piperidines and 1-(3-trifluoromethylphenyl)piperazine

Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole.

Topics: Animals; Benzamides; Benzothiazoles; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Food; Hypothermia; Indoles; Male; Motor Activity; Penile Erection; Physostigmine; Piperazines; Piperidines; Pramipexole; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Yawning

D-16949 [6-chlor-2-(piperidyl-4-thio)-pyridine; Anpirtoline] is a novel centrally acting compound with serotonergic effects. To assess its discriminative stimulus effects, rats were trained to discriminate D-16949 (2.0 mg/kg i.p., 30 min) from no drug. D-16949 induced dose-dependent discriminative stimulus effects (ED50, 0.31 mg/kg), and did not produce sedation. The opioid analgesics codeine, pentazocine and tramadol all failed to substitute for D-16949. The opioid antagonist naltrexone did not antagonize the discriminative stimulus effects of D-16949. Phencyclidine, d-amphetamine, lysergic acid diethylamide and quipazine produced between 0 and 35% responding on the D-16949 lever. 8-Hydroxy-2-(di-n-propylamino)-tetralin substituted partially (45%) for D-16949, whereas 1-(m-trifluoromethylphenyl)-piperazine and RU 24969 completely and dose-dependently substituted for D-16949. The discriminative stimulus effects of D-16949 were not reversed by either cyproheptadine, ketanserin, pirenperone, spiperone or methylsergide. The 5-hydroxytryptamine3 (5-HT3) active antagonists ICS 205-930 and MDL 72222 were also ineffective as D-16949 antagonists. It is concluded that the discriminative stimulus effects of D-16949 are not mediated through opioid or 5-HT2 mechanisms. The present data also do not suggest the involvement of 5-HT3 mechanisms, but that D-16949 produces its discriminative stimulus effects in the rat primarily via agonistic actions at 5-HT1B receptors.

Topics: Animals; Antidepressive Agents; Dextroamphetamine; Discrimination Learning; Male; Piperazines; Piperidines; Pyridines; Rats; Rats, Inbred F344; Receptors, Opioid; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Our work has focused on identifying the type of serotonin receptor through which serotonin acts as a developmental signal in the central nervous system. Previously, we have found that the regulation of development of ascending serotonergic neurons is through the balance of two serotonin receptors. One, the 5-HT1a receptor, releases a growth factor from astroglial cells. The other receptor is related to a release-regulating autoreceptor and can be stimulated indirectly by serotonin releasers such as fenfluramine. In the present study, we examined the receptors which regulate development of the descending neurons by treating pregnant rats with selective serotonergic drugs, from gestation day 12 until birth. Pups were subsequently tested for alterations in development by nociceptive testing (tail-flick latency) and by determining the binding of 3H-paroxetine, an indicator of serotonin terminal density, in spinal cord. Our results show that agents stimulating the 5-HT1a receptor (8-OH-DPAT) or the 5-HT1b receptor (TFMPP) or substances which release serotonin (fenfluramine) had no effect on the development of spinal serotonergic pathways. However, agents acting on the 5-HT3 receptor did--the agonist phenylbiguanide (PG) increased latency on tail-flick testing (postnatal days 10 and 30), while the antagonist, MDL 72222, decreased latency (postnatal days 10 and 18). Interestingly, both the agonist and the antagonist significantly increased 3H-paroxetine binding on postnatal day 18. Our results are discussed in terms of a possible mechanism by which 5-HT3 receptors may influence development.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aging; Animals; Biguanides; Female; Fenfluramine; Hypoglycemic Agents; Maternal-Fetal Exchange; Neurons; Pain; Paroxetine; Piperazines; Piperidines; Pregnancy; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Spinal Cord; Tetrahydronaphthalenes; Tropanes

8-OH-DPAT (2.5-10 mg/kg) and buspirone (10 mg/kg) but not 5,7-DHT (200 micrograms/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1-100 micrograms/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.

Topics: 5,7-Dihydroxytryptamine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Body Temperature Regulation; Buspirone; Diazepam; Ergolines; Fenclonine; Fever; Flumazenil; Imidazoles; Male; Mice; Ondansetron; Piperazines; Piperidines; Ritanserin; Serotonin; Serotonin Antagonists; Stress, Psychological; Tetrahydronaphthalenes

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT1C activity while RU 24969 differs with a high 5-HT1A activity. Proaversive effects were found with the mixed 5-HT1C/5-HT2 antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT1C/5-HT2 antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT2 antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT1C receptors appear to play a predominant function.

Topics: Amphetamines; Animals; Cyproheptadine; Indoles; Ketanserin; Male; Periaqueductal Gray; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Reinforcement, Psychology; Ritanserin; Serotonin; Serotonin Antagonists

Administration of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI, 0.125-2.0 mg/kg i.v.) triggered dose-dependent increases in plasma glucose; plasma insulin levels remained unchanged. Pretreatment with the 5-HT1C/5-HT2 receptor antagonists LY 53857, ritanserin, or the mixed 5-HT2/alpha 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT1C receptor agonists/5-HT2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-trifluoromethyl)phenyl)piperazine level (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The alpha 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, Whilst the alpha 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT1C/5-HT2 receptor agonist alpha-methyl-5-HT (0.5-1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished alpha-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT2 receptors, but not 5-HT1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT2 receptors may affect glycemia.

Topics: Amphetamines; Animals; Blood Glucose; Catecholamines; Ergolines; Hyperglycemia; Insulin; Male; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin

Using a two-lever operant procedure, eleven rats were trained to discriminate 0.2 mg/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) from saline using a variable-interval 15 sec schedule of reinforcement. Once trained, these animals were used in a series of stimulus generalization and stimulus antagonism studies. The 8-OH DPAT-stimulus did not generalize to the 5-HT1B agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), nor could it be attenuated by pre-treatment of the animals with the 5-HT2 antagonist ketanserin. Low doses of spiperone and propranolol were without effect on 8-OH DPAT-appropriate responding, whereas higher doses of these agents resulted in disruption of behavior. Some preliminary structure-activity data were also obtained using several related tetralin analogs. The results of this study demonstrate that the serotonin agonist 8-OH DPAT serves as a discriminative stimulus in rats and that it produces stimulus effects that are probably not 5-HT1B or 5-HT2-mediated.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Discrimination Learning; DOM 2,5-Dimethoxy-4-Methylamphetamine; Ketanserin; Male; Naphthalenes; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Tetrahydronaphthalenes

The behavioral effects of the serotonin (5-HT) precursor l-5-hydroxytryptophan (l-5-HTP) and the phenylpiperazine 5-HT agonists 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), 1-(m-trifluromethylphenyl) piperazine (TFMPP), 1-(m-chlorophenyl)piperazine (CPP) and 2-(1-piperazinyl)quinoline (quipazine) were compared with those of the putative 5-HT antagonists metergoline, methysergide, cyproheptadine, cinanserin and ketanserin under a multiple 5-min fixed-interval schedule of food or electric shock presentation in squirrel monkeys. Intramuscular administration of l-5-HTP (0.3-17 mg/kg), MK-212 (0.01-1.0 mg/kg), TFMPP and CPP (0.03-10 mg/kg) produced dose-related decreases in responding under both the food- and shock-presentation schedules. Quipazine differed from the other 5-HT agonists in that it increased shock-maintained behavior at doses (0.1-1.0 mg/kg) that decreased responding maintained by food. The 5-HT antagonists produced mixed behavioral effects. Metergoline (0.03-1.0 mg/kg), cyproheptadine (0.1-1.0 mg/kg) and cinanserin (1.0-10 mg/kg) produced dose-related increases in responding maintained by food, whereas only metergoline and methysergide increased behavior maintained by shock presentation. The prototype 5-HT2-receptor ligand ketanserin (0.3-10 mg/kg) differed from the other 5-HT antagonists in that it decreased behavior maintained by either event. Thus, performances maintained by food or shock presentation reveal both qualitative and quantitative differences in the behavioral effects of 5-HT receptor agonists and antagonists.

Topics: 5-Hydroxytryptophan; Animals; Cinanserin; Conditioning, Operant; Cyproheptadine; Electroshock; Female; Ketanserin; Male; Metergoline; Methysergide; Piperazines; Piperidines; Pyrazines; Quipazine; Receptors, Serotonin; Saimiri

1-Arylpiperazines (MK-212, quipazine, m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine) caused a serotonin (5-HT) receptor-mediated contraction of rat fundic strips. m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine had high affinity for the receptor but little efficacy, whereas quipazine and MK-212 had lesser affinity and much greater efficacy. 5-HT itself was the most potent (EC50 = 6-9 nM) agonist and possessed the greatest affinity (KA = 9.7 nM). Assessment of receptor occupancy vs. functional response (as well as receptor alkylation studies) demonstrated a very small, if any, receptor reserve in this tissue. Several arylquinolizines were found to be competitive antagonists of 5-HT-induced contraction, the most potent being L-653,267 and rauwolscine (KB values = 1.9 and 3.8 nM). Clozapine, trazodone and propranolol were identified as less potent, competitive antagonists, whereas various ergolines (including LY 53857), L-646,462 (cyproheptadine analog) and mianserin were noncompetitive. Potent 5-HT2 receptor antagonists (pirenpirone and ketanserin) antagonized only weakly or were without effect against 5-HT, indicating that the fundic 5-HT receptor is not of the 5-HT2 subtype. Because the fundic receptor has high affinity for 5-HT (as does the 5-HT1 binding site in brain tissue), the possible correspondence of the fundic 5-HT receptor with the 5-HT1 recognition site in rat brain cortex was considered. 5-HT, the nonindole agonists (1-arylpiperazines) and the competitive antagonists all competed with [3H]-5-HT for the 5-HT1 site. However, all compounds except 5-HT had Hill slopes significantly less than 1.0, precluding a valid comparison with dissociation constants derived pharmacologically in the fundus. With respect to having a high affinity for 5-HT, the 5-HT receptor mediating contraction of fundic smooth muscle resembles the 5-HT1 recognition site (as defined in brain tissue by radioligand binding), but identity remains unproven.

Topics: Animals; Binding, Competitive; Brain Chemistry; Gastric Fundus; In Vitro Techniques; Ketanserin; Male; Muscle Contraction; Piperazines; Piperidines; Propranolol; Pyrazines; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tritium