Dopamine-Sensitive Adenylate Cyclase in Mammalian Brain: A Possible Site of Action of Antipsychotic Drugs

Abstract

Adenylate cyclase (EC 4.6.1.1), selectively stimulated by low concentrations of dopamine, has been found in the olfactory tubercle, the nucleus accumbens, and the caudate nucleus of several mammalian species. Several different classes of drugs effective in the treatment of schizophrenia (antipsychotic drugs) were potent inhibitors of the stimulation by dopamine of the enzyme from these various regions. The drugs studied included representatives of the phenothiazine, butyrophenone, and dibenzodiazepine classes. The inhibition by these antipsychotic drugs was competitive with respect to dopamine. The most potent of the antipsychotic agents tested was fluphenazine, which had a calculated inhibition constant ( K i ) of about 5 × 10 -9 M. For each of several drugs tested, the K i for the enzyme from the olfactory tubercle was similar to that for the enzyme from the caudate nucleus. Several compounds closely related structurally to the psychoactive phenothiazines, but which have little or no antipsychotic or extrapyramidal actions clinically, had low relative potencies as inhibitors of dopamine-stimulated adenylate cyclase activity. The results, considered together with other data, raise the possibility that the therapeutic effects, as well as the extrapyramidal side effects, of these antipsychotic agents may be attributable, at least in part, to their ability to block the activation by dopamine of specific dopamine-sensitive adenylate cyclases in the human brain.