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Cellular Ca2+-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 Ca2+-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 Ca2+-release from Ca2+-loaded rat brain microsomes. In the presence of either the Ca2+-channel blockers or the neuroleptic drugs, Ca2+-release was blocked in a dose-dependent fashion. For the neuroleptics, the EC50 ranged from 22 μM for fluspirilene to 145 μM for haloperidol. The EC50 for nimodipine was 160 μM and 450 μM 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 Ca2+-channel blockers, directly block the IP3-induced Ca2+-release in a rat brain microsome assay.
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Received in revised form: December 18, 1995
Received: February 6, 1995
This research was supported by an intramural Uniformed Services University of the Health Sciences (USUHS) grant (C0-8893) to F.S. We express our appreciation to Mrs. Eleanore Gamble for all of her assistance in the laboratory.
© 1996 Society of Biological Psychiatry. Published by Elsevier Inc.