Adenylate cyclase from various dopaminergic areas of the brain and the action of loxapine

Abstract

The present report is a comparative study of adenylate cyclase activity in various areas of the brain identified as dopaminergic. Low levels of dopamine were found to stimulate adenylate cyclase from the striatum, median eminence, olfactory tubercle, nucleus accumbens and amygdala. Apomorphine, known to mimic the pharmacological and physiological effects of dopamine, stimulated adenylate cyclase from these areas. Several different classes of drugs effective in the treatment of schizophrenia were potent inhibitors of the stimulation by dopamine of the enzyme from these various regions. The drugs studied included representatives of the phenothiazine, butyrophenone, dibenzodiazepine and dibenzoxazepine classes. The inhibition by the dibenzoxazepine, loxapine, which is structurally very similar to the dibenzodiazepine, clozapine, was competitive with respect to dopamine. The calculated inhibition constant (Ki) for loxapine of about 15 nM was similar to that observed for some of the more potent phenothiazines. The results, considered together with previously published data, support the possibility that the therapeutic effects as well as the extrapyramidal and endocrinological side effects, of these antipsychotic agents may be attributable to their ability to block the activation of adenylate cyclase in various select areas of the brain.