Specificity of the dopamine sensitive adenylate cyclase for antipsychotic antagonists

Chlorpromazine, haloperidol and clozapine are approximately equipotent in antagonizing dopamine sensitive adenylate cyclase activity in homogenates of rat brain striatum, in contrast to the differences in clinical antipsychotic potencies reported by others. The antagonism appeared to occur at a structurally specific dopamine site, as inhibition by a series of chlorpromazine analogues of similar hydrophobicity exhibited a structural specificity similar to that found for their neuroleptic and cataleptic activities. Sulpiride, a dopamine antagonist with antipsychotic activity, and metoclopramide, a structurally related central dopamine antagonist, failed to inhibit the dopamine sensitive adenylate cyclase. Pre-treatment of rats with haloperidol (3 mg/kg per day) for 6 or 28 days did not induce a supersensitive response of the adenylate cyclase to stimulation by dopamine or apomorphine or inhibition by clozapine. It was concluded that the dopamine sensitive adenylate cyclase may not be the site of action of all anti-psychotic agents.