CLOZAPINE - SELECTIVE LABELING OF SITES RESEMBLING 5HT(6) SEROTONIN RECEPTORS MAY REFLECT PSYCHOACTIVE PROFILE

Background: Clozapine, the classic atypical neuroleptic, exerts therap eutic actions in schizophrenic patients unresponsive to most neurolept ics. Clozapine interacts with numerous neurotransmitter receptors, and selective actions at novel subtypes of dopamine and serotonin recepto rs have been proposed to explain clozapine's unique psychotropic effec ts. To identify sites with which clozapine preferentially interacts in a therapeutic setting, we have characterized dozapine binding to brai n membranes. Materials and Methods: [H-3]Clozapine binding was examine d in rat brain membranes as well as cloned-expressed 5-HT6 serotonin r eceptors. Results: [H-3]Clozapine binds with low nanomolar affinity to two distinct sires. One reflects muscarinic receptors consistent with the drug's anticholinergic actions. The drug competition profile of t he second site most closely resembles 5HT(6) serotonin receptors, thou gh serotonin itself displays low affinity. [H-3]Clozapine binding leve ls are similar in all brain regions examined with no concentration in the corpus striatum. Conclusions: Besides muscarinic receptors, clozap ine primarily labels sites with properties resembling 5HT(6) serotonin receptors. If this is also the site with which clozapine principally interacts in intact human brain, it may account for the unique benefic ial actions of clozapine and other atypical neuroleptics, and provide a molecular target for developing new, safer, and more effective agent s.