Antipsychotic drugs block IP3-dependent Ca(2+)-release from rat brain microsomes

Cellular Ca(2+)-dysregulation has been proposed as an important mechanism in certain diseases such as bipolar affective disorder (BPAD) and malignant hyperthermia. Recently it has been found that in BPAD, the plasma membrane Ca(2+)-channel blockers verapamil and nimodipine are useful substitutes in Li(+)-treatable patients. We have investigated the effects of these drugs and the antipsychotic drugs (clozapine, fluspirilene, and haloperidol) on IP3-induced Ca(2+)-release from Ca(2+)-loaded rat brain microsomes. In the presence of either the Ca(2+)-channel blockers or the neuroleptic drugs, Ca(2+)-release was blocked in a dose-dependent fashion. For the neuroleptics, the EC50 ranged from 22 microM for fluspirilene to 145 microM for haloperidol. The EC50 for nimodipine was 160 microM and 450 microM for verapamil. Carbamazapine and valproic acid, anticonvulsants recently used for treating BPAD, were relatively ineffective, as were various haloperidol metabolites. The research described in this paper establishes for the first time that antipsychotic drugs, as well as certain Ca(2+)-channel blockers, directly block the IP3-induced Ca(2+)-release in a rat brain microsome assay.