A noradrenaline sensitive adenylate cyclase in the rat limbic forebrain: Preparation, properties and the effects of agonists, adrenolytics and neuroleptic drugs

Abstract

A method for the preparation of a noradrenaline sensitive adenylate cyclase from homogenates of the rat ‘limbic’ forebrain is described using Krebs-Ringer as the homogenising medium. Some of its properties resemble those reported previously by other workers, using slices. Its response to agonists show that it has the characteristics of a β 1-receptor i.e. the potency of l-isoprenaline exceeds that of l-noradrenaline which exceeds that of l-adrenaline. Structure-activity analysis of the response of the adrenylate cyclase to a range of adrenergic agonists shows a strict requirement for a catechol moiety and a β-hydroxyl group. The activation of the enzyme by l-noradrenaline is sensitive to stereoselective inhibition by l-propranolol. The effect of a number of neuroleptic drugs was examined. Promazine was the most effective agent tested in antagonising the stimulation produced by 50 μM l-noradrenaline, whilst the potent dopamine receptor antagonist, α-flupenthixol was only weakly active. Furthermore, there was no stereoselectivity in the antagonism produced by α- and β-isomers of flupenthixol. Pimozide was not found to be a potent antagonist. Thus the spectrum of antagonism produced by neuroleptic drugs was quite different from that seen in the dopamine sensitive denylate cyclase of the rat corpus striatum.