dizocilpine-maleate and 1-3-ditolylguanidine

New 1-[omega-(2,3-dihydro-1H-inden-1-yl)- and (2,3-dihydro-5-methoxy-1H-inden-1-yl)alkyl]- and 1-[omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- and (6-methoxy- or 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)alkyl] derivatives of 3,3-dimethylpiperidine were synthesized, as homologous compounds of an existing series of sigma ligands, in order to carry out sigma receptor subtypes structure-affinity relationships. The new compounds and some of their related analogues, already reported, were tested in new multireceptorial radioligand binding assays. As reference compounds, the known sigma(1) ligands SA 4503, BD 1008 and NE 100 were also prepared and tested. All reported compounds showed high sigma(1) affinity assayed by (+)-[(3)H]-pentazocine on guinea-pig brain (apparent K(i)=1.75-72.2 nM) and moderate or low sigma(2) affinity by [(3)H]-DTG on rat liver, in contrast with previous results. One tertiary amine function spaced by a five-membered chain from a phenyl group is the structural feature shared by the most active compounds 26 and 43 and some reference sigma(1) ligands. The reported sigma(1) ligands, including reference compounds, also demonstrated a high affinity towards EBP (Delta(8)-Delta(7) sterol isomerase) site (apparent K(i)=0.48-14.8 nM) and some of them (37 and 44) were good ligands at L-type Ca(++) channel. 1-[4-(2,3-Dihydro-1H-inden-1-yl)butyl]-3,3-dimethylpiperidine (26) was the best mixed sigma(1) and EBP ligand (apparent K(i)=1.75 and 1.54 nM, respectively) with a good selectivity versus sigma(2) receptor (138- and 157-fold, respectively).

Topics: Animals; Binding Sites; Brain; Calcium Channels, L-Type; Carrier Proteins; Dizocilpine Maleate; Guanidines; Guinea Pigs; In Vitro Techniques; Inhibitory Concentration 50; Ligands; Liver; Pentazocine; Piperidines; Radioligand Assay; Rats; Receptors, Opioid, delta; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Structure-Activity Relationship

Ketamine, which is a non-competitive NMDA receptor antagonist, has been used as a dissociative anesthetic agent. However, chronic use of ketamine produces psychotomimetic effects, such as nightmares, hallucination and delusion. Therefore, the present study was designed to ascertain the role of the NMDA receptor and sigma receptor in the discriminative stimulus effect induced by ketamine. Fischer 344 rats were trained to discriminate between ketamine (5 mg/kg, i.p.) and saline under a fixed-ratio 10 food-reinforced procedure. Non-competitive antagonists for both NR2A- and NR2B-containing NMDA receptors, such as phencyclidine (0.1--1 mg/kg, i.p.) and dizocilpine (3--30 microg/kg, i.p.), and the NR2A-containing NMDA receptor-preferred antagonist dextromethorphan (3--56 mg/kg, i.p.) fully substituted for the ketamine cue in a dose-dependent manner. By contrast, the NR2B-containing NMDA receptor antagonist ifenprodil (5--20 mg/kg, i.p.) exhibited no generalization. Additionally, the competitive NMDA antagonist 3-[(+/-)-2-carboxypiperazine-4-yl] propyl-1-phosphonic acid ((+/-)-CPP; 0.3--5.6 mg/kg, i.p.) and a sigma receptor ligand DTG (0.3--3 mg/kg, s.c.) displayed no generalization to the ketamine cue. These results suggest that NR1/NR2A subunit containing NMDA antagonism may be critical for the production of the ketamine cue.

Topics: Animals; Dextromethorphan; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Guanidines; Ketamine; Ligands; Male; Phencyclidine; Piperazines; Piperidines; Protein Subunits; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801-induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. Published by Elsevier Science Inc., 2000

Topics: Animals; Conditioning, Psychological; Dizocilpine Maleate; Drug Interactions; Eating; Excitatory Amino Acid Antagonists; Food Preferences; Guanidines; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Sucrose; Taste

(+)-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

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 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

Radioligand binding techniques were used to determine the affinity of a series of substituted guanidine derivatives for 1) the binding site within the ion channel of the N-methyl-D-aspartate (NMDA) receptor, as defined by displacement of MK-801 ([3H]dizocilpine) and 2) sigma sites as defined by displacement of [3H]N,N'-di-(o-tolyl)guanidine. The goal was to find ligands with high affinity and selectivity for the NMDA receptor ion-channel site. The neuroprotective activity of these compounds was assessed by their ability to protect cortical neurons from injury caused by a 5-min exposure to 500 microM glutamate in vitro. Release of lactate dehydrogenase into the culture medium by damaged neurons was used as an index of neuronal injury. The 14 compounds tested had IC50 values ranging from 37.3 nM to 12.7 microM for the NMDA receptor ion-channel site and from 8.3 nM to 7.25 microM for sigma sites. Affinity for the ion-channel site was improved by unsymmetrical substitutions on the guanidine moiety. All compounds in the series protected cortical neurons against glutamate toxicity, with EC50 values (concentration affording 50% protection) ranging from 0.38 to 28.25 microM. The neuroprotective effect of each compound was positively correlated with its ion-channel site affinity (r = 0.94); no correlation between neuroprotective efficacy and sigma site binding affinity was found (r V -0.13) establishing clearly that neuroprotection in this assay was linked to NMDA antagonist properties.

Topics: Animals; Cells, Cultured; Dizocilpine Maleate; Glutamic Acid; Guanidines; Ion Channels; Neurons; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Structure-Activity Relationship

MK-801 (30-100 micrograms/kg, SC) impaired spontaneous alternation behavior of mice, a behavior related to the spatial working memory. 1,3-Di-(2-tolyl)guanidine (DTG), (+)-pentazocine and (+)-SKF 10,047 (100 micrograms/kg, SC), putative sigma agonists, administered 10 min before MK-801, partially but significantly reversed the impairment, without affecting the concomitant hyperlocomotion. The antagonizing effects by DTG were prevented by BMY-14802 (5 mg/kg, IP), a purported sigma antagonist. These findings suggest that, at low doses, sigma ligands may modulate the N-methyl-D-aspartate dependent memory processes.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Guanidines; Male; Memory; Mice; Mice, Inbred Strains; Motor Activity; Pentazocine; Phenazocine; Pyrimidines; Receptors, sigma; Space Perception

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

Radioligand binding assay conditions were established for the selective labeling of sigma-1 and sigma-2 sites in membrane homogenates of rat brain. Selective sigma-1 assays were conducted using 5 nM(+)[3H]SKF-10,047 in the presence of 300 nM dizocilpine (MK-801). Selective sigma-2 assays were conducted using 5 nM [3H]DTG in the presence of 1 microM (+)SKF-10,047. Distributions of sigma-1 and sigma-2 binding among brain regions were found to differ. While the brain stem yields the highest level of sigma-1 binding, it yields among the lowest levels of sigma-2 binding. The reverse is true in hippocampal membranes. Different ontogenetic patterns were also observed. Sigma-2 binding decreases substantially during brain development, whereas sigma-1 binding does not vary significantly. Patterns of distribution among subcellular fractions of rat brain homogenates were found to be similar. Both sigma-1 and sigma-2 sites are most enriched in microsomal fractions, and neither is enriched in synaptosomal or mitochondrial fractions. The present results suggest that sigma-1 and sigma-2 sites are distinct entities; they do not appear to be located on a common macromolecule, and they do not represent two different affinity states of a single type of binding site. While the precise subcellular locations of sigma-1 and sigma-2 sites remain to be determined, we conclude that localization of either type of binding site to synaptic regions of plasma membrane or to mitochondria is highly unlikely.

Topics: Animals; Anticonvulsants; Brain; Brain Chemistry; Dizocilpine Maleate; Female; Guanidines; In Vitro Techniques; Male; Membranes; Phenazocine; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, sigma; Subcellular Fractions

The potentiating effect of low doses of sigma ligands on the N-methyl-D-aspartate (NMDA)-induced excitation of pyramidal CA3 dorsal hippocampal neurons has recently been reported. In the present study, we investigated behavioral effects relevant to these findings in the experimental amnesia induced by the non-competitive NMDA antagonist, dizocilpine (MK-801), in mice. At doses below 1 mg/kg s.c., the sigma ligands, 1,3-di-(2-tolyl)guanidine (DTG), (+)-SKF 10,047, and (+)-pentazocine, but not their (-)-isomers, significantly decreased MK-801 (100 microgram/kg s.c.)-induced impairment of spontaneous alternation performances in 8-min sessions of a Y-maze exploration, an index of spatial working memory, without affecting the concomitant hyperlocomotion. The effect of DTG (100 micrograms/kg s.c.) was completely antagonized by the simultaneous administration of BMY 14802 (10 mg/kg i.p.) and NE-100 (1 mg/kg i.p.), two putative sigma antagonists, which had no effect by themselves. In long-term memory tests (step-down and step-through types of passive avoidance, elevated plus-maze), DTG exhibited a significant attenuation of MK-801-induced amnesia, at doses of 10 and 100 micrograms/kg s.c. In all tests of short- and long-term memory, the effects exhibited by the sigma ligands tested had a bell-shaped curve; no effect was seen at 1 mg/kg. DTG did not affect the impairment of alternation induced by CPP (5 mg/kg i.p.): the modulation may selectively target the blockade of NMDA receptor-associated ion channels. Moreover, DTG (1-1000 micrograms/kg) did not affect the impairment induced by scopolamine (1 mg/kg i.p.) or diazepam (4 mg/kg i.p.), but significantly prevented the impairment induced by mecamylamine (10 mg/kg i.p.). These results suggest that the potentiating effect of sigma ligands on NMDA receptor-mediated glutamatergic neurotransmission, already demonstrated electrophysiologically, may have some relevance to learning and memory processes in the hippocampus. A similar modulation may also affect cholinergic nicotinic systems.

Topics: Amnesia; Animals; Behavior, Animal; Dizocilpine Maleate; Guanidines; Ligands; Male; Memory; Mice; Receptors, sigma

To determine the role of NMDA receptor blockade and sigma receptors in the behavioral effects of PCP during development, we assessed the behavioral effects of PCP, (+)-MK-801 and 1,3-Di(2-tolyl)guanidine (DTG) in preweanling rats. In the first experiment, rats were injected sc on postnatal day (PND) 19 with 0.5-4.5 mg/kg PCP, and locomotor activity and wall climbing behavior were scored. PCP induced high levels of locomotor activity on PND 19 in a dose dependent manner with the 2.0 mg/kg dose producing the greatest activity. In the second experiment, rats were injected on PND 12 or 19 with 1.0-4.0 mg/kg PCP or 0.1-0.4 mg/kg (+)-MK-801 and tested using the same procedures. Both PCP and (+)-MK-801 induced activity increases on PND 19 in a dose dependent manner, with 2.0 and 3.0 mg/kg PCP and 0.2 mg/kg (+)-MK-801 inducing the highest activity levels. Peak activity levels on PND 12 were approximately 30% of those observed on PND 19, with the lowest dose of PCP and (+)-MK-801 producing the greatest activity. Large amounts of wall climbing behavior were elicited by PCP on PND 12, whereas (+)-MK-801 induced only minor amounts of wall climbing. In the third experiment, the effects of 0, 1, 3, 6, or 12 mg/kg DTG were examined in PND 13-14 and 16-17 rats. DTG had little effect on locomotor activity on PND 13-14, although the highest dose did inhibit activity. On PND 16-17, all doses of DTG tended to increase locomotor activity. The results suggest (1) the robust locomotor effects of PCP on PND 19 are mediated in part by NMDA mechanisms (2) this period of increased sensitivity to both PCP and (+)-MK-801 might represent a critical period of development when systems mediating locomotor activity are vulnerable to neurotoxic insult (3) NMDA blockade alone does not mediate PCP-induced wall climbing behavior and (4) that at the doses of DTG and the ages tested, sigma receptors do not play a role in the locomotor-inducing effects of PCP.

Topics: Animals; Animals, Suckling; Anticonvulsants; Ataxia; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Guanidines; Male; Motor Activity; Phencyclidine; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma

Behavioral responses to kainic acid (KA) injected intrathecally in mice are enhanced by N-but not C-terminal fragments of substance P (SP). Repeated injections of KA result in sensitization to KA-induced activity, an effect that appears to be mediated by SP N-terminal activity and inhibited by PCP ligands. The present study was initiated to determine whether the ability of SP N-terminal fragments to enhance KA activity is also sensitive to PCP ligands. We compared the effect of a PCP ligand, dizocilpine (MK-801), to that of haloperidol, a sigma ligand and dopamine antagonist. MK-801 (1 nmol) failed to alter the enhancement of behavioral responses to KA (25 pmol) produced by SP(1-7) (22.5 pmol, 30 min). However, pretreatment with 1 nmol of either haloperidol or the N-terminal SP antagonist, [D-Pro2-D-Phe7]SP(1-7) [D-SP(1-7)], prevented potentiation of KA by SP(1-7). Like SP(1-7), 5 nmol of the sigma ligand 1,3-di(2-tolyl)guanidine (DTG) also enhanced behaviors elicited by KA, and this effect was also blocked by haloperidol or D-SP(1-7), but not spiperone (2.5 nmol), a dopamine antagonist. Together these data suggest that sigma receptors are involved in the potentiation of KA. A large dose of SP(1-7) (10 nmol) or DTG (20 nmol) did not alter the response to KA 24 hr later, yet further potentiated responses to KA 30 min after SP(1-7) (22.5 pmol) or DTG (5 nmol), suggesting sensitization to the effects of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Drug Synergism; Guanidines; Haloperidol; Injections, Spinal; Kainic Acid; Male; Mice; N-Methylaspartate; Peptide Fragments; Piperazines; Receptors, N-Methyl-D-Aspartate; Receptors, Phencyclidine; Receptors, sigma; Spinal Cord; Substance P; Up-Regulation

Five minutes of oxygen and glucose deprivation (termed "in vitro ischemia") causes long-term synaptic transmission failure (LTF) in the CA1 region of the rat hippocampal slice. Dependence of LTF on cell calcium was tested by generating graded reductions in cell Ca. There was a strong correlation between the average level of exchangeable cell Ca in CA1 during ischemia, and the extent of LTF. In standard buffer, exchangeable cell Ca in CA1 increased by 35% after 3 min of ischemia and remained elevated for the entire 5 min of ischemia. Unidirectional Ca influx increased by 35% during the first 2.5 min of ischemia and remained at that level for the next 2.5 min. There were no changes in unidirectional Ca efflux during this period. Thus, the accumulation results from increased influx of Ca. Ca influx during the first 2.5 min of ischemia depended entirely on NMDA channels; it was completely blocked by the noncompetitive NMDA receptor antagonist MK-801. However MK-801 had no effect during the second 2.5 min. This inactivation of NMDA-mediated influx during ischemia appears to result from dephosphorylation. Okadaic acid increased Ca influx during the second 2.5 min of ischemia and this increase was blocked by MK-801. The ischemia-induced Ca influx during the second 2.5 min of ischemia was attenuated 25% by nifedipine (50 microM) and an additional 35% by the Na/Ca exchange inhibitor benzamil (100 microM). The AMPA/kainate antagonist DNQX had no effect on the Ca influx. Antagonists were used to relate Ca influx to LTF. Blockade of enhanced Ca entry during ischemia in standard buffer (2.4 mM Ca) had no effect on LTF, consistent with total cell Ca prior to ischemia being adequate to cause complete LTF. However, MK-801 strongly protected against LTF when the buffer contained 1.2 mM Ca, a more physiological level. MK-801 combined with DNQX prevented transmission damage in standard buffer. Thus, AMPA/kainate receptor activation contributes to ischemic damage, although not by enhancing Ca entry.

Topics: Amiloride; Animals; Calcium; Dizocilpine Maleate; Ethers, Cyclic; Guanidines; Hippocampus; In Vitro Techniques; Ischemic Attack, Transient; Kinetics; Male; Microscopy, Electron; Okadaic Acid; Pyramidal Tracts; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors

The effects of i.v. administration of the noncompetitive NMDA receptor antagonists, phencyclidine and MK-801, and the sigma receptor ligand, 1,3-di(2-tolyl)guanidine (DTG), on the firing rates of non-dopaminergic mid brain neurons were evaluated in chloral hydrate-anesthetized rats. Phencyclidine and MK-801 inhibited the activity of putative gamma-aminobutyric acid (GABA)-containing interneurons identified by their response to foot-pinch. DTG did not significantly alter neuronal activity. These results suggest that the reported excitatory effects of non-competitive NMDA receptor antagonists on dopamine neuronal activity are due, in part, to disinhibition secondary to the inhibition of interneuron activity.

Topics: Action Potentials; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Guanidines; Injections, Intravenous; Male; Mesencephalon; Neurons; Phencyclidine; Rats; Rats, Sprague-Dawley; Receptors, sigma

The behavioral effects of the selective sigma ligand 1,3-di(2-tolyl)guanidine (DTG) were studied in rats. In the radial 8-arm maze, DTG (2, 4 and 8 mg/kg i.p.) reduced the number of arm entries in the spontaneous alternation task. In animals receiving 4 mg/kg DTG, the percentage of 135 degrees angles between consecutive arm entries decreased. In the open field, equipped with a holeboard, DTG (8 mg/kg) reduced the number of line crossings, rearings and head dips. Sniffing, measured in an experimental chamber, was also reduced. DTG prolonged the time that the animals were inactive. In combination with DL-amphetamine (4 mg/kg) or dizocilpine (0.16 mg/kg), DTG (8 mg/kg) decreased--but did not antagonize--the induced enhancement of locomotion and sniffing. These results demonstrate motor depressant effects of DTG on locomotion, rearing and sniffing. Since antagonists of sigma binding sites are known to produce opposite effects, we conclude that DTG--in behavioral terms--acts like an antagonist at sigma binding sites.

Topics: Amphetamine; Animals; Behavior, Animal; Binding Sites; Dizocilpine Maleate; Guanidines; Male; Models, Biological; Motor Activity; Rats; Rats, Sprague-Dawley; Receptors, sigma; Schizophrenia

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

The present study examined the behavioural effects of sigma agonists and PCP-like non-competitive N-methyl-D-aspartate (NMDA) antagonists in guinea-pigs. Subcutaneous (SC) injection of the putative sigma agonist (+)NANM (1 and 10 mg/kg SC) and (-)NANM (1 and 10 mg/kg SC) produced a behavioural response in guinea-pigs which was characterized by sedation and exophthalmos, with locomotor depression, flattened posture and flaccidity, whereas the sigma ligand pentazocine induced sedation but no flattened posture. Ketamine (20 mg/kg SC) and (+)dizocilpine (0.025, 0.1 and 1 mg/kg SC) produced similar effects to those of (+) and (-)NANM. However, the putative sigma receptor ligand DTG (1 and 10 mg/kg SC) had no observable effect on behaviours in guinea-pigs, similar to results for other species. The behavioural effects produced by (+) and (-)NANM were not reversed by injection 1 h later of naloxone hydrochloride (15 mg/kg SC), haloperidol (10 mg/kg SC) or DTG (10 and 30 mg/kg SC), but the effects of all drugs were reversed by the selective dopamine D-2 agonist quinpirole (3 mg/kg IP). Moreover, injection of naloxone (15 mg/kg SC), DTG (10 and 30 mg/kg SC) or haloperidol (1 and 10 mg/kg SC) 10 min before, did not reverse the behaviour induced by (+)NANM (10 mg/kg SC). These data indicate that sigma and PCP-like drugs have a similar gross behavioural effect in guinea-pigs, possibly mediated by non-competitive antagonism of the NMDA subtype of glutamate receptors. The results demonstrating behavioural depression were in contrast to the stimulatory effects of these drugs at similar doses in other rodent species.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Benzamides; Dizocilpine Maleate; Dopamine Agents; Dopamine Antagonists; Ergolines; Female; Guanidines; Guinea Pigs; Haloperidol; Ketamine; Male; Motor Activity; N-Methylaspartate; Pentazocine; Phenazocine; Phencyclidine; Quinpirole; Receptors, Dopamine D2; Receptors, Opioid; Receptors, sigma; Remoxipride

Release of glutamate from brain cells is increased during ischemia and is thought to be involved in ischemic damage. In rat hippocampal slices the release of glutamate during 'in vitro ischemia' (anoxia without glucose) is shown to be blocked by two groups of compounds: non-competitive N-methyl-D-aspartate (NMDA) antagonists and sigma ligands. The effects are selective for the ischemic glutamate release, which is independent of extracellular Ca2+. High K+, Ca2+ dependent, induced release of glutamate is not inhibited. NMDA receptor blockade normally does not prevent ischemic transmission damage in the rat hippocampal slice. However, when ischemic glutamate release is attenuated, NMDA receptor antagonists do prevent the damage. This indicates that high levels of glutamate may cause damage via non-NMDA as well as NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Cyclazocine; Dizocilpine Maleate; Glutamates; Guanidines; Haloperidol; Hippocampus; In Vitro Techniques; Ischemic Attack, Transient; Ketamine; Kynurenic Acid; Male; Models, Neurological; Phencyclidine; Pyramidal Tracts; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, sigma

Rats injected with haloperidol, which binds to both D2 dopamine and sigma receptors or the specific D2 dopamine receptor antagonist YM 09151-2, but not the specific D1 dopamine receptor antagonist SCH 23390, showed induction of c-fos protein and c-fos-related antigens in striatal neurons. This effect of haloperidol and YM 09151-2 was inhibited by the N-methyl-D-aspartate antagonist MK801 but was not affected by 1,3-di-O-tolylguanidine, a selective sigma receptor ligand. Two different antisera were used to detect c-fos protein: one was specific for c-fos protein itself while the other recognized c-fos protein as well as c-fos protein-related antigens. In time-course immunocytochemical studies, the c-fos protein was induced maximally by 1 h and had returned to baseline by 24 h. However, c-fos protein-related antigens were induced maximally after 2 h and remained elevated for at least three days after haloperidol injection. Furthermore, the c-fos protein-specific antiserum detected two to three times fewer immunopositive striatal cells than the antiserum which detected both c-fos protein-related antigens and c-fos protein in haloperidol-treated rats. This result suggests that some striatal neurons express c-fos protein-related antigens but not c-fos protein after haloperidol injection. In some striatal sections from haloperidol-injected rats immunostained with the antiserum which recognizes both c-fos protein and c-fos protein-related antigens, there were large areas of immunopositive neurons interspersed with "areas" of striatum devoid of immunostaining. The implications of these results for theories concerning the biochemical mechanism of action of haloperidol are discussed.

Topics: Animals; Benzamides; Benzazepines; Corpus Striatum; Dizocilpine Maleate; Dopamine Antagonists; Guanidines; Haloperidol; Male; N-Methylaspartate; Neurons; Oncogene Proteins v-fos; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred Strains; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid; Receptors, sigma

At concentrations greater than or equal to 100 microM, phencyclidine (PCP), N-(1-(2-thienyl)-cyclohexyl)piperidine (TCP), and MK-801 induced [3H]dopamine release from dissociated cell cultures of rat mesencephalon. This release was Ca2+ independent and tetrodotoxin insensitive. Tetrodotoxin (2 microM) itself had no effect on spontaneous release of [3H]dopamine. [3H]Dopamine release was induced by 1,3-di(2-tolyl)guanidine, a sigma ligand, and by 4-aminopyridine (1-3 mM), a K+ channel blocker. No stereoselectivity was observed for [3H]dopamine release evoked by the dioxadrol enantiomers, dexoxadrol, and levoxadrol, or by enantiomers of N-allylnormetazocine (SKF 10,047). The selective dopamine uptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909) did not affect spontaneous or TCP-evoked [3H]dopamine release. Together, these data suggest that the dopamine-releasing effects of PCP-like compounds on the mesencephalic cells were not mediated by actions at the PCP receptor or sigma binding site, Ca2+, or Na+ channels, or at the high affinity dopamine uptake site. It remains conceivable that blocking actions of PCP-like compounds at voltage-regulated K+ channels may at least partly explain the response. These results are discussed in comparison with findings in intact brain.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Binding Sites; Cells, Cultured; Dioxolanes; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Guanidines; Mesencephalon; N-Methylaspartate; Neurotransmitter Uptake Inhibitors; Phencyclidine; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Sigma Factor; Tritium

Several lines of evidence suggest a tight functional coupling between N-methyl-D-aspartate (NMDA) and phencyclidine (PCP) receptors. The effects of PCP receptor agonists (PCP, dexoxadrol, ketamine and MK-801) and NMDA receptor antagonists, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) and 3-(2-carboxypiperizin-4-yl)-propyl-1-phosphonic acid (CPP), have been examined on the metabolism of dopamine in the mesocortex, with a view of studying the coupling between these two receptor systems. Phencyclidine receptor agonists selectively increased the metabolism of dopamine in the mesocortex without affecting the metabolism of dopamine in the striatum. N-Methyl-D-aspartate and the competitive antagonists of NMDA receptors did not effect the metabolism of dopamine, neither did the sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) and rimcazole. Rimcazole also did not affect the increases in the metabolism of dopamine in the mesocortex, seen after MK-801. These data indicate that dopaminergic neurons in the mesocortex are positively modulated by PCP receptors but tentatively suggest that those recognition sites for PCP are not coupled to NMDA receptors.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain Chemistry; Carbazoles; Cerebral Cortex; Dibenzocycloheptenes; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Neural Pathways; Pipecolic Acids; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Stereoisomerism

1. The involvement of the haloperidol-sensitive, sigma recognition site and the N-methyl-D-aspartic acid (NMDA) receptor in the mediation of the discriminative stimulus properties of (+)-N-allylnormetazocine [+)-NANM, (+)-SKF 10,047), has been investigated in the rat by use of a two-lever, operant drug discrimination paradigm. 2. Six compounds with nanamolar affinity for the sigma recognition site [+/-)-pentazocine, (+)-3-(hydroxyphenyl)-N-propylpiperidine [+)-3-PPP), ditolylguanidine (DTG), haloperidol, (-)-butaclamol and BMY 14802) were investigated for their ability to generalise or antagonise the (+)-NANM discriminative stimulus. Each drug was tested at doses found in an ex vivo radioligand binding assay to displace [3H]-DTG from the central sigma recognition site by more than 40%. 3. While (+/-)-pentazocine (in the presence of naloxone) generalised and (+)-3-PPP partially antagonised the (+)-NANM cue, the other putative sigma ligands were ineffective either as agonists or antagonists at doses clearly occupying the sigma site in vivo. 4. Dose-dependent generalisation to the (+)-NANM cue was seen with the selective non-competitive NMDA receptor antagonist, MK-801, a compound devoid of significant affinity for the sigma recognition site. 5. (+/-)-Pentazocine was found to antagonise seizures induced in the mouse by NMDLA, a model reflecting antagonism of central NMDA receptors, and a strong correlation was found between the rank order of potency of compounds to generalise to the (+)-NANM discriminative stimulus and their potencies as anticonvulsants. 6. In conclusion, no evidence was found to substantiate the contention that the discriminative stimulus properties of (+)-NANM are mediated by the haloperidol-sensitive sigma recognition site. On the other hand, the results are consistent with the interoceptive stimulus being mechanistically based in the NMDA receptor complex.

Topics: Animals; Aspartic Acid; Binding, Competitive; Dibenzocycloheptenes; Discrimination, Psychological; Dizocilpine Maleate; Guanidines; Haloperidol; Male; Mice; N-Methylaspartate; Phenazocine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Seizures

Radiation inactivation technique has been used to measure the molecular sizes of the N-methyl-D-aspartate (NMDA) receptor and the sigma recognition site. Target size analysis of [3H]MK-801 (dizocilpine maleate) binding to the NMDA receptor channel complex in rat cortical membranes has given a molecular size of 128,000 +/- 9,000 Da. This is in contrast to the target size of the sigma site in the same tissue as labelled by [3H]DTG (ditolylguanidine), giving a value of 36,000 +/- 2,900 Da. These studies have provided evidence for a clear difference in the molecular sizes of these two recognition sites.

Topics: Animals; Brain Chemistry; Cerebral Cortex; Dibenzocycloheptenes; Dizocilpine Maleate; Guanidines; In Vitro Techniques; Ion Channels; Membranes; Molecular Weight; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Opioid, delta

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 purpose of this study was to examine the binding and behavioral effects mediated by PCP and sigma receptors in the rat. From the radioreceptor assays, it was possible to characterize two binding sites that interact with PCP and sigma ligands. The two sites, a PCP and sigma receptor, could be differentiated based on drug selectivity and potency. In the behavioral assays, MK-801, which bound preferentially to the PCP receptor, and 1,3-di-0-tolylguanidine, which bound preferentially to the sigma receptor, induced sniffing, rearing, circling, backpedaling, and weaving behavior. These results indicate that there are distinct PCP and sigma receptors that are both involved in mediating stereotyped behavior and ataxia in the rat.

Topics: Animals; Anticonvulsants; Binding, Competitive; Brain; Dibenzocycloheptenes; Dizocilpine Maleate; Guanidines; Kinetics; Ligands; Male; Membranes; Narcotics; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Stereotyped Behavior