MUSCARINIC M4 RECEPTOR ACTIVATION BY SOME ATYPICAL ANTIPSYCHOTIC-DRUGS

To clarify the findings that clozapine is both a muscarinic receptor a gonist and antagonist, we examined the effects of neuroleptics on fors kolin-stimulated cAMP accumulation in Chinese hamster ovary cells expr essing human muscarinic m4 receptors (CHO-hm4) and in rat striatum. Wi th CHO-hm4 cells, clozapine induced a concentration-dependent and atro pine-sensitive inhibition on cAMP formation, with EC(50) = 60 nM and E (max) = 74% of carbachol maximum. Other atypical neuroleptics, fluperl apine, tenilapine and olanzapine, were similar but less potent, while risperidone, rilapine, quetiapine (ICI 204,636), sertindole, and zipra sidone had almost no effect. Typical neuroleptics, haloperidol, chlorp romazine, fluphenazine, thiothixene, thioridazine, and molindone, show ed either no effect or an atropine-resistant inhibition of cAMP format ion. However, in rat striatal tissues, clozapine, up to 10 mu M did no t show a significant inhibition of cAMP formation, probably due to a r elatively low abundance of muscarinic m4 receptors and the presence of multiple types of muscarinic and other receptors, with which clozapin e interacts. Nevertheless, muscarinic m4 receptor agonism, to some ext ent, may be a relevant mechanism for the therapeutic efficacy and side effects of clozapine and some atypical neuroleptics.