Catecholamine-sensitive adenylate cyclase in frontal cortex of primate brain.

Adenylate cyclase activity (AC) of homogenates of monkey frontal cortex was stimulated by catecholamines (dopamine, norepinephrine and isoproterenol), apomorphine, clonidine, NaF and GPP(NH)P. The increment in activity due to dopamine was enhanced in the presence of GPP(NH)P. The AC was also stimulated by 0.2-0.4 mM Ca2+ in the presence of 0.2 mM EGTA; at 0.8 mM Ca2+ had little or no influence on basal or NaF-stimulated activity. However, as Ca2+ concentration was increased from 0.2 to 0.8 mM stimulation by dopamine or GPP(NH)P was progressively inhibited. These results suggest a possible function of Ca2+ in modulating neurotransmitter stimulation of AC in the monkey frontal cortex. The AC exhibited higher sensitivity to dopamine than to norepinephrine or isoproterenol; however dopamine and norepinephrine caused the same maximum stimulation of the enzyme, a stimulation womewhat greater than that produced by isoproterenol. An additivity in stimulating AC was observed for dopamine and isoproterenol but not for dopamine and norepinephrine. Norepinephrine- or dopamine-stimulated AC was effectively blocked by fluphenazine and other dopamine-receptor blocking agents (relative potency for blockade; fluphenazine, haloperidol greater than clozapine, thioridazine greater than pimozide) but not by propranolol, a beta-receptor blocker. In contrast, isoproterenol-stimulated AC was antagonized by propranolol or alprenolol but not by fluphenazine. On the basis of these results, at least two distinct receptors appear to be associated with AC of monkey frontal cortex: (1) a beta-receptor stimulated by isoproterenol and (2) a new type of dopamine or dopamine-norepinephrine receptor, stimulated by either dopamine or norepinephrine. This latter system differs from more typical dopamine receptors found in caudate, retina and limbic cortex in that (a) it is not stimulated by 1-(3,4-dihydroxybenzyl)-4-(2-pyrimidinyl) piperazine (S584); (b) it is stimulated significantly by the putative alpha-receptor agonist, clonidine; (c) it is more sensitive to blockade by clozapine than primate retina or caudate; also the sensitivity to haloperidol is greater than has been reported for non-primate caudate; (d) it is very sensitive to stimulation by norepinephrine and to blockade by phentolamine (an alpha-receptor blocker).