Pharmacological Implications of the Effects of Amphetamine and Its Analogs on the Turnover Rate of Tissue Catecholamines

Abstract

It is now well established that an acute paranoid psychosis may follow d-amphetamine administration (Young and Scoville 1938). Hence, Connell (1958), Bell (1965), and Kety (1967) have proposed this psychosis as a model for the study of affective disorders and schizophrenia. A better understanding of the biochemical factors involved in the actions elicited by d-amphetamine may increase the practical utility of this model. The picture that has emerged from our studies in rats on the biochemical correlates of the pharmacological effects of d-amphetamine can be summarized as follows: 1. d-Amphetamine depletes central and peripheral norepinephrine (NE) stores when injected in doses ten-fold greater than those required to increase exploratory motor activity (0.3 mg/kg i.V.); the doses of d-amphetamine decreasing brain NE content, however, fail to deplete striatal dopamine (DA) (Costa and Groppetti 1970a; Groppetti, Naimzada, and Costa 1971). 2. The d-amphetamine doses depleting brain NE also cause accumulation of p-hydroxynorephedrine in peripheral and central noradrenergic neurons. Since the biological half-life of p-hydroxynorephedrine concentrations in rat brain is twenty times longer than that of d-amphetamine, this metabolite persists in brain tissue longer than its parent compound (Groppetti and Costa 1969). Similar findings were independently reported by Brodie et al. (1969). 3. The persistent localization of p-hydroxynorephedrine in central and peripheral noradrenergic neurons parallels the long-lasting depletion of NE (Costa and Groppetti 1970a). 4. After a single peritoneal injection of 3 to 10 mg/kg of d-amphetamine, the pharmacological responses, including stereotype behavior and increase of locomotor activity,have disappeared 24 to 36 hours earlier than the depletion of NE. This finding suggests that the time course of the depletion of brain NE is unrelated to that of the pharmacological effects (hyperthermia, increase of motor activity, stereotype behavior, and anorexia) (Costa and Groppetti 1970b).