TY - JOUR
T1 - Muscarinic m4 receptor activation by some atypical antipsychotic drugs
AU - Zeng, Xiang Ping
AU - Le, Fei
AU - Richelson, Elliott
N1 - Funding Information:
This work was funded in part by Mayo Foundation for Medical Education and Research and grant MH 27692 from the National Institute of Mental Health.
PY - 1997/3/5
Y1 - 1997/3/5
N2 - To clarify the findings that clozapine is both a muscarinic receptor agonist and antagonist, we examined the effects of neuroleptics on forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing human muscarinic m4 receptors (CHO-hm4) and in rat striatum. With CHO-hm4 cells, clozapine induced a concentration-dependent and atropine-sensitive inhibition on cAMP formation, with EC50 = 60 nM and E(max) = 74% of carbachol maximum. Other atypical neuroleptics, fluperlapine, tenilapine and olanzapine, were similar but less potent, while risperidone, rilapine, quetiapine (ICI 204,636), sertindole, and ziprasidone had almost no effect. Typical neuroleptics, haloperidol, chlorpromazine, fluphenazine, thiothixene, thioridazine, and molindone, showed either no effect or an atropine-resistant inhibition of cAMP formation. However, in rat striatal tissues, clozapine, up to 10 μM, did not show a significant inhibition of cAMP formation, probably due to a relatively low abundance of muscarinic m4 receptors and the presence of multiple types of muscarinic and other receptors, with which clozapine interacts. Nevertheless, muscarinic m4 receptor agonism, to some extent, may be a relevant mechanism For the therapeutic efficacy and side effects of clozapine and some atypical neuroleptics.
AB - To clarify the findings that clozapine is both a muscarinic receptor agonist and antagonist, we examined the effects of neuroleptics on forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing human muscarinic m4 receptors (CHO-hm4) and in rat striatum. With CHO-hm4 cells, clozapine induced a concentration-dependent and atropine-sensitive inhibition on cAMP formation, with EC50 = 60 nM and E(max) = 74% of carbachol maximum. Other atypical neuroleptics, fluperlapine, tenilapine and olanzapine, were similar but less potent, while risperidone, rilapine, quetiapine (ICI 204,636), sertindole, and ziprasidone had almost no effect. Typical neuroleptics, haloperidol, chlorpromazine, fluphenazine, thiothixene, thioridazine, and molindone, showed either no effect or an atropine-resistant inhibition of cAMP formation. However, in rat striatal tissues, clozapine, up to 10 μM, did not show a significant inhibition of cAMP formation, probably due to a relatively low abundance of muscarinic m4 receptors and the presence of multiple types of muscarinic and other receptors, with which clozapine interacts. Nevertheless, muscarinic m4 receptor agonism, to some extent, may be a relevant mechanism For the therapeutic efficacy and side effects of clozapine and some atypical neuroleptics.
KW - Atypical
KW - CAMP
KW - Chinese hamster ovary cell
KW - Clozapine
KW - Muscarinic m4 receptor
KW - Neuroleptic
KW - Neuroleptics
KW - Rat
KW - Striatum
KW - Typical
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U2 - 10.1016/S0014-2999(96)00956-9
DO - 10.1016/S0014-2999(96)00956-9
M3 - Article
C2 - 9085047
AN - SCOPUS:0031043685
SN - 0014-2999
VL - 321
SP - 349
EP - 354
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -