Modification of the receptor component of adenylate cyclase in the rat brain by phenothiazine derivatives

Abstract

Incubated tissue slices from rat cerebral cortex and medial and lateral hypothalamus readily accumulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) in response to added norepinephrine (NE). The monohydroxylated derivatives of chlorpromazine (CPZ), prochlorperazine, perphenazine, promazine and fluphenazine and respective parent compounds including promethazine and thiothixene were the most potent inhibitors of the stimulation of cyclic AMP by NE. For the most part, the NE-induced cyclic AMP response in the medial hypothalamus was more sensitive to inhibition by these pharmacologically active phenothiazines. In specific brain areas an antagonism of cyclic AMP stimulation was seen with haioperidol, 3,7-dimethoxy-CPZ, the dihydroxylated and 8-hydroxylated derivatives of CPZ, prochlorperazine and perphenazine. No actions on the NE response were observed with phenothiazine, 3-OH-phenothiazine, 2-chloro-7,8-dioxo-phenothiazine, CPZ-sulphoxide, 7,8-dimethoxy-CPZ. 7-methoxy-CPZ, 7,8-dioxo-CPZ and 2,3-diOH promazine. A limited number of compounds inhibited basal levels of cyclic AMP, while others, notably the dihydroxylated analogues, enhanced basal levels of the cyclic nucleotide. The α and β adrenergic blocking agents (phentolamine and propranolol) at 10 −5 M acted to antagonize cyclic AMP accumulation in response to NE in all brain regions, while at 10 −6 M the α blocker was ineffective in the cerebral cortex and less effective in the medial hypothalamus. The results suggest that antiadrenergic actions of pharmacologically active phenothiazines may be manifested at the receptor component of adenylate cyclase.