clozapine and bemesetron

Sixteen known 5-HT3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 microM GABA on [35S]TBPS binding, indicating that they are also GABA(A) antagonists, some of them selective for subsets of GABA(A) receptors. The 5-HT3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [35S]TBPS binding. Additivity experiments suggest that ten 5-HT3 receptor blockers tested at low concentrations preferentially block subtypes of GABA(A) receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABA(A) antagonist described here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severely decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(-)-zacopride as a GABA(A) antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT3 receptor blockers are due to selective antagonism of certain GABA(A) receptors, and not to blockade of 5-HT3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of alpha1beta2gamma2 GABA(A) receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABA(A) antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Drug Interactions; Female; GABA Antagonists; gamma-Aminobutyric Acid; Male; Ondansetron; Quinacrine; Quipazine; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Sulfur Radioisotopes; Tropanes

The atypical neuroleptic clozapine has been shown to have cue properties in two-lever drug discrimination procedures. Although it has been demonstrated that clozapine acts at several types of receptors in vitro and in vivo, including dopamine, serotonin [5-hydroxytryptamine (5-HT)], and acetylcholine receptors, the mechanism of action for its discriminative stimulus properties has not yet been determined. The present study examined the effects of haloperidol (D2 dopamine antagonist), ritanserin (5-HT2 antagonist), 1-alpha H,3-alpha,5-alpha H-tropan-3yl-3,5-dichlorobenzoate (MDL 72222) (5-HT3 antagonist), and buspirone (5-HT1A agonist) in stimulus substitution tests with rats trained to discriminate clozapine (5.0 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure under a fixed ratio 30 schedule of food reinforcement. Analysis of the results revealed that, while clozapine produced dose-dependent responding on the clozapine lever, haloperidol and the three serotonin drugs failed to produce full substitution for clozapine at any of the doses tested. These results suggest that the discriminative stimulus properties are not mediated by D2 dopamine receptor blockade, antagonism at 5-HT2 or 5-HT3 receptors, or agonistic activity at 5-HT1A receptors. The neural basis of clozapine's discriminative stimulus properties has not yet been determined.

Topics: Animals; Buspirone; Clozapine; Discrimination, Psychological; Dose-Response Relationship, Drug; Generalization, Psychological; Haloperidol; Male; Rats; Rats, Sprague-Dawley; Ritanserin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropanes

Clozapine, an atypical neuroleptic drug devoid of extrapyramidal side effects, was a moderately potent, competitive inhibitor of the binding of [3H]quaternised ICS 205-930 to 5-HT3 receptor sites in rat cortical membranes, possessing a pKi value of 7.0. In contrast, several other antipsychotic agents, including fluphenazine, alpha-flupenthixol, haloperidol, spiperone and (-)-sulpiride were essentially inactive. Clozapine also antagonised the 2-methyl 5-HT-induced depolarisation of the rat isolated superior cervical ganglion, a response known to be mediated via 5-HT3 receptors. Clozapine (0.1-1 microM) induced parallel displacements to the right of the dose-response curve to 2-methyl 5-HT in this tissue, possessing a pKb value of 7.3. These data suggest that the atypical antipsychotic profile of clozapine may be related, at least, in part to its ability to interact with central 5-HT3 receptor sites.

Topics: Animals; Antipsychotic Agents; Cerebral Cortex; Clozapine; Ganglia, Sympathetic; In Vitro Techniques; Indoles; Kinetics; Male; Rats; Rats, Inbred Strains; Receptors, Serotonin; Tropanes; Tropisetron