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Clozapine's Antipsychotic Effects do not Depend on Blockade of 5-HT$_{3}$ Receptors

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Neurochemical Research : Volume 24, Issue 4, April 1999

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Clozapine's Antipsychotic Effects do not Depend on Blockade of 5-HT$_{3}$ Receptors

Content Provider	Springer Nature Link
Author	Squires, Richard F. Saederup, Else
Copyright Year	1999
Abstract	Sixteen known 5-HT$_{3}$ receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 μM GABA on [$^{35}$S]TBPS binding, indicating that they are also GABA$_{A}$ antagonists, some of them selective for subsets of GABA$_{A}$ receptors. The 5-HT$_{3}$ 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-HT$_{3}$ receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [$^{35}$S]TBPS binding. Additivity experiments suggest that ten 5-HT$_{3}$ 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 decribed here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severly 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-HT$_{3}$ receptor blockers are due to selective antagonism of certain GABA$_{A}$ receptors, and not to blockade of 5-HT$_{3}$ receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of α1β2γ2 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.
Starting Page	659
Ending Page	667
Page Count	9
File Format	PDF
ISSN	03643190
Journal	Neurochemical Research
Volume Number	24
Issue Number	5
e-ISSN	15736903
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	1999-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Neurosciences Neurology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Medicine Biochemistry Cellular and Molecular Neuroscience

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