receptors. The distribution of (+)3H-3-PPP binding sites in brain and spinal cord of both guinea pig and rat has been determined by in vitro autoradiography with binding densities quantitated by computer-assisted densitometry. (+)3H-3-PPP binding to slide-mounted brain sections is saturable and displays high affinity and a pharmacological specificity very similar to sites labeled in homogenates. (+)3H-3-PPP binding sites are heterogeneously distributed. Highest concentrations of binding sites occur in spinal cord, particularly the ventral horn and dorsal root ganglia; the pons-medulla, associated with the cranial nerve and pontine nuclei and throughout the brain stem reticular formation; the cerebellum, over the Purkinje cell layer; the midbrain, particularly the central gray and red nucleus; and hippocampus, over the pyramidal cell layer. Lowest levels are seen in the basal ganglia and parts of the thalamus, while all other areas, including hypothalamus and cerebral cortex, exhibit moderate grain densities. Quinolinic acid-induced lesions of the hippocampus indicate that (+)3H-3-PPP labels hippocampal pyramidal cells and granule cells in the dentate gyrus. Intrastriatal injection of ibotenic acid dramatically reduces (+)3H-3-PPP binding in this area, while injection of 6-hydroxydopamine produces a relatively slight decrease. The distribution of (+)3H-3-PPP binding sites does not correlate with the receptor distribution of any recognized neurotransmitter or neuropeptide, including dopamine. However, there is a notable similarity between the distribution of (+)3H-3-PPP sites and high-affinity binding sites for psychotomimetic opioids, such as the benzomorphan (+)SKF 10,047.

Topics: Animals; Autoradiography; Binding Sites; Brain Chemistry; Guinea Pigs; Male; Piperidines; Rats; Receptors, Opioid; Spinal Cord; Tritium

(+)[3H]SKF 10,047 and (+)[3H]3-PPP label a homogeneous population of sites in NCB-20 cell membranes that apparently represent benzomorphan specific binding sites previously reported for this cell line. Their drug specificity indicates that these sites are very similar to sigma receptor binding sites labeled in brain tissues by these ligands and do not represent PCP receptors.

Topics: Animals; Brain; Cells, Cultured; Cricetinae; Cricetulus; Hybrid Cells; Kinetics; Neuroblastoma; Phenazocine; Phencyclidine; Piperidines; Receptors, Opioid; Receptors, Opioid, delta; Stereoisomerism

The benzomorphan opioid, SKF 10,047, is the prototypical agonist for the sigma receptor. In this study, pharmacological and autoradiographic analyses reveal that (+)-[3H]SKF 10,047 labels two sites in brain: a high affinity site resembling the sigma receptor and a second site, labeled with lower affinity by (+)-[3H] SKF 10,047, similar to the phencyclidine (PCP) receptor. The drug specificity of the high affinity site for (+)-[3H]SKF 10,047 resembles that of the putative sigma receptor labeled with (+)-[3H]-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [(+)-[3H]-3-PPP], being potently inhibited by (+)-3-PPP, haloperidol and (+/-)-pentazocine, and demonstrating stereoselectivity for the (+)-isomer of SKF 10,047. In contrast, these drugs are weak in inhibiting binding of (+)-[3H]SKF 10,047 to the low affinity site, whereas PCP analogs, such as 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and 1-[1-(m-aminophenyl)cyclohexyl]piperidine (m-NH2-PCP), are potent inhibitors. No stereoselectivity for the isomers of SKF 10,047 is noted at the low affinity binding site. Autoradiographic localizations of high affinity (+)-[3H]SKF 10,047 binding sites closely resemble those of (+)-[3H]-3-PPP labeled sites with high levels of binding in the hippocampal pyramidal cell layer, hypothalamus, pontine and cranial nerve nuclei and cerebellum. By contrast, low affinity (+)-[3H]SKF 10,047 sites are most abundant in nonpyramidal layers of the hippocampus, the cerebral cortex and thalamic nuclei, similar to the distribution of [3H]TCP labeled PCP receptors.

Topics: Animals; Autoradiography; Binding, Competitive; Brain Chemistry; In Vitro Techniques; Kinetics; Male; Phenazocine; Phencyclidine; Piperidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Stereoisomerism

The functional significance of the reported affinity of (+)-3-PPP and (+)-N-allylnormetazocine (NANM) for the same binding site in rat brain membranes was assessed by studying (+)-3-PPP as a agonist and antagonist of (+)-NANM in rats trained to discriminate 5.0 mg/kg (+)-NANM from saline. Over a wide dose range, (+)-3-PPP was able to block the discriminative stimulus effects of (+)-NANM, with complete antagonism at 1.0 mg/kg i.p. Since (+)-NANM is a prototype sigma-opioid agonist, (+)-3-PPP is a good candidate for being a competitive sigma antagonist.

Topics: Animals; Binding Sites; Conditioning, Operant; Discrimination, Psychological; Generalization, Stimulus; Phenazocine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta

Alterations in motor activity induced by the isomers of 3-(3-hydroxyphenyl)-N,n-propylpiperidine (3-PPP) were studied in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. In both normal and MPTP-treated animals motor activity was suppressed in a dose-dependent manner by the administration of (-)-3-PPP. In control animals (+)-3-PPP caused biphasic changes in motor activity, namely suppression of activity in low doses but stimulation at higher doses. In contrast (-)-3-PPP only caused locomotor stimulation in MPTP-treated marmosets. (+)-3-PPP may potentially be of use as a post-synaptic dopamine agonist drug in Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Callitrichinae; Female; Isomerism; Levodopa; Male; Motor Activity; Piperidines; Pyridines; Receptors, Dopamine; Time Factors

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Azepines; Female; Male; Phenanthrenes; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Tetrahydronaphthalenes

The activities of substantia nigra pars compacta dopamine and globus pallidus neurons have been examined following the systemic administration of ( +/- )-3-PPP and the enantiomers of 3-PPP to investigate the relative effects of these putative dopamine agonists on dopamine autoreceptors and postsynaptic dopamine receptors. ( +/- )-3-PPP inhibited the firing rates of 7 out of 10 dopamine cells completely (ED50 = 0.18 +/- 0.06 mg/kg) but caused no consistent or significant alterations in the firing rates of globus pallidus neurons, exhibiting an apparent selectivity for the dopamine D-2 autoreceptors. However, (+)-3-PPP effectively inhibited the activity of all dopamine neurons studied (ED50 = 0.09 +/- 0.03 mg/kg) and, like d-amphetamine, apomorphine and other dopamine agonists, significantly stimulated pallidal activity. (-)-3-PPP was less effective at inhibiting dopamine cell activity; it had no effect on firing rates of pallidal cells when given alone, but it reversed the pallidal rate increases induced by (+)-3-PPP and also blocked the rate increases induced by systemically administered apomorphine. The results show that (-)-3-PPP, given systemically, acts as a partial agonist in the substantia nigra pars compacta and as an antagonist on postsynaptic dopamine receptors. These effects of (-)-3-PPP appear to account for the apparent dopamine autoreceptor selectivity demonstrated by racemic 3-PPP and further indicate that the autoreceptors and postsynaptic dopamine receptors may be differentially affected by a drug with mixed agonist/antagonist properties. These conclusions are consistent with those obtained from other techniques and support the idea that the effects of dopamine agonists on the activity of dopamine neurons and globus pallidus cells can provide an indication of the relative selectivity of these drugs for pre- or postsynaptic dopamine receptors.

Topics: Action Potentials; Animals; Apomorphine; Electrodes, Implanted; Globus Pallidus; Male; Neurons; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Substantia Nigra; Synapses

We describe a device to measure speed of movement and time at rest for use with a commercially available infrared photobeam activity monitor. This system is a reliable substitute for a human observer and provides additional measures of activity that can help in interpreting how psychoactive drugs alter behavior. The effects of graded doses of d-amphetamine, haloperidol and (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine, (-)-3-PPP, were studied with the device, and the results confirmed that these drugs differentially alter speed of movement and time at rest.

Topics: Animals; Dextroamphetamine; Dose-Response Relationship, Drug; Female; Haloperidol; Motor Activity; Neurophysiology; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Apomorphine; Chemical Phenomena; Chemistry; Dopamine; Dopamine Antagonists; Molecular Conformation; Naphthalenes; Piperidines; Receptors, Dopamine; Stereoisomerism; Structure-Activity Relationship; Tetrahydronaphthalenes; Thermodynamics

The novel atypical dopamine (DA) receptor agonist HW-165 (trans-7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline), a 'rigid' 3-PPP congener, and its enantiomers were investigated with regard to their actions on prolactin (PRL) release in rats. Racemic HW-165 dose dependently inhibited the elevation of PRL secretion induced by monoamine synthesis disruption (NSD 1015) combined either with abolished DA nerve impulse flow (GBL) or with monoamine depletion (reserpine). Racemic HW-165 was roughly equipotent to 3-PPP but 5-10-fold less potent than apomorphine. The PRL inhibitory action of racemic HW-165 was stereoselectively prevented by the DA antagonist (+)-butaclamol. Since the chiral aspect of lactotroph DA receptor activation by 'atypical' DA receptor agonists has not been covered in previous investigations the effects of the HW-165 enantiomers were now studied. Our findings suggest that the PRL inhibitory properties of racemic HW-165 reside in its (-) enantiomer, (+)-HW-165 being devoid of activity. Taken together, the results reinforce the concept that the pituitary lactotroph DA receptors mediating the inhibition of PRL release are similar, notably also from a stereochemical point of view, to central DA receptor sites with presumed high agonist sensitivity, such as DA autoreceptors.

Topics: 4-Butyrolactone; Animals; Apomorphine; Depression, Chemical; Male; Phenanthrenes; Piperidines; Pituitary Gland; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Stereoisomerism

This study emphasizes the importance of the metabolic conversion of the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) into their catechol analogues, the enantiomers of 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine. These isomers are both shown to be excellent substrates for COMT, with a slight preference for the S-(-) enantiomer. Assessment of the dopaminergic activity of these catechols and the results from the determination of brain levels of the enantiomers of 3-PPP and their metabolites indicate that the metabolites probably do not alter the pharmacological profiles established for (R)-(+)- and (S)-(-)-3-PPP. The conversion of the monophenols into catecholic metabolites is only 1-5%, and the further conversion of these catecholic metabolites into methoxylated analogues is very rapid. However, the very interesting observation was made that, when inhibiting COMT by means of tropolone and subsequently treating the rats with high doses of (S)-(-)-3-PPP (ip), postsynaptic dopaminergic activity was elicited. This has never been seen for (S)-(-)-3-PPP without tropolone pretreatment and might indicate that, in this special case, the catecholic metabolite affects the in vivo pharmacological profile of (S)-(-)-3-PPP.

Topics: Animals; Brain; Kinetics; Male; Methylation; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

Molecular mechanics (MMP2) calculated geometries and conformational energies have been employed in an attempt to elucidate the molecular basis for presynaptic dopamine receptor selectivity of centrally acting agonists of the phenylpiperidine series. A receptor interaction model based on the McDermed receptor concept, on superimpositions of calculated structures, and on conformational analysis is presented. The model focuses on the interaction between N-alkyl substituents and the receptor. From comparisons with rigid structures having either agonistic or antagonistic properties it is concluded that the presynaptically selective compound (S)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S)-3PPP) is acting as an agonist in one rotameric form and as an antagonist in another one. The selectivity of (S)-3PPP and the nonselectivity of its enantiomer are suggested to be due to differences in the interactions between N-alkyl substituents and the receptor. The receptor model presented led to the hypothesis that the piperidine ring in the compounds studied should be equivalent to a N-methyl group in its receptor interactions. Examples are given in support of this idea. Presynaptic selectivity was predicted for an aminotetralin derivative and was also observed in subsequent testing.

Topics: Brain; Models, Molecular; Molecular Conformation; Piperidines; Receptors, Dopamine; Structure-Activity Relationship

In the further development of CNS dopamine autoreceptor active compounds related to 3-PPP, the transfused 7-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline HW-165 and its enantiomers were synthesised. This paper describes the basic pharmacological properties of these latter, novel "atypical" dopaminergic agents, based on an extensive series of biochemical and behavioural experiments in rats. By and large, the pharmacological activities of HW-165 - essentially, if not exclusively, residing in its (4aS,10bS)-(-)-enantiomer - were similar to those displayed by (S)-(-)-3-PPP, indicating the simultaneous presence of central dopamine (autoreceptor) agonist and weak (postsynaptic) antagonist properties in the molecule. Thus, in non-pretreated animals HW-165 and its active species monotonically suppressed the spontaneous locomotion without causing catalepsy or other appreciable motor disabilities, and at the same time selectively reduced the dopamine synthesis, release/turnover and utilisation. Some differences in these biochemical responses to HW-165 [racemate or (-)-enantiomer] were, however, noted in the limbic vs. striatal brain areas (e.g. decrease of dopamine synthesis particularly in the limbic parts). On the other hand, while failing to reverse reserpine-induced akinesia or to elicit stereotyped behaviour, the agents markedly inhibited the dopamine synthesis in either of the dopamine-dominated cerebral regions in the reserpinised as well as in gamma-butyrolactone (GBL)-treated rats. As shown for racemic HW-165 after reserpine pretreatment, the inhibition of dopamine synthesis was completely and stereoselectively blocked by (+)-butaclamol, thereby supporting direct dopamine receptor interaction. Racemic HW-165 readily antagonised the d-amphetamine-induced locomotor hyperactivity. Apomorphine-induced hyperactivity was, however, distinctly more resistant to antagonism by HW-165 [racemate or (-)-enantiomer]. Moreover, the latter agents fully prevented the apomorphine-induced inhibition of striatal dopamine synthesis in otherwise non-pretreated rats, while only partly counteracting this effect of apomorphine in the limbic regions of such animals, and in either brain area of rats treated with gamma-butyro-lactone. The findings are interpreted within the context of the mixed dopamine agonist/antagonist properties (referred above) of HW-165 and its active (-)-species in relation to the adaptive state of central dopamine receptors and possible regional varia

Topics: 4-Butyrolactone; Animals; Behavior, Animal; Catecholamines; Corpus Striatum; Limbic System; Male; Motor Activity; Phenanthrenes; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Stereoisomerism

The ability of the enantiomers of the atypical dopamine receptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) to counteract gamma-butyrolactone-induced hyperprolactinemia was compared in male and female rats. Following gamma-butyrolactone (GBL) pretreatment serum prolactin concentrations were higher in female than in male rats. In males (-)-3-PPP tended to be somewhat less effective than (+)-3-PPP in decreasing serum prolactin concentrations (levels after (+)-3-PPP and (-)-3-PPP: 21% and 33%, respectively, of levels in GBL-pretreated control(s). In females the (-)-form induced a much weaker response than did the (+)-form (levels after (+)-3-PPP and (-)-3-PPP: 8% and 74%, respectively, of levels in GBL pretreated controls). Parallel experiments replacing GBL by reserpine yielded similar results. Data are discussed in terms of sex differences in responsiveness of pituitary dopamine receptors.

Topics: 4-Butyrolactone; Animals; Female; Furans; Male; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sex Factors; Stereoisomerism

Extracellular single unit and microiontophoretic studies were carried out in rats, anesthetized with chloral hydrate, to investigate the actions of the enantiomers of the dopamine (DA) agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) on the firing rate of noradrenaline-containing neurons in the locus coeruleus (LC). Intravenously-administered (+)-3-PPP dose-dependently reduced firing of cells in the locus coeruleus with a 50% inhibition occurring after 2 mg/kg. This action was partially antagonized by the alpha 2-noradrenaline (NA) antagonist, yohimbine, but not by the DA antagonist haloperidol or the alpha 1-antagonist prazosin. Pretreatment with reserpine completely blocked the suppressant effect of (+)-3-PPP on firing rate. Iontophoretically-applied (+)-3-PPP did not influence the basal firing rate of cells in the locus coeruleus and failed to influence the inhibitory action of simultaneously-applied DA. Neither intravenously nor iontophoretically administered (-)-3-PPP influenced basal firing rate of neurones in the locus coeruleus. However, intravenously-administered drug weakly reversed the inhibitory action of the alpha 2-agonist clonidine (100 micrograms/kg) and iontophoretic ejection antagonized the inhibitory action of DA. These findings suggest that (-)-3-PPP possesses a weak antagonist action at alpha 2-adrenoceptors present in the locus coeruleus. In contrast, administration of (+)-3-PPP resulted in a weak activation of these receptors which was possibly the result of an enhanced release of NA.

Topics: Animals; Dose-Response Relationship, Drug; Electrophysiology; Haloperidol; Injections, Intravenous; Iontophoresis; Locus Coeruleus; Male; Neurons; Piperidines; Prazosin; Rats; Rats, Inbred Strains; Stereoisomerism; Yohimbine

In rats trained to discriminate the prototypic sigma receptor agonist, (+)-N-Allylnormetazocine [(+)-N-Allylnormetazocine [(+)-NANM/SKF 10,047], from saline, the (+)- but not the (-)-isomer of 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) produced (+)-NANM-like discriminative stimuli. (+)-3-PPP binds stereo selectively to the (+)-NANM binding site, but not to the phencyclidine binding site. Additionally, phencyclidine was found to produce (+)-NANM-like discriminative stimuli. Although the 3-PPP isomers were shown to produce changes in central dopaminergic activity (Hjorth et al. Life Sci 37, 673, 1985), the discriminative stimulus properties of (+)-3-PPP are apparently not mediated via the dopaminergic system. This hypothesis is supported by the fact that apomorphine did not produce (+)-NANM-like discriminative stimuli. These stimuli are thus non-dopaminergic and may be due to the (+)-3-PPP actions at the sigma binding site. However, it is possible that (+)-NANM, PCP, and (+)-3-PPP may have common non-sigma pharmacologic properties that account for the similar discriminative stimulus properties of these compounds.

Topics: Animals; Apomorphine; Discrimination Learning; Dose-Response Relationship, Drug; Isomerism; Male; Phenazocine; Phencyclidine; Piperidines; Rats; Rats, Inbred F344

Yawning was induced in rats by the (+) enantiomer of 3PPP, while (-)-3PPP was inactive. Yawning was present 24, but not 1, 6 and 12 h after reserpine treatment. The (+)-3PPP-induced yawning was antagonized by haloperidol and sulpiride but not by domperidone. Reserpine-induced yawning was antagonized by sulpiride and by alpha-methyltyrosine suggesting that this behavior may be induced by endogenously released dopamine. Reserpine-pretreatment potentiated (+)-3PPP-induced yawning. The results argue against the view that yawning is the behavioural correlate of autoreceptor-mediated inhibition of DA transmission, and suggest that this behaviour is due to the stimulation of a special population of central postsynaptic DA receptors.

Topics: Animals; Domperidone; Drug Synergism; Haloperidol; Male; Methyltyrosines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reflex; Reserpine; Stereoisomerism; Sulpiride

In vitro radioligand binding and autoradiographic distribution studies have suggested the possible involvement of central sigma-opiate sites in the effects of several purportedly dopaminergic agents. Specifically, Largent et al. (Proc. Nat. Acad. Sci. 81, 4983, 1984) proposed that "actions of 3-PPP at sigma receptors may account for the effect of the drug on behavior and dopaminergic nerve function". Using the sigma-opiate- and dopamine (DA)-preferring (-)- and (+)-enantiomer, respectively, of butaclamol, and the two enantiomers of 3-PPP, the present study was undertaken to address the in vivo functional significance of this proposal. To this end we investigated various biological responses considered to reflect drug interactions with DA cell body and terminal autoreceptors and with presumed non-synaptic and postsynaptic DA receptors in the rat CNS. (+)- but not (-)-butaclamol antagonized the 3-PPP (either enantiomer)-induced DA synthesis and prolactin decreases in GBL-treated rats, the (+)-3-PPP-induced inhibition of substantia nigra DA cell firing and the (+)-3-PPP-induced reversal of reserpine akinesia. Taken together with previous findings available data suggest that DA rather than sigma-opiate receptors mediate the neurochemical, electrophysiological, behavioral and other physiological (prolactin, body temperature) effects of 3-PPP and its enantiomers. The in vivo pharmacological relevance of the claimed non-dopaminergic, proposedly sigma-opiatergic, radioligand binding demonstrated in vitro (with e.g. (+)-3-PPP) thus remains to be established.

Topics: Animals; Butaclamol; Corpus Striatum; Dopamine; Limbic System; Male; Motor Activity; Pentazocine; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, sigma; Reserpine; Stereoisomerism

6,7-Dihydroxy-2-dimethylaminotetralin (TL-99), N-n-propyl-3-(3-hydroxyphenylpiperidine [(+/-)-3-PPP], N-n-propylnorapomorphine and pergolide were evaluated for activity on a number of biochemical parameters that are presumed to indicate an agonist effect at dopamine (DA) autoreceptors (antagonism of the gamma-hydroxybutyrate-induced increase in dopa formation), at postsynaptic DA receptors (elevation of acetylcholine levels) or at both types of DA receptors (diminution of DA synthesis and homovanillic acid levels) in rat striatum. All four agents decreased striatal dopa accumulation (in the presence and in the absence of gamma-hydroxybutyrate). N-propylnorapomorphine, pergolide and TL-99 also reduced homovanillic acid levels and increased acetylcholine concentrations in striatum whereas (+/-)-3-PPP was inactive. The compounds were all more potent in diminishing dopa accumulation caused by gamma-hydroxybutyrate treatment than in increasing acetylcholine levels [(+/-)-3-PPP showing the highest dissociation] indicating a preferential agonist activity at DA autoreceptors. The relative selectivity of the compounds for DA autoreceptors and postsynaptic DA receptors was evaluated further by studying the antagonism by these drugs of the activation of striatal dopa formation (index of both DA autoreceptor and postsynaptic DA receptor stimulation) and tyrosine hydroxylase (index of postsynaptic DA receptor stimulation only) induced by haloperidol or reserpine. The DA agonists were all more potent in antagonizing the neuroleptic-induced increase in DA synthesis than in counteracting the drug-induced activation of tyrosine hydroxylase, with (+/-)-3PPP exhibiting the highest dissociation. The present results indicate that the DA agonists studied possess some selectivity for striatal DA autoreceptors, (+/-)-3-PPP being the most selective in this respect.

Topics: Acetylcholine; Animals; Apomorphine; Corpus Striatum; Dihydroxyphenylalanine; Ergolines; Haloperidol; Homovanillic Acid; Male; Naphthalenes; Pergolide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Sodium Oxybate; Tetrahydronaphthalenes; Tyrosine 3-Monooxygenase

Striatal acetylcholine concentration was determined after administration of varying doses of apomorphine, (+)-PPP and (-)-PPP to rats. (+)-PPP at 3 and 10 mg kg-1 is a dopamine agonist, whereas (-)-PPP at 0.3 and 3 mg kg-1 is a dopamine antagonist in the striatum.

Topics: Acetylcholine; Animals; Apomorphine; Corpus Striatum; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The dopamine agonist 3-PPP and its enantiomers are hydroxylated in-vitro by rat liver microsomes to the catecholamine 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine (4-OH-3-PPP) with Km and Vmax values of about 1 microM and 2 nmol (mg protein)-1 min-1 respectively. As the catecholamine formed appears to be a good substrate for catechol-O-methyltransferase, in-vivo catecholamine formation in rats from 3-PPP was only detectable after inhibition of COMT by tropolone. The resulting brain levels of 4-OH-3-PPP, as measured by HPLC with electrochemical detection 45 min after administration, were about 350 pmol g-1 after i.p., and about 100 pmol g-1 after s.c. injection of 45 mumol kg-1 3-PPP, with no significant difference between racemic, ( + ) or (-) 3-PPP. It was estimated that these catecholamine levels represent about 1-5% of the 3-PPP levels after i.p., and about 0.2-0.5% after s.c. administration of 3-PPP. The relevance of this metabolic conversion of 3-PPP for its pharmacological profile is discussed.

Topics: Animals; Biotransformation; Catecholamines; Female; Hydrogen-Ion Concentration; Hydroxylation; In Vitro Techniques; Kinetics; Methylation; Microsomes, Liver; Piperidines; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Stereoisomerism

Rat striatal synaptosomal tyrosine hydroxylation was inhibited dose- and pH dependently by a number of dopamine agonists. The catecholic agonists apomorphine and (-)N-n-propylnorapomorphine inhibited synaptosomal tyrosine hydroxylase completely, with IC50 values of around 0.3 mumol/l at pH 6.6. The noncatechol agonists pergolide and bromocriptine and the putative dopamine autoreceptor agonists 3-PPP(-), 3-PPP(+), HW-165 and B-HT 920 produced only partial inhibition of synaptosomal tyrosine hydroxylation at high concentrations. Comparison of the inhibition of synaptosomal and soluble tyrosine hydroxylase indicated that the inhibition produced by apomorphine could be ascribed to a direct effect on the enzyme, whereas this was not the case for the noncatechol agonists. The inhibition produced by pergolide and 3-PPP(-) was not antagonised by either dopamine receptor or alpha-adrenoceptor antagonists. The present results have been compared with results reported in the literature for inhibition of synaptosomal tyrosine hydroxylation and for two other tests of dopamine autoreceptor agonist activity (inhibition of dopamine release from striatal slices in vitro, and inhibition of the gamma-butyrolactone induced increase in dopamine synthesis in vivo). It is concluded that inhibition of striatal synaptosomal tyrosine hydroxylation by dopamine agonists does not fulfil the criteria required for it to be considered as a useful measure of dopamine autoreceptor function.

Topics: Adrenergic alpha-Agonists; Animals; Apomorphine; Azepines; Corpus Striatum; Depression, Chemical; Dopamine; Ergolines; Hydrogen-Ion Concentration; In Vitro Techniques; Male; Pergolide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Neurotransmitter; Synaptosomes; Tyrosine 3-Monooxygenase

(-)-3-PPP, is a unique dopamine analogue, reported to have selective agonist actions at dopamine autoreceptors and antagonist actions at postsynaptic receptors. The interactions of D2 dopamine receptors with (-)-3-PPP in vitro were examined, using [3H]spiperone to label D2 receptors in brain regions containing both pre- and postsynaptic D2 receptors (caudate nucleus, corpus striatum) and a region containing nonsynaptic D2 receptors (anterior pituitary). In the absence of sodium ions, (-)-3-PPP detected D2 receptors in high- and low-affinity states in all regions examined, as is typical of dopamine agonists. That these two subpopulations of (-)-3-PPP-detected sites were dopaminergic in nature was assured by precluding [3H]spiperone binding to serotonergic receptors. In the presence of sodium ions, there was a significant increase in the affinity of some D2 receptors detected by (-)-3-PPP, and (-)-3-PPP in the presence of sodium was unable to discriminate between the two D2 affinity states in pituitary and striatum. The addition of guanine nucleotide led to (-)-3-PPP recognition of a single D2 binding site; the enhanced affinity of D2 receptors for (-)-3-PPP in the presence of sodium was retained in the presence of guanine nucleotide. These in vitro characteristics of (-)-3-PPP recognition of dopamine D2 receptor binding sites, when compared with dopamine and spiperone are seen to have clear features of both typical agonist and antagonist interactions with D2 receptors in both brain and pituitary.

Topics: Animals; Brain; Cattle; Caudate Nucleus; Cell Membrane; Corpus Striatum; Dopamine Antagonists; Guanine Nucleotides; Male; Piperidines; Pituitary Gland, Anterior; Rats; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Serotonin; Sodium Chloride; Swine

Topics: Autoradiography; Brain; Humans; In Vitro Techniques; Membranes; Phenazocine; Phencyclidine; Piperidines; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Phencyclidine

Selective presynaptic dopamine receptor agonists appear to offer promise as putative antipsychotic agents with a low risk of extrapyramidal side-effects, including tardive dyskinesia. However, no such agent with a reasonable degree of selectivity has yet reached the stage of clinical trial. In the present paper the particular pharmacological profile of presynaptic dopamine receptor (autoreceptor) agonists is described, and underlying mechanisms are discussed. Special attention is paid to the compound 3-(3-hydroxyphenyl-N-n-propylpiperidine(3-PPP), especially its levotatory enantiomer. This agent shows affinity for both pre- and postsynaptic dopamine receptors. Its intrinsic activity in different locations varies between virtually zero and 100%, leading to a mixture of agonist and antagonist properties. It is suggested that this variability depends on the adaptive properties of the dopamine receptor.

Topics: Animals; Binding, Competitive; Brain; Corpus Striatum; Dogs; Dopamine; Piperidines; Prolactin; Rats; Receptors, Dopamine; Stereoisomerism; Substantia Nigra; Synapses; Vomiting

The effects of several dopamine agonists were determined on medial septal self-stimulation in rats and compared with selected dopamine antagonists and with the psychostimulants, d-amphetamine and nomifensine. Apomorphine, 3-PPP, TL-99, N,N-dipropyl-5,6-ADTN and N,N-dipropyl-6,7-ADTN inhibited self-stimulation at dose ranges selective for the dopamine autoreceptor as indicated by biochemical studies. Haloperidol and molindone produced dose-related inhibition but sulpiride increased self-stimulation. D-amphetamine and nomifensine also increased responding. The agonist-induced inhibition differed from neuroleptic-induced inhibition of self-stimulation. Both (+) and (-) 3-PPP inhibited responding by a similar amount over the dose range 0.25-1.0 mg/kg. At higher doses, (-) 3-PPP further decreased responding whereas the effects of (+) 3-PPP plateaued at approximately 55% of controls. These studies show that dopamine agonists, like neuroleptics, inhibit medial septal self-stimulation. This effect appears to be mediated via autoreceptor activation. Differences between neuroleptic- and agonist-induced inhibition and the 3-PPP stereoisomer data accord with the hypothesis that behavioural inhibitory effects caused by autoreceptor activation are less severe than those caused by dopamine postsynaptic blockade.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Appetite Depressants; Benzazepines; Dextroamphetamine; Drug Interactions; Haloperidol; Male; Nomifensine; Piperidines; Rats; Receptors, Dopamine; Self Stimulation; Stereoisomerism; Sulpiride; Tetrahydronaphthalenes

The behavioural and biochemical effects of racemic 3-PPP (3-[3-hydroxyphenyl]-N-n-propyl-piperidine) and its enantiomers was studied in developing rats, aged 1-28 days. All three compounds exhibit dopamine (DA) autoreceptor-stimulating properties. Moreover, the (+)-enantiomer displays agonist and the (-)-enantiomer antagonist actions, respectively, on the postsynaptic DA receptor. This means that the racemate has a DA autoreceptor stimulatory action with slight or no effects on the postsynaptic receptor. Locomotor experiments demonstrated that (+/-)-3-PPP inhibited spontaneous locomotor activity dosedependently in the 28 days old rats. No effects were seen in the age groups 14 days and younger. While the racemate and the (-)-enantiomer inhibited spontaneous locomotor activity in 28 days old rats, the (+)-enantiomer had no effects compared to saline. Interestingly, the (+)-enantiomer increased locomotor activity in the 4 days old rats, while the (-)-enantiomer and the racemate did not induce any effects. In the biochemical experiments, after blockade of DA neurotransmission with gamma-butyrolactone (GBL), (+/-)-3-PPP inhibited the increase in tyrosine hydroxylase activity (DOPA accumulation after NSD 1015) after GBL in the DA rich striatum region of the 28 days but not of the 4 days old rats. From these experiments it may be concluded that functional postsynaptic but not presynaptic DA receptors exist in the brain of 4 days old rats. Presynaptic DA receptors do not seem to be functionally mature until 28 days postnatally in the rat, i.e. during adolescent age.

Topics: 3,4-Dihydroxyphenylacetic Acid; Age Factors; Animals; Brain; Brain Chemistry; Dihydroxyphenylalanine; Motor Activity; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

In an attempt to enhance the potency of the dopamine autoreceptor agonist 3-PPP, racemic cis-3-(3-hydroxyphenyl)-5-[(methylmercapto)methyl]-N-n-propylpiperidine has been prepared in a stereoselective synthesis. NMR studies of 3 show a diequatorial conformation for the 3- and 5-substituents, which gives compound 3 an intriguing overlap with the ergoline derivative pergolide. Pharmacological testing revealed that 3, which is a 5-(methylmercapto)methyl derivative of racemic 3-PPP does not show the anticipated potency increase as a dopamine autoreceptor agonist. In vitro (inhibition of tyrosine hydroxylation) 3 and 1 have similar potency, and the in vivo potency (inhibition of GBL accelerated dopamine synthesis) of 3 is inferior to that of 1.

Topics: 4-Butyrolactone; Animals; Chemical Phenomena; Chemistry; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Mice; Piperidines; Rats; Receptors, Dopamine; Structure-Activity Relationship

The effects of sub-chronic treatment with (-)-3-PPP (8 mg/kg, s.c., b.i.d. for 21 days), a dopaminergic agent with mixed agonist/antagonist properties, were investigated by means of behavioural and in vivo biochemical methods. There was no change in basal locomotor activity and central dopamine (DA) synthesis after 24 hours withdrawal. A slight, though significant reduction of the locomotor suppressive effect and of the DA synthesis-stimulating effect of acute (-)-3-PPP challenge doses of 0.125 and 1.0 mg/kg (s.c.), respectively, were demonstrated in (-)-3-PPP-pretreated as compared to vehicle-pretreated rats. No change in either action was evident after acute challenge with 8.0 mg/kg (s.c.) of the drug. The plasma levels of (-)-3-PPP were virtually unchanged by pretreatment with active drug. The findings are discussed in terms of a modest down- and up-regulation of DA autoreceptors and postsynaptic receptors, respectively, induced by the subchronic (-)-3-PPP treatment.

Topics: Animals; Body Weight; Brain; Corpus Striatum; Dihydroxyphenylalanine; Limbic System; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

In contrast to racemic 3-PPP (3-(3-hydroxyphenyl)-N-n-propylpiperidine), (+)-3-PPP appeared to inhibit the electrically evoked release of both [3H]dopamine (DA) and [14C]acetylcholine (ACh) from superfused rat neostriatal slices, although it was considerably less potent in this respect that the DA receptor agonists apomorphine, TL-99 (6,7-dihydroxy-N,N-dimethyl-2-aminotetralin) and LY 141865. At concentrations higher than 1 microM both of the 3-PPP enantiomers increased the spontaneous efflux of 3H but not that of 14C. (+)3-PPP also inhibited the cholera toxin-stimulated release of immunoreactive alpha-MSH from dispersed intermediate lobe cells of the rat pituitary gland. The inhibitory effects of (+)3-PPP on both transmitter and alpha-MSH release were antagonized by the selective D-2 receptor antagonist (-)-sulpiride. Neither [3H]DA nor [14C]ACh release were inhibited by (-)3-PPP but, in contrast, the release-inhibiting effect of the selective D-2 receptor agonist LY 141865 as well as that of (+)3-PPP were antagonized by (-)3-PPP, although less effectively than by (-)sulpiride. The inhibitory effect of LY 141865 on alpha-MSH release from intermediate lobe cells was also antagonized by (-)3-PPP. The data indicate that (+)3-PPP is a weak agonist and (-)3-PPP a weak antagonist at D-2 receptors and that neither of the 3-PPP enantiomers interacts selectively with DA autoreceptors mediating presynaptic modulation of striatal DA release.

Topics: Acetylcholine; Animals; Cholera Toxin; Corpus Striatum; Dopamine; In Vitro Techniques; Male; Melanocyte-Stimulating Hormones; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Sulpiride

The novel dopaminergic agents (+)- and (-)-3-PPP were evaluated for their effects upon thermoregulation in rats maintained at room temperature (approximately 22 degrees C). Although approximately 30 times less potent than apomorphine, (+)-3-PPP induced a clearcut, dose-dependent and haloperidol/pimozide-reversible hypothermia. In contrast, the (-)-enantiomer per se lacked a significant effect upon rat body temperature. However, (-)-3-PPP clearly attenuated apomorphine-induced hypothermia. Simultaneous biochemical investigations confirmed the presence of central dopamine (DA) agonist and antagonist properties for (+)- and (-)-3-PPP, respectively, at the doses employed. The results are compared to the agonist and antagonist effects of the 3-PPP enantiomers in various other central DA receptors systems. Particular reference is made to the recent hypothesis by Carlsson (J. Neural Transm. 57 (1983) 309, relating agonist intrinsic activity to the DA receptor responsiveness state, in turn determined by the endogenous tone. Based on the findings with (+)- and (-)-3-PPP it is suggested that DA receptors mediating hypothermia in the rat may be more akin to 'normosensitive' postsynaptic than to highly 'agonist-responsive' autoreceptors.

Topics: Animals; Apomorphine; Biogenic Amines; Body Temperature; Brain Chemistry; Dose-Response Relationship, Drug; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

Criteria for distinguishing dopamine autoreceptor agonism from other mechanisms of inhibiting locomotion were examined, together with the relationship between inhibition of locomotion and dopamine synthesis. ED50 potencies to inhibit locomotion of mice were established for drugs from a number of categories. Spiperone 0.02 mg kg-1 significantly (P less than 0.05) reversed inhibition of locomotion by known dopamine agonists but not that by the other types of drug. Idazoxan antagonized inhibition of locomotion due to alpha 2-agonists but not dopamine agonists. RU 24926 (N-propyl-N,N-di[2-(3-hydroxyphenyl)ethyl]amine) was antagonized by both spiperone and idazoxan. Only for dopamine agonists was there good correlation (r = 0.97) between potencies to inhibit locomotion in mice and L-dihydroxyphenylalanine (L-DOPA) accumulation in the nucleus accumbens of rats treated with gamma-butyrolactone and 3-hydroxybenzylhydrazine. The specific dopamine D1-agonist, SK&F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine), was inactive in both tests at doses up to 10 mg kg-1. The mixed dopamine agonist/antagonist, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine, commonly known as (-)-3-PPP, acted as a dopamine agonist in both tests but inhibited locomotion more potently than L-DOPA accumulation. The inhibitory effects of dopamine agonists on locomotion were not prevented by alpha-methyl-p-tyrosine pretreatment. The data suggest that spiperone-reversible inhibition of locomotion in mice is a good criterion for dopamine autoreceptor agonists. The receptors involved are affected by low doses of both dopamine agonists and antagonists and seem similar to those involved in the autoreceptor mediated inhibition of dopamine synthesis. However, inhibition of locomotion is not due simply to suppression of dopamine release brought about as a secondary consequence of effects on synthesis; a separate mechanism for inhibiting dopamine release is probably involved.

Topics: alpha-Methyltyrosine; Animals; Dopamine; Levodopa; Locomotion; Male; Methyltyrosines; Mice; Mice, Inbred Strains; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

Bilateral injection of apomorphine into the zona reticulata of substantia nigra in rats reduced locomotor activity and striatal dopamine (DA) turnover. In contrast, bilateral injection of (+/-)-3-(3-hydroxyphenyl)-N,n-propylpiperidine [(+/-)-3-PPP] into the zona reticulata (ZR) did not reduce locomotor activity and did not affect striatal DA turnover. A high dose of (+/-)-3-PPP increased locomotor activity. Unilateral injection of (+/-)-3-PPP, but not of apomorphine, into the ZR induced a brief period of contraversive rotation. (+/-)-3-PPP may not alter nigral DA autoreceptor function but may interact with DA receptors located on non-dopaminergic nigral neurones.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Apomorphine; Corpus Striatum; Dopamine; Female; Homovanillic Acid; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Substantia Nigra

The effects of subcutaneous administration of the two enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), a new dopamine analogue, were studied with regard to their effects on sleep parameters in the rat. The studies with both enantiomers were carried out taking into account their different effects on central dopaminergic receptors. At low doses they act preferentially as autoreceptor agonists; at higher doses the (+)-form is also an agonist while the (-)-form acts as an antagonist at postsynaptic dopamine receptors. The results showed the following: (1) with the high dose of (+)-3-PPP there was no change in REM sleep, but a marked increase in wakefulness; (2) with the high dose of (-)-3-PPP there was a significant increase in REM sleep and in the mean duration of REM episodes; (3) with the low dose of (+)-3-PPP similar results to those described for high-dose (-)-3-PPP were obtained; (4) there was no significant alteration of sleep parameters with the low dose of (-)-3-PPP. The data are discussed in terms of an active role for dopamine in the regulation of REM sleep.

Topics: Animals; Isomerism; Male; Piperidines; Rats; Rats, Inbred Strains; Reaction Time; Sleep; Sleep Stages

Extracellular single unit recording and microiontophoretic studies were carried out in chloral hydrate-anesthetized gallamine-paralyzed rats to investigate the actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, on the nigrostriatal DA system. Intravenously administered (+)- or (-)-3-PPP consistently inhibited nigral DA neuronal activity; these actions were readily antagonized by haloperidol but were not affected by a pretreatment of reserpine plus alpha-methyltyrosine. In contrast to (+)-3-PPP, the (-)-enantiomer produced only partial inhibition of the majority of cells studied and was also capable of partially reversing the inhibitory action of apomorphine. A prior hemitransection of the brain did not alter the inhibitory action of either enantiomer. Whereas iontophoretically ejected (+)-3-PPP consistently reduced DA cell firing rate, similarly applied (-)-3-PPP reduced the activity of only some DA cells, while the majority were not influenced. In addition, iontophoresis of (-)-3-PPP could reduce the inhibitory effect of similarly applied DA or (+)-3-PPP. The (+)-enantiomer reduced caudate neuronal activity both after intravenous administration and iontophoresis. Intravenously administered (-)-3-PPP failed to influence or increased the activity of these neurons and reversed the inhibitory action of apomorphine. However, iontophoretically ejected drug reduced caudate cell activity and did not influence the inhibitory action of DA. The activity of non-DA zona reticulata neurons was inconsistently influenced by the 3-PPP enantiomers. It is concluded that (+)-3-PPP is a directly acting DA agonist, stimulating both DA autoreceptors and postsynaptic DA receptors. In contrast, (-)-3-PPP appears to be a partial agonist at nigral DA autoreceptors, whereas the action of the drug at putative postsynaptic DA receptors in the caudate remains to clarified.

Topics: Animals; Caudate Nucleus; Chloral Hydrate; Dopamine; Dose-Response Relationship, Drug; Electrophysiology; Iontophoresis; Male; Piperidines; Rats; Rats, Inbred Strains; Stereoisomerism; Substantia Nigra

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Catechol O-Methyltransferase; Cattle; Dopamine; Kinetics; Liver; Methylation; Piperidines; Pyrogallol

The (+)- and (-)-enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) were studied for their effects on DA1 and DA2 dopamine receptors in pentobarbital anesthetized dogs. 3-PPP enantiomers were administered into the renal artery after phenoxybenzamine pretreatment to determine possible DA1 activity; dopamine was also injected for comparison. DA2 activity was determined by injection of the enantiomers into the femoral vascular bed with intact nerve supply and without phenoxybenzamine; dipropyl dopamine (DPDA) or apomorphine were used as standard DA2 agonists. Antagonist activity of the enantiomers on DA1 or DA2 receptors was determined by simultaneous administration of the enantiomer with DA in the renal vascular bed and with DPDA or apomorphine in the femoral vascular bed. Neither enantiomer was active as a DA1 agonist, but both exhibited antagonist activity. Both enantiomers were found to be agonists of the DA2 receptor; in addition, both showed DA2 antagonist activity. In all actions the (-)-enantiomer was approximately 4 times more potent than the (+)-enantiomer.

Topics: Animals; Dogs; Femoral Artery; Models, Biological; Piperidines; Receptors, Dopamine; Regional Blood Flow; Renal Artery; Stereoisomerism

The enantiomers of 3-PPP or haloperidol were injected in various doses to rats 1 hour after the established dopamine receptor ligand N,N-dipropyl-5,6-ADTN. After another 40 minutes the binding of the ligand to the striatum was measured by high performance liquid chromatography, using the level in the cerebellum as "blank". (-)-3-PPP was found to cause a maximum 71% displacement of the ligand from the striatal binding sites. Haloperidol proved to be more potent but not significantly more efficacious in displacing the ligand. However, the combined treatment with (-)-3-PPP and haloperidol caused a stronger displacement of the ligand than (-)-3-PPP alone, suggesting that the binding-site populations available for the two agents are not fully identical. (+)-3-PPP also caused displacement of the ligand but was considerably less potent than its enantiomeric twin. The results are discussed against the background of the different pharmacological profiles of the 3-PPP enantiomers and haloperidol. It is suggested that an inverse relationship may exist between receptor affinity and intrinsic activity and that such a relationship may be inherent in the mechanism underlying receptor stimulation.

Topics: Animals; Binding, Competitive; Brain; Cerebellum; Corpus Striatum; Haloperidol; Isomerism; Male; Naphthalenes; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Tetrahydronaphthalenes

Seven enantiomeric pairs of N-alkyl analogues of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 12) have been synthesized and evaluated pharmacologically (biochemistry and behavior) in order to examine their ability to interact with central dopamine (DA) receptors, particularly DA autoreceptors. In the R series it seems as if all compounds behave as classical DA receptor agonists with affinity and intrinsic activity for both pre- and postsynaptic receptors. The same bifunctional profile seems to be valid for the S enantiomers with N-substituents larger or bulkier than n-propyl. Likewise, the S enantiomers with ethyl or n-propyl N-substituents seem to have affinity for both pre- and postsynaptic receptors. In the total series, (S)-(-)-3-PPP [(S)-12] seems to be the most interesting compound both from the theoretical and the therapeutical point of view, possibly attenuating DA function in two different ways by stimulating the presynaptic receptors and blocking the postsynaptic receptors. This compound has been selected for extended pharmacological studies as a potential antipsychotic drug.

Topics: Animals; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Male; Motor Activity; Norepinephrine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Reserpine; Serotonin; X-Ray Diffraction

3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist in the central nervous system. This report describes the pharmacology and localization of specific high-affinity binding sites for (+)-[3H]3-PPP in brain. The drug specificity of (+)-[3H]3-PPP binding is identical to that of sigma receptors, which may mediate psychotomimetic effects of some opiates. Haloperidol and the opioid derivatives, pentazocine, cyclazocine, and SKF 10,047 are potent inhibitors of (+)-[3H]3-PPP binding. Stereoselectivity is exhibited for the (+) isomers of cyclazocine and SKF 10,047 at the sigma site, opposite to the stereoselectivity seen at mu, delta, and kappa opiate receptors. (+)-[3H]3-PPP does not label dopamine receptors, as potent dopamine agonists and antagonists are weak inhibitors of binding and the localization of specific (+)-[3H]3-PPP binding sites does not parallel that of dopamine neurons. Discrete localizations of (+)-[3H]3-PPP binding sites in many brain areas including limbic, midbrain, brainstem, and cerebellar regions may explain psychotomimetic actions of opiates and behavioral effects of 3-PPP.

Topics: Animals; Brain Mapping; Brain Stem; Cerebellum; Guinea Pigs; Haloperidol; Hypothalamus; Limbic System; Mesencephalon; Piperidines; Rats; Receptors, Dopamine; Receptors, Opioid; Stereoisomerism

The two enantiomers of 3PPP were tested on the spontaneous and electrically-evoked release of 3H-dopamine from slices of the rabbit caudate nucleus and of 3H-acetylcholine (3H-ACh) from slices of the rat caudate nucleus. In caudate slices labelled with 3H-dopamine, exposure to (+)3PPP (0.1-1 microM) facilitated the spontaneous outflow of radioactivity with a concomitant inhibition of the electrically-evoked release of 3H-dopamine. In the presence of cocaine 10 microM, exposure to (+)3PPP (1 microM) inhibited the electrically evoked release of 3H-dopamine without modifying the spontaneous outflow of radioactivity. This inhibitory effect was not significantly antagonized by S-sulpiride 0.01 microM. Exposure to (+)3PPP 1 microM inhibited the electrically-evoked release of 3H-ACh, and this effect was not modified by pretreatment with reserpine alone, or in combination with alpha-methyl-p-tyrosine (alpha-MT). In contrast to the (+) enantiomer, exposure to (-)3PPP (0.1-1 microM) facilitated the electrically-evoked release of 3H-dopamine without affecting the spontaneous outflow of radioactivity. (-)3PPP antagonized the inhibitory effect of apomorphine on the electrically-evoked release of 3H-dopamine. Exposure to (-)3PPP 1 microM did not modify the spontaneous or the electrically-evoked release of 3H-ACh. Yet, this concentration of (-)3PPP antagonized significantly the inhibitory effect of 0.03 microM apomorphine, 1 microM d-amphetamine, and 1 microM (+)3PPP on the electrically-evoked release of 3H-ACh (-)3PPP (0.1-1 microM) was about 100 times less potent than S-sulpiride at antagonizing the inhibitory effect of apomorphine on the electrically-evoked release of 3H-ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Animals; Corpus Striatum; Dextroamphetamine; Dopamine; Electric Stimulation; In Vitro Techniques; Male; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Synaptic Transmission; Tritium

Both enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP; 0.5-32 mg/kg s.c.) dose dependently reduced the increase in striatal dopamine (DA) synthesis rate produced by gamma-butyrolactone (GBL). Whereas (+)-3-PPP completely prevented the action of GBL, (-)-3-PPP was only partially effective. In addition, (-)-3-PPP partially antagonised the inhibitory action of apomorphine on the GBL-induced increase in DA synthesis rate. These findings suggest that (+)- and (-)-3-PPP act as full and partial agonists respectively, at striatal DA autoreceptors controlling DA synthesis.

Topics: 4-Butyrolactone; Animals; Apomorphine; Corpus Striatum; Dopamine; Isomerism; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Neurotransmitter

Dopaminergic agonists, apomorphine (APO) (0.025-0.25 mg/kg, s.c.), TL-99 (0.5-3 mg/kg, s.c.) and 3-PPP (0.15-10 mg/kg, s.c.) elicited yawning in rats and the dose-response curves of all 3 compounds showed a bell-shaped form. Haloperidol (0.02 mg/kg, s.c.) reduced the yawning induced by DA-agonists to about 50%. The potencies of the DA-agonists in inducing yawning were APO greater than TL-99 greater than 3-PPP (comparable to potencies obtained in other in vivo tests, determining DA-ergic activity). The findings support the validity of the yawning phenomenon as a screening test for DA-agonists. Additionally, it was found that apomorphine induced yawning was significantly and dose-dependently enhanced by the beta-agonist, formoterol. This effect was counteracted by scopolamine, not changed by metergoline and further increased by l-propranolol. These data support the hypothesis of cholinergic involvement in yawning and indicate a role, though unclear at present, of beta-receptors in this behaviour.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Apomorphine; Behavior, Animal; Haloperidol; Male; Naphthalenes; Piperidines; Rats; Tetrahydronaphthalenes

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.

Topics: Adenylyl Cyclases; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antiemetics; Catalepsy; Dogs; Dopamine; Female; Guinea Pigs; Histamine Antagonists; Humans; Male; Mice; Motor Activity; Norepinephrine; Parasympatholytics; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Stereotyped Behavior; Synaptosomes

The effects of the (+) and (-) enantiometers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), 9,10-didehydro-6-methyl-8 beta-(2-pyridylthiomethyl)ergoline (CF 25-397) and 6,7-dihydroxy-2-dimethyl-aminotetralin (TL 99), three agonists of the postulated presynaptic dopamine receptor, on the pattern of brain glucose metabolism were studied using the autoradiographic technique of Sokoloff et al. [19]. It was found that these drugs modify brain glucose metabolism in a way similar to the neuroleptics but different from postsynaptic agonists. These results support the suggestion that these drugs could represent a new type of neuroleptic.

Topics: Animals; Antipsychotic Agents; Apomorphine; Brain; Catecholamines; Ergolines; Glucose; Naphthalenes; Piperidines; Rats; Reserpine; Tetrahydronaphthalenes

The actions in vitro of SCH 23390, YM 09151-2 and both enantiomers of 3-PPP on D-1 and D-2 dopamine receptors were investigated in superfused rat neostriatal slices. For comparison the following neuroleptics of different chemical classes were incorporated in our investigations: (+)-bulbocapnine, clozapine, chlorpromazine, cis-flupenthixol, (-)-sulpiride and haloperidol. The increase in the efflux of cyclic AMP was used as a measure for D-1 receptor stimulation. The decrease in the K+-evoked release of [3H]acetylcholine was used as measure of D-2 receptor stimulation. None of the drugs stimulated the D-1 receptor. Only (+)-3-PPP stimulated the D-2 receptor. All other drugs, including (-)-3-PPP, behaved as antagonists on the D-2 receptor, YM 09151-2 being the most potent. SCH 23390 was the most potent antagonist on the D-1 receptor. Haloperidol, cis-flupenthixol and (+)-bulbocapnine showed an appreciable D-1 receptor blocking potency in our model, whereas the other drugs were inactive. We found SCH 23390 to be the most D-1 selective antagonist although the drug still displayed considerable potency on the D-2 receptor. YM 09151-2 was the most D-2 selective antagonist.

Topics: 1-Methyl-3-isobutylxanthine; Acetylcholine; Animals; Antipsychotic Agents; Aporphines; Benzamides; Benzazepines; Caudate Nucleus; Chlorpromazine; Clozapine; Flupenthixol; Haloperidol; In Vitro Techniques; Male; Piperidines; Potassium; Putamen; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2

The effects of (+)- and (-)-3-PPP on cAMP levels of rabbit retina were investigated in vitro in the absence or presence of exogenous dopamine. In some experiments, a pre-incubation with reserpine was undertaken to deplete endogenous dopamine before the test. (+)- and (-)-3-PPP were found to be a weak dopamine-agonist and a weak dopamine-antagonist, respectively. Thus, the 3-PPP enantiomers may have opposite actions at the level of postsynaptic dopamine receptors, as previously suggested by studies in vivo.

Topics: Animals; Cyclic AMP; Dopamine; In Vitro Techniques; Isomerism; Piperidines; Rabbits; Receptors, Dopamine; Receptors, Dopamine D1; Retina

The motor effects of some DA autoreceptor agonists and apomorphine in rats with bilateral 6-hydroxydopamine lesions of the median forebrain bundle were studied. Whereas (-)-3-PPP, (+)-3-phenethyl-PP and EMD 23448 decreased motility in sham-operated controls, a pronounced hypermotility was induced in 6-OHDA-lesioned rats. 3-PPP enantiomers and apomorphine had similar potency as that found in test models for DA autoreceptor activity in normal rats, e.g. motility inhibition. The DA receptor involvement in the effect of (-)-3-PPP was confirmed by neuroleptic antagonism. (-)-3-PPP and EMD 23448 had similar intrinsic activity as apomorphine, whereas (+)-3-phenethyl-PP and (+)-3-PPP had lower maximal effect. However, the DA autoreceptor agonists differed from apomorphine: The development of postsynaptic supersensitivity to these drugs appeared 4-7 days after the lesion compared to 1-2 days for apomorphine and (+)-3-PPP. Furthermore, no active oral stereotypy was induced by the autoreceptor selective compounds in contrast to the effect observed after apomorphine and (+)-3-PPP. In a separate experiment using circling behaviour in unilaterally 6-OHDA-lesioned rats the different time-course of appearance of supersensitivity to (-)-3-PPP, (+)-3-PPP and apomorphine was confirmed. After chronic reserpine treatment a similar postsynaptic supersensitivity to (-)-3-PPP was observed with a development time between 4 and 7 days and with a similar intensity as that observed in 6-OHDA-lesioned rats. In contrast, after chronic neuroleptic treatment for 12 days, (-)-3-PPP was unable to induce hyperactivity 3-7 days after withdrawal. The results indicate that DA autoreceptor agonists are able to stimulate postsynaptic DA receptors in conditions without endogenous transmitter supply for at least 4-7 days, but not after chronic receptor blockade in a similar period. This should lead to consideration of DA autoreceptor agonists as potential antiparkinsonian drugs without stimulant effects on normosensitive postsynaptic DA receptors.

Topics: Animals; Antiparkinson Agents; Apomorphine; Behavior, Animal; Drug Interactions; Hydroxydopamines; Male; Oxidopamine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Stereoisomerism; Stimulation, Chemical

The administration of (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) was found to partially, but significantly, suppress the acquisition (4-8 mg/kg IP) and performance (8-16 mg/kg IP) of a conditioned avoidance response (CAR) in male Sprague-Dawley rats. All statistically significant effects were observed within 2 h of injection. Furthermore, using a situation in which the CAR was dependent on a visual successive discrimination, it was shown that discriminative performance was unaffected, and that (-)3-PPP (12.5-25 mg/kg IP) but not (+)3-PPP, suppressed the CAR. When (-)3-PPP (6.25 mg/kg IP) was combined with haloperidol (0.1-0.4 mg/kg IP), additive effects on the CAR performance were observed. Considering these effects, and the doses of (-)3-PPP required to suppress the CAR performance, it is concluded that the effects obtained in the present experiments are primarily due to a blockade of postsynaptic DA receptors.

Topics: Animals; Avoidance Learning; Conditioning, Operant; Discrimination Learning; Haloperidol; Male; Piperidines; Rats; Rats, Inbred Strains

Several novel dopamine (DA) agonists (SKF 38393, 3-PPP, TL-99) have been reported to induce rotational behavior (RB) in rats unilaterally denervated of the nigro-striatal pathway by 6-hydroxydopamine. Other reports have indicated no RB, however, and these drugs do not cause other behavioral manifestations of postsynaptic DA agonism. In the present experiments, two groups of 6-hydroxydopamine-denervated rats were distinguished by their relative responsiveness to apomorphine-induced RB. A highly sensitive group showed maximal RB in response to doses as low as 0.03 mg/kg, while a less sensitive group exhibited comparable RB only in response to 15- to 20-fold higher doses. The high sensitivity group exhibited RB in response to SKF 38393, 3-PPP and pergolide, but the low sensitivity group did not show appreciable RB after these drugs, even at doses 50 to 100-fold higher. Haloperidol markedly attenuated apomorphine-induced RB in the low sensitivity subgroup, but only reduced by approximately one-half the number of turns induced by apomorphine or SKF 38393 in the high sensitivity group. The atypical antipsychotics, clozapine and RMI 81582, and the muscle relaxant, methocarbamol, reduced RB in all groups, but only at doses that caused performance impairment in a rotorod test. These results appear to reflect qualitative differences in responsiveness to different DA agonists. Behavioral preselection of 6-hydroxydopamine-denervated animals is necessary to achieve consistent pharmacological results with the 6-hydroxydopamine RB model.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Benzazepines; Clozapine; Ergolines; Humans; Hydroxydopamines; Male; Oxidopamine; Pergolide; Piperidines; Postural Balance; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior; Sympathectomy, Chemical

The injection of (-)3-PPP into the nucleus accumbens, 10 microgram/side, produced a suppression of exploratory locomotor activity without affecting treadmill locomotion. Furthermore, the suppression of exploratory locomotor activity produced by (-)3-PPP was antagonized by the administration of haloperidol, 25-50 micrograms/kg i.p.

Topics: Animals; Exploratory Behavior; Haloperidol; Male; Motor Activity; Nucleus Accumbens; Piperidines; Rats; Rats, Inbred Strains; Septal Nuclei

The efficacy of several drugs to elicit yawning and penile erections were determined in rats. The dopamine agonists, N-propylnorapomorphine, apomorphine, pergolide, (+/-)-3-PPP, TL-99 and N,N-dipropylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (N,N-dipropyl A-5,6-DTN) all elicited yawning accompanied by an increase in spontaneous penile erections. The potencies of these drugs in causing yawning closely resemble published data concerning their actions in biochemical tests reputedly indicative of autoreceptor activity. In contrast, SK&F 38393, A-5,6-DTN and clonidine produced no yawning and few or no penile erections. Although physostigmine also caused yawning, the effect was not accompanied by penile erections. Studies with the optical isomers of 3-PPP showed that (+)-3-PPP was considerably more potent than (-)-3-PPP. Haloperidol antagonised dopamine agonist-induced yawning and penile erections. Apomorphine-induced yawning and penile erections were also antagonised by sulpiride and atropine but not by domperidone. The suitability of elicitation of the combined syndrome of yawning plus penile erections as useful behavioural model for dopamine autoreceptor agonists is discussed.

Topics: Animals; Apomorphine; Drug Interactions; Haloperidol; Inhalation; Isomerism; Male; Models, Psychological; Penis; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Respiration; Sexual Behavior, Animal; Syndrome

Male Sprague-Dawley rats were treated for 3 weeks with (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP). Twenty-four hours, but not 72 hours, after withdrawal of the treatment there was an increase in locomotor activity in comparison with saline treated controls. At the same time there was a decrease in striatal DOPAC and HVA and an increased locomotor activity response to apomorphine, indicating supersensitive dopamine receptors. There was no evidence for behavioral tolerance since the suppression of locomotor activity after an acute dose of (-)3-PPP was the same in (-)3-PPP-pretreated as in saline-treated controls. Plasma levels of (-)3-PPP in these animals were, however, slightly decreased.

Topics: Animals; Body Weight; Corpus Striatum; Dopamine; Kinetics; Male; Motor Activity; Nucleus Accumbens; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The administration of apomorphine (0.2-0.8 mg/kg IP) or (+)3-PPP(4-8 mg/kg IP) produced a facilitation of the male rat sexual behavior. Apomorphine in lower doses, as well as the selective DA autoreceptor agonist (-)3-PPP were ineffective. Except for a decrease in number of intromissions and an increase in the postejaculatory interval at the highest dose (0.32 mg/kg IP) there were no effects after administration of haloperidol. These data indicate that activation or inhibition of the presynaptic dopamine receptor does not affect male rat sexual behavior.

Topics: Animals; Apomorphine; Brain; Haloperidol; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sexual Behavior, Animal

The interaction of the enantiomers of the novel dopamine agonist, 3-PPP (3-hydroxyphenyl)-N-n-piperidine) with the dopamine receptor in the anterior pituitary gland was examined. Both (+)- and (-)-3-PPP were effective in suppressing the elevation in serum prolactin (PRL) concentrations in rats treated with alpha-methyl-paratyrosine, an inhibitor of dopamine synthesis. The (+)-enantiomer was slightly more potent than the (-)-enantiomer in this regard. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by both isomers of 3-PPP, with (+)-3-PPP being approximately 10 times more potent than (-)-3-PPP. Both (+)- and (-)-3-PPP displaced 3H-(-)-N-n-propylnorapomorphine (3H-NPA) and 3H-spiperone from bovine anterior pituitary membranes. The Hill coefficients of (+)- and (-)-3-PPP for the displacement of 3H-spiperone were 0.6 and 0.7, respectively. These results are consistent with the view that the (+)- and (-)-enantiomer exhibit dopamine agonist effects at dopamine receptor sites in the anterior pituitary gland. However, (+)-3-PPP demonstrated marked differences in affinity for 3H-NPA- and 3H-spiperone labeled-sites, whereas (-)-)3-PPP showed the same order of affinity for these two sites. In view of these results and the fact that (-)-3-PPP has also been characterized as a dopamine antagonist at postsynaptic receptor sites in the striatum, (-)-3-PPP might be best described as a partial agonist at pituitary dopamine receptors. Moreover, these data are suggestive of a similarity, at least on a pharmacological basis, between dopamine autoreceptors and dopamine receptors in the anterior pituitary gland.

Topics: Animals; Apomorphine; Binding Sites; Cell Membrane; Depression, Chemical; In Vitro Techniques; Male; Methyltyrosines; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spiperone; Stereoisomerism

Following treatment with dopamine (DA) receptor agonists, such as apomorphine, N-n-propyl-norapomorphine, lisuride and 3-(3-hydroxyphenyl)-N-n-propyl-piperidine (3-PPP) (50, 2.5, 400 and 5000 micrograms/kg, respectively), male rats attain ejaculation with receptive females sooner and after fewer penile intromissions than controls. Since doses of DA agonists needed to produce "premature ejaculation" are within the low dose range needed to stimulate DA autoreceptors, it is suggested that "premature ejaculation" in rats results from inhibition of DA neurotransmission. This hypothesis is supported by the finding that 6 hr after haloperidol (1 mg/kg), rats achieve ejaculation after fewer intromissions than normal.

Topics: Animals; Apomorphine; Copulation; Domperidone; Dopamine Antagonists; Ejaculation; Female; Haloperidol; Lisuride; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sexual Behavior, Animal

The inhibitory actions of 3 putative dopamine receptor agonists on the firing of neurons in slices of rat substantia nigra in vitro was examined. The EPMR values for 3-PPP, RDS-127 and TL-99 were 1.11, 2.66 X 10(-3) and 2.4 X 10(-4) respectively. All 3 agonist effects were antagonized by 1 microM sulpiride.

Topics: Action Potentials; Animals; Depression, Chemical; Dopamine Antagonists; Indans; Indenes; Male; Naphthalenes; Piperidines; Rats; Substantia Nigra; Tetrahydronaphthalenes

Yawning behaviour in rats was studied by direct observation. Apomorphine dose dependently induced yawning: 0.05 mg/kg was most effective, 0.2 mg/kg induced locomotor and sniffing behaviour but less yawning. Sulpinide (2 and 10 mg/kg) dose dependently blocked the apomorphine (0.05 mg/kg)-induced yawning. (+)-3-PPP (1-10 mg/kg) induced yawning in a manner similar to that of apomorphine but (-)-3-PPP (1-10 mg/kg) did so only weakly. Yawning induced by (+)-3-PPP was blocked by sulpiride 10 mg/kg. It is concluded that (+)-3-PPP but not (-)-3-PPP is at least as effective as apomorphine to induce yawning in rats, indicating that (+)-3-PPP, but not (-)-3-PPP, is a pure agonist on dopamine autoreceptors.

Topics: Animals; Apomorphine; Behavior, Animal; Domperidone; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Sulpiride

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Corpus Striatum; Ergolines; Male; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine

The putatively selective dopamine autoreceptor agonists TL-99 and 3-PPP were compared with apomorphine for the production of contraversive turning in the 6-hydroxydopamine-lesioned rat. Although less potent than apomorphine, 3-PPP produced dose-related contralateral turning. The contralateral turning produced by TL-99 plateaued at the 3 mg/kg i.p. dose level. Yohimbine significantly enhanced the TL-99-induced turning, whereas it failed to modify the 3-PPP turning. The results suggest that the alpha 2-adrenergic properties of TL-99 at doses of greater than 3.0 mg/kg masked its dopaminergic effects. Hence, 3-PPP is clearly the more selective agent for DA receptors.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Apomorphine; Female; Hydroxydopamines; Motor Activity; Naphthalenes; Oxidopamine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Substantia Nigra; Tetrahydronaphthalenes; Yohimbine

The agonist actions of 3-PPP at central dopamine (DA) autoreceptors were found to reside mostly in its (+) enantiomer, (+)-3-PPP also reduced striatal content of DOPAC and HVA, whereas (-)-3-PPP elevated HVA levels. Only (-)-3-PPP antagonized DA stimulation of DA-receptor linked adenylate cyclase. It was more effective than (+)-3-PPP at inhibiting [3H]DA binding to striatal membranes. The results suggest that (+)-3-PPP may act predominantly at DA autoreceptors, while (-)-3-PPP exhibits weak affinity for presynaptic and postsynaptic DA receptors.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Apomorphine; Corpus Striatum; Dopamine; Homovanillic Acid; Male; Mice; Molecular Conformation; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Synaptosomes; Tyrosine 3-Monooxygenase

The effects of the enantiomers of 3-PPP on the maintenance of conditioned avoidance responding (CAR) were studied. The weak classical dopamine (DA) agonist (+)-3-PPP failed to interfere with CAR at any dose tested (0.8-13.6 mg/kg). Low doses of the drug produced sedation, while high doses produced behavioural stimulation. (-)-3-PPP, which acts as an antagonist on postsynaptic and as an agonist on autoreceptor DA sites, reduced avoidance with no effect on escape behaviour (6.8-13.6 mg/kg). However, this reduction of CAR occurred at doses much higher than those previously demonstrated to inhibit locomotor activity. This profile is discussed in relation to the behavioural effects of classical postsynaptic DA receptor antagonists.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Catalepsy; Humans; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Stereoisomerism; Time Factors

As part of an ongoing research project aimed at developing novel selective monoamine-, in particular DA-, receptor active agents the DA analogue 3-PPP, and its enantiomers, were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments revealed clearcut DA autoreceptor-stimulatory properties for all three compounds. In addition, the (+)-enantiomer displayed agonist and the (-)-enantiomer antagonist actions, respectively, on postsynaptic DA receptors. Thus the racemate was rendered a biological profile consonant with selective DA autoreceptor stimulation. Both biochemical and behavioural indices of central DA activity suggested a preferentially limbic impact for racemic 3-PPP and, more interestingly, the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with neuroanatomical differences in the feedback organisation in central (viz. limbic vs. striatal) DA systems. Due to their aforementioned characteristics, it is suggested that compounds like racemic and (-)-3-PPP may find potential clinical utility in the treatment of neuropsychiatric disorders, whilst lacking in the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy. An overview of the literature covering various in vivo and in vitro aspects of 3-PPP pharmacology is also included and taken into consideration, where pertinent. The results suggest that the use of chemical tools like 3-PPP and its enantiomers may provide new insight into central dopaminergic function, e.g. in investigating the consequences of interacting with specific DA receptor populations and the relative importance of pre- vs. postsynaptic feedback regulation in different DA systems, as well as their possible implications.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Brain; Cyclic AMP; Escape Reaction; Humans; Locomotion; Male; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Stereotyped Behavior

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenylyl Cyclases; Animals; Antiemetics; Antipsychotic Agents; Catalepsy; Dogs; Dopamine; Female; Guinea Pigs; Humans; Male; Mice; Motor Activity; Norepinephrine; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Serotonin; Stereoisomerism; Stereotyped Behavior; Synaptosomes

The claim that TL-99 (6,7-dihydroxy-2-dimethylaminotetralin hydrobromide) is a selective dopamine autoreceptor agonist relies partly upon indirect behavioral evidence, particularly the absence of stereotyped behavior in treated rats. The possibility was examined that concurrent alpha 2-adrenoceptor agonist properties of TL-99 could have masked postsynaptic dopamine agonist activity. Co-administration of yohimbine or piperoxan with a high dose of TL-99 (30 mg/kg) dramatically increased motor activity in reserpinized rats, whereas each drug by itself had no effect. Contralateral rotational behavior in 6-hydroxydopamine-lesioned rats resulted from combined treatment with yohimbine and a high dose of TL-99 (30 mg/kg) but appeared to be suppressed by concurrent flaccidity if TL-99 was given by itself. Yohimbine failed to alter the effects of 3-PPP (N-n-propyl-3-(3-hydroxyphenyl)-piperidine), another putative dopamine autoreceptor agonist, in either model of postsynaptic dopamine agonism. It is concluded that a concurrent behaviorally depressant action of TL-99, possibly alpha 2-agonism, masks the stimulation of postsynaptic dopamine receptors by high doses of TL-99.

Topics: Animals; Male; Motor Activity; Naphthalenes; Piperidines; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Dopamine; Rotation; Tetrahydronaphthalenes; Yohimbine

3-PPP has been reported to be a selective dopamine autoreceptor agonist, a conclusion based on in vivo studies. In rat neostriatum in vitro however, 3-PPP antagonized concentration-dependently the stimulation of cyclic AMP efflux caused by the D-1 receptor agonist SKF 38393 and the inhibition of K+-induced [3H]acetylcholine release caused by the D-2 receptor agonist LY 141865. 3-PPP alone did not affect [3H]acetylcholine release or cyclic AMP efflux. When interpreting the effects of 3-PPP in vivo dopamine receptor antagonism should be considered.

Topics: Acetylcholine; Animals; Corpus Striatum; Cyclic AMP; In Vitro Techniques; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine

The racemic mixture and the (-)enantiomer of the putative dopamine autoreceptor agonist 3-PPP were investigated in vitro using dopamine-sensitive adenylate cyclase in homogenates of rat striatum as a model for a postsynaptic D1-receptor type and inhibition of electrically-evoked tritium overflow from rat striatal slices preincubated with [3H]choline and [3H]dopamine as a model for a postsynaptic D2- and a presynaptic dopamine autoreceptor type, respectively. In contrast, to apomorphine, neither the racemic mixture nor the (-)enantiomer exerted any effect, suggesting agonistic properties in all three receptor models. However, both (+/-)3-PPP and (-)3-PPP were weak antagonists at postsynaptic D1- and D2-receptors. The results of the present investigation suggest that the in vivo effects of 3-PPP are either the result of metabolic activation or that this drug activates an other dopamine autoreceptor type, pharmacologically different from that one modulating dopamine release.

Topics: Adenylyl Cyclases; Animals; Corpus Striatum; Cyclic AMP; Male; Models, Neurological; Piperidines; Rats; Receptors, Dopamine; Stereoisomerism

trans- and cis-7-hydroxy-octahydrobenzo(f)quinoline were synthesized as analogues of the selective dopamine autoreceptor agonist 3-PPP. The trans compound appeared more effective than 3-PPP in the dopamine autoreceptor test model, but it also exhibited postsynaptic dopamine receptor stimulating activity. The cis compound was inactive in both these test models. It is concluded that in the trans compound the dopamine autoreceptor stimulating potency of 3-PPP has been much enhanced at the cost of dopamine autoreceptor selectivity.

Topics: 4-Butyrolactone; Animals; Corpus Striatum; Dihydroxyphenylalanine; Female; Hydroxyquinolines; Male; Mice; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine

The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.

Topics: Animals; Apomorphine; Behavior, Animal; Biogenic Amines; Brain Chemistry; Dextroamphetamine; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Stereoisomerism

Based on observations with the novel dopamine-receptor agonist 3-(3-hydroxyphenyl-)-N-n-propylpiperidine, 3-PPP, especially its levorotatory enantiomer, it is proposed that the intrinsic activity of a receptor agonist depends in part on the responsiveness of the receptor; this in turn is determined by the degree of previous agonist occupancy on the receptor. A change in occupancy will induce a slow conformational change, influencing the responsiveness. This may constitute an important aspect of receptor adaptation and may help to explain otherwise puzzling phenomena, e.g. that compounds such as (-)-3-PPP or transdihydrolisuride can act as strong dopamine-receptor agonists in some locations and as antagonists in others. The observations discussed in the present paper may be interpreted to indicate that the dopamine receptors in different locations are, in fact, derived from a homogenous receptor population, though in a varying state of adaptation. Thus it may prove worth-while to reconsider the various subclassifications of DA receptors proposed so far.

Topics: Animals; Apomorphine; Brain; Denervation; Exploratory Behavior; Hydroxydopamines; Oxidopamine; Piperidines; Prolactin; Rats; Receptors, Dopamine; Stereoisomerism; Sympathectomy, Chemical

In the course of a search for new selective dopamine (DA) autoreceptor agonists the DA analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, was resolved into its dextro-(+) and levo-(-) rotatory enantiomers. The compounds were pharmacologically evaluated by means of behavioural and biochemical methods. Surprisingly, both (+)-and (-)-3-PPP show clearcut, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA receptor agonist with activity on autoreceptors as well as postsynaptic receptors, whereas (-)-3-PPP similarly activates DA autoreceptors but, in contrast, concomitantly acts as an antagonist on postsynaptic DA receptors. Moreover, the behavioural/biochemical profile seems to indicate a preferential limbic action for the (-)-enantiomer. Such an action could be explained on the basis of different feedback arrangements in the nigrostriatal and mesolimbic DA systems and it is suggested that compounds such as (-)-3-PPP may find future clinical application as "second-generation" antipsychotic agents, lacking in the debilitating motor side effects produced by drugs in current therapeutic use.

Topics: Animals; Apomorphine; Dextroamphetamine; Dose-Response Relationship, Drug; Motor Activity; Optical Rotation; Piperidines; Rats; Receptors, Dopamine; Reserpine

Slices of the rabbit caudate nucleus were preincubated with 3H-dopamine or 3H-choline and then superfused and stimulated electrically. DiPr-5,6-ADTN reduced the stimulation-evoked overflow of tritium over the same concentration range, independently of whether slices had been preincubated with 3H-dopamine or 3H-choline, and the same was true for apomorphine, NPA and pergolide. Three other putative dopamine receptor agonists, namely 3-PPP, DPI and SKF 38393, failed to decrease the evoked overflow of tritium. Each of six antagonists--(-)-sulpiride, (+)-sulpiride, CGP 11109 A, cis-flupentixol, domperidone and corynanthine--increased the evoked overflow over the same concentration range in experiments with 3H-dopamine and in those with 3H-choline. For each of these antagonists except cis-flupentixol, and also for chlorpromazine, haloperidol and rauwolscine, the pA2 values against apomorphine obtained in 3H-dopamine and in 3H-choline experiments were closely similar. The antagonist effect of cis-flupentixol against apomorphine was not purely competitive. (-)-Sulpiride was a more potent antagonist than (+)-sulpiride, and cis-flupentixol was more potent than trans-flupentixol. This study supplements a previous one in which (+/-)-sulpiride, metoclopramide and molindone were used as antagonists. It is a functional in vitro approach to receptor characterization, as opposed to radioligand binding studies or in vivo investigations. The results show that a large number of dopamine receptor agonists and antagonists are unable to distinguish between the presynaptic, release-inhibiting dopamine autoreceptors and those postsynaptic dopamine receptors which, when activated, depress the release of acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acetylcholine; Animals; Apomorphine; Benzazepines; Caudate Nucleus; Choline; Clonidine; Female; Male; Piperidines; Rabbits; Receptors, Dopamine

NCA, the chloro analog of the potent dopamine agonist NPA is an irreversible ligand at dopamine receptors in mammalian brain. The chloroethyl analog of the recently described putative dopamine autoreceptor agonist 3-PPP, 3-PPP-C1, was evaluated for its potential use as an irreversible autoreceptor ligand. N-Chloroethylation of 3-PPP reduced the intrinsic affinity of the agonist seven-fold and, consequently, in contrast to NCA, it was found that 3-PPP-C1 was not a good irreversible ligand at dopamine receptors.

Topics: Animals; Aporphines; Brain; In Vitro Techniques; Ligands; Piperidines; Rats; Receptors, Dopamine

The effect of different dopamine (DA) agonists on spontaneous activity and d-amphetamine-induced hyperactivity was studied in 11, 20 and 30 day old rats. The proposed selective DA autoreceptor agonist 3-PPP induced biphasic hyperactivity at 11 and 20 days of age, whereas only hypoactivity was observed at 30 days of age, as shown previously for adult rats. The enantiomers of 3-PPP had differential effect: (+)-3-PPP increased activity in 11 and 20 day old rats, where (-)-3-PPP had no effect in similar doses but motility decreased at a higher dose. At 30 days of age (+)-3-PPP decreased motility at low doses and increased motility at a high dose, whereas (-)-3-PPP induced a monotonic decrease, as observed in adult rats. The reference DA agonists apomorphine and pergolide induced only hyperactivity at 11 and 20 days of age. At 30 days the usual sedative effect of low doses was seen. These results confirm that DA autoreceptors mediating sedation are developed later than postsynaptic DA receptors mediating hyperactivity and suggest that 3-PPP (by its (+)-enantiomer) stimulates postsynaptically. (-)-3-PPP had no detectable postsynaptic DA stimulating activity and may, in contrast, act as a postsynaptic antagonist at high doses. Racemic-and (-)-3-PPP antagonized the d-amphetamine-induced hyperactivity at all ages, whereas (+)-3-PPP had no effect and apomorphine was effective at 30 days of age only. These results suggest that the d-amphetamine antagonism by (-)-3-PPP cannot be explained solely by DA autoreceptor stimulation but that autoreceptor stimulation may contribute to the inhibitory effect in mature rats.

Topics: Age Factors; Animals; Dextroamphetamine; Female; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

The behavioral effects of the putative dopamine autoreceptor agonists, TL-99 and 3-PPP, were explored in animal procedures that reveal highly characteristic effects of neuroleptics currently in clinical use. Sidman avoidance responding in rats was not altered appreciably by doses up to 10 mg/kg TL-99 or 30 mg/kg 3-PPP. Higher doses of TL-99 attenuated Sidman avoidance performance in squirrel monkeys, although 3-PPP had no effect. Lever pressing for intracranial self-stimulation (ICSS) was attenuated in a dose-related fashion by TL-99 and 3-PPP, with relatively shallow dose-response relationships. A low dose of haloperidol (0.03 mg/kg) partly reversed the effects of 3-PPP (3 mg/kg) on lever pressing ICSS, but not those of TL-99 (3 mg/kg). Yohimbine (3 mg/kg) failed to alter the effects of TL-99 at a dose that abolished the suppressant effect of clonidine on ICSS. Analysis of within-session ICSS response decrement patterns indicated that TL-99 reduced ICSS to a greater extent towards the end of the session than during the first 5 min. No such within-session trend was produced by 3-PPP, suggesting that 3-PPP attenuates ICSS by virtue of a performance deficit. Similar conclusions were reached using a shuttlebox task that involved self-regulation of ICSS duration by rats. Therefore, the clinical profile of neuroleptics is unlikely to be mimicked precisely by 3-PPP or TL-99. Clinical trials of DA autoreceptor agonists for antipsychotic efficacy will indicate whether or not avoidance and ICSS behaviors are relevant to the detection of the intrinsic antipsychotic activity of drugs.

Topics: Animals; Avoidance Learning; Haloperidol; Male; Models, Psychological; Naphthalenes; Piperidines; Rats; Rats, Inbred F344; Receptors, Dopamine; Saimiri; Self Stimulation; Tetrahydronaphthalenes

Acute administration of 3-3-hydroxyphenyl-N-n-propyl-piperidine (3-PPP), selectively increased intracellular serotonin (5-HT) fluorescence in the dorsal raphe and 5-HT as well as 5-hydroxyindoleacetic acid (5-HIAA) in the corresponding projection site of the dorsal raphe, the striatum. These effects are similar to those produced by systemic treatments with apomorphine (APO). Serotonin neurons in the median raphe and its corresponding terminal area hippocampus were not affected by either APO or 3-PPP. Haloperidol at a dose having no significant effect alone, antagonized the APO-induced elevation of striatal 5-HT. The differential effects of 3-PPP on the mesostriatal and mesolimbic serotonergic systems further confirm that the dorsal and median raphe nuclei constitute two anatomically and functionally distinct cell groups and the similarities of the effects of APO and 3-PPP indicate that dopamine autoreceptors may mediate the observed effects of APO on 5-HT neurons.

Topics: Animals; Apomorphine; Chromatography, High Pressure Liquid; Corpus Striatum; Haloperidol; Hippocampus; Male; Neurons; Piperidines; Raphe Nuclei; Rats; Rats, Inbred Strains; Receptors, Dopamine; Serotonin; Spectrometry, Fluorescence

3-(3-Hydroxyphenyl)-N-n-propylpiperidine (3-PPP) is a novel compound existing in two enantiomers which, as judged by recent biochemical and behavioural studies, both have clearcut though differential effects on central dopamine (DA) receptors. Thus, while both enantiomers act in low doses as agonists preferentially on autoreceptors, in higher doses the (+)-form is an agonist also postsynaptically while the (-)-form acts as an antagonist on postsynaptic DA receptors in the striatum and in the limbic system. In the present study both enantiomers were evaluated with respect to their effects on pituitary DA receptors involved in prolactin release. In previously untreated rats, no increase in prolactin release was observed after administration of either enantiomer in low or high doses. The lack of effect of high doses of the (-)-form indicates that DA receptors on the lactotrophs are pharmacologically different from postsynaptic DA receptors in nigrostriatal and mesolimbic systems. The finding that both enantiomers exerted a dose-dependent prolactin suppressive effect in reserpine-pretreated animals suggests instead that DA receptors on the lactotrophs are pharmacologically similar to DA autoreceptors in the brain. The effect of both 3-PPP enantiomers on prolactin release in reserpine-pretreated animals was antagonized by haloperidol, sulpiride and metoclopramide while pimozide and clozapine appeared less active. This finding is discussed with respect to possible selectivity on pre- vs. postsynaptic DA receptors for various antagonists.

Topics: Animals; Isomerism; Male; Piperidines; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Tranquilizing Agents

Four Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol were subjected to a trial of the dyskinesia-modifying effects of a novel dopamine autoreceptor agonist 3-PPP (3[3-hydroxyphenyl]-N-n-propyl-piperidine). Three monkeys had choreic dyskinesia involving trunk and extremities whereas one had a buccolingual form including tongue protrusion with choreoathetotic twitching and twisting movements of the tongue. Two monkeys (1 choreic, 1 buccolingual) responded with dose-dependent symptom alleviation to 3-PPP, 1-4 mg/kg, with no signs of concomitant sedation or catalepsy. In the monkey with buccolingual dyskinesia all dyskinetic signs disappeared completely 2 hours after 2 mg/kg of 3-PPP. This animal participated in a separate study where the same doses of 3-PPP but also its enantiomers were given. The (-) enantiomer was a more potent antidyskinetic agent than the (+) enantiomer, the racemate falling between these two. Four mg/kg of the (+) enantiomer precipitated an amphetamine-like excitation and after 4 hours aggravation of dyskinesia was noted. These observations support the notion that the (+) enantiomer has both postsynaptic and presynaptic stimulatory effects, whereas the (-) enantiomer acts as a presynaptic dopamine receptor agonist.

Topics: Animals; Cebus; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Fluphenazine; Haloperidol; Male; Piperidines; Stereoisomerism

It was found that (-)-3-PPP, 5-160 microgram/side produced a statistically significant suppression of exploratory locomotor activity after application to the nucleus accumbens. The (+)-isomer was about 8 times less potent in suppressing exploratory activity. Except for suppression of the locomotor activity by 160 micrograms of (-)-3-PPP no statistically significant effects were produced by either isomer applied in the neostriatum.

Topics: Animals; Exploratory Behavior; Male; Motor Activity; Nucleus Accumbens; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Septal Nuclei; Stereoisomerism

Topics: Acetylcholine; Animals; In Vitro Techniques; Naphthalenes; Piperidines; Potassium; Rats; Receptors, Dopamine; Tetrahydronaphthalenes

Since the reduction of striatal dopaminergic transmission decreases striatal acetylcholine (ACh) levels due to disinhibition of the respective neurons, such an effect might be expected after selective stimulation of dopamine (DA) autoreceptors. The effects of a number of DA agonists, including the purportedly selective presynaptic agents 3-PPP and TL 99, on striatal ACh levels were investigated over a wide dose range. Apomorphine and 3-PPP decreased ACh levels in a lower dose range (0.01-0.03 mg/kg s.c. and 0.2-1 mg/kg s.c., resp.) TL 99 showed a significant, but much smaller effect (0.1-0.3 mg/kg s.c.), whereas piribedil and bromocriptine only increased ACh. However, 3-PPP (at 3 mg/kg and above) and TL 99 (at 3 mg/kg) increased ACh in much the same way as did conventional DA agonists. These results suggest (a) that pre- and postsynaptic DA receptors are distinct in a functionally relevant manner, and (b) that 3-PPP and TL 99 possess postsynaptic effects on DA receptors associated with cholinergic neurons. Since 3-PPP does not elicit stereo sterotypes in spite of evidence for an involvement of cholinergic neurons in the mediation of this behaviour it might be assumed that it acts on other postsynaptic DA receptors than does apomorphine. Moreover, it seems possible that the two types of DA receptors are located on two different types of cholinergic neurons with different functions.

Topics: Acetylcholine; Animals; Apomorphine; Corpus Striatum; Dopamine; Male; Piperidines; Piribedil; Rats; Tetrahydronaphthalenes; Time Factors

TL-99 and 3-PPP, two putative dopamine autoreceptor agonists, effectively suppressed serum prolactin (PRL) concentrations in rats treated with alpha-methyltyrosine. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by TL-99 and 3-PPP. These findings are supportive of the view that TL-99 and 3-PPP exert a dopamine agonist action at dopamine receptors in the anterior pituitary gland.

Topics: Animals; Male; Naphthalenes; Piperidines; Pituitary Gland, Anterior; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Tetrahydronaphthalenes

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Dextroamphetamine; Humans; Male; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Stereotyped Behavior; Time Factors

Topics: Animals; Apomorphine; Butaclamol; Corpus Striatum; Dopamine; Hydroxydopamines; In Vitro Techniques; Male; Nerve Tissue Proteins; Piperidines; Potassium; Protein Methyltransferases; Protein O-Methyltransferase; Rats; Rats, Inbred Strains; S-Adenosylhomocysteine; S-Adenosylmethionine; Synaptosomes

The putative dopamine autoreceptor agonists, 3-PPP and TL-99 were examined for their ability to stimulate postsynaptic dopamine receptors associated with adenylate cyclase (D1-receptors) in the carp retina. In intact pieces of retina, 3-PPP had no significant effect on cyclic AMP production at concentrations up to 100 microM, whereas the aminotetralin, TL-99, caused a concentration-dependent increase in cyclic AMP levels with an approximate EC50 of 3.6 microM. Dopamine and ADTN had EC50 values of 3.5 and 3.1 microM respectively. Furthermore, in homogenates of the retina, 100 microM ADTN and 100 microM TL-99 stimulated adenylate cyclase activity 92 and 79% respectively as compared to the stimulation evoked by 100 microM DA. In contrast, 100 microM 3-PPP was essentially inactive at stimulating adenylate cyclase in carp retinal homogenates. These findings suggest that TL-99 can interact with postsynaptic D1-receptors and is not as selective a dopamine autoreceptor agonist as 3-PPP, which has no apparent activity at the D1-receptor.

Topics: Adenylyl Cyclases; Animals; Carps; Cyclic AMP; Enzyme Activation; Naphthalenes; Piperidines; Receptors, Dopamine; Retina; Tetrahydronaphthalenes

In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and alpha-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and alpha-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were most sensitive to the activating effects of d-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25 micrograms/kg) potentiated the locomotor stimulant effects of d-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or alpha-adrenergic receptor sensitivity. The increased sensitivity to d-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by the d-amphetamine due to the DA autoreceptors having become subsensitive.

Topics: Animals; Apomorphine; Behavior, Animal; Dextroamphetamine; Dose-Response Relationship, Drug; Male; Motor Activity; Muridae; Piperidines; Receptors, Dopamine; Synaptic Transmission

Topics: Adenylyl Cyclases; Animals; Carps; Cyclic AMP; Cyprinidae; In Vitro Techniques; Piperidines; Receptors, Dopamine; Retina; Synapses

Topics: 4-Butyrolactone; Animals; Apomorphine; Cell Membrane; Corpus Striatum; Female; Humans; Hydroxydopamines; Naphthalenes; Oxidopamine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spiperone; Stereotyped Behavior; Tetrahydronaphthalenes

Topics: Animals; Behavior, Animal; Male; Mice; Piperidines; Receptors, Dopamine

Examination of the binding of [3H]apomorphine to rat striatal membranes in the presence and absence of the dopamine antagonist, domperidone, confirmed the previously reported presence of two classes of dopamine binding site, those designated D2 which show a high affinity for both agonist and antagonists and those designated D3 which have a high affinity for agonists and a low affinity for antagonists. In contrast to the previously reported single high affinity (KD congruent to 1 nM) D2- and D3-binding sites, two lower affinity sites (D2KD = 7-50 nM; D3KD = 41 nM) were also observed. Examination of the binding characteristics of the putative dopamine autoreceptor agonists, 3-PPP (N,N-propyl-3-(3-hydroxyphenyl)piperdine) and TL-99 (6,7-dihydroxy-2-dimethylaminotetraline) showed that they, like a number of other dopamine agonists including n-propylnorapomorphine, apomorphine and dopamine showed no preferential affinity for the D3, presynaptic binding site. It is concluded that the selectivity of dopamine agonists for the autoreceptor cannot be assessed by the in vitro radioligand binding parameters defined by the use of domperidone.

Topics: Animals; Apomorphine; Binding Sites; Binding, Competitive; Corpus Striatum; In Vitro Techniques; Kinetics; Membranes; Naphthalenes; Piperidines; Rats; Receptors, Dopamine; Spiperone; Tetrahydronaphthalenes

Topics: Animals; Behavior, Animal; Brain; Dopamine; Drug Interactions; Humans; Kinetics; Male; Motor Activity; Piperidines; Rats; Receptors, Dopamine; Stereotyped Behavior; Tyrosine 3-Monooxygenase

Topics: Animals; Apomorphine; Binding, Competitive; Humans; Male; Piperidines; Prolactin; Rats; Receptors, Dopamine; Reserpine; Spiperone; Stereotyped Behavior

The putative dopamine (DA) autoreceptor agonists, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and 6, 7-dihydroxy-2-dimethylaminotetralin (TL-99) were compared with apomorphine in a series of tests indicative of DA receptor activation. All three agents displaced [3H] apomorphine and [3H] spiroperidol from DA recognition sites in rat brain and caused contralateral turning in the 6-hydroxydopamine lesioned rat. Apomorphine and TL-99 were generally more potent than 3-PPP. All three agents were also active at the DA autoreceptor that controls the synthesis of dopamine as indicated in vivo using the gamma-butyrolactone (GBL) procedure and in vitro using a synaptosomal preparation. In addition, all agents produced emesis in beagles. clear differences in the drugs' actions were observed in other test procedures. In the rat, apomorphine was the only compound which caused stereotypy or rotation following a reversible KCI-induced lesion of the striatum. Conversely, TL-99 and 3-PPP lacked activity in these procedures. Presumably, activity in these two tests indicates postsynaptic DA receptor activation. Each of the putative autoreceptor agonists produced a monotonic dose-related decrease in the mouse locomotor activity as opposed to the biphasic effect exerted by apomorphine. This action on the mouse locomotor activity, coupled with the results for the GBL test, provides an index of autoreceptor activation. In contrast to 3-PPP, both apomorphine and TL-99 increased locomotor activity in animals pretreated with reserpine and alpha-methyl-p-tyrosine and caused rotation in unilaterally caudectomized mice. In these test procedures thought to reflect activity at the postsynaptic DA receptor, TL-99 differed in its action from 3-PPP in a manner which suggests 3-PPP may be a more selective DA autoreceptor agonist.

Topics: 4-Butyrolactone; Animals; Apomorphine; Brain; Dogs; Dopamine; Female; Male; Mice; Motor Activity; Naphthalenes; Piperidines; Rats; Receptors, Dopamine; Tetrahydronaphthalenes

Topics: Animals; Behavior, Animal; Brain; Dopamine; Piperidines; Rats; Receptors, Dopamine