Effects of amphetamines on the metabolism of catecholamines in the rat brain

Abstract

THE BIZARRE, stereotyped behavior observed after the administration of amphetamines to several mammahan species (RANDRUP and MUNKVAD, 1967r, 1970”) has been attributed to an increase of dopamine (DA) at its receptors, due to an increased release or an inhibition of reuptake of DA in dopaminergic terminals of the basal ganglia and portions of the limbic system (CARLSSON et aZ.,3 COYLE and SNYDER~). The dextrorotatory isomer appears to be at least 2 (TAYLOR and SNYDER~) and possibly four-to-six-times (SCHEEL-Kx~_?GER~) more potent than levoamphetamine in vivo with respect to the development of stereotyped behavior in the rat and this difference in potency remains unexplained. When we studied the uptake of [3H]DA by a synaptosomal preparation of the rat corpus striatum (HARRIS and BALDESSARINI’), the inhibitory concentration (IC,,,) required to produce a 50 per cent reduction of the accumulation of 0.1 PM rH]DA for the (+)-isomer of amphetamine was about four-times less than for the ( -)-isomer in inhibiting the net accumulation of DA (Table 1). Similarly, in kinetic experiments, the apparent inhibitory constants (&) were found to be O-1 and 0.4 PM for (+)- and (-)-amphetamine, respectively. Furthermore, the (+)-isomer of the para-hydroxylated product of amphetamine was about equipotent against DA-uptake with the corresponding (+)-isomer of amphetamine, whereas racemic mixtures of the beta-hydroxylated products of amphetamine and p-OHamphetamine (norephedrine and p-OH-norephedrine, respectively) had much less inhibitory potency than (-J-)-p-OH-amphetamine or (-)-amphetamine (Table 1). In addition, (-)amphetamine, cocaine and (-)-metaraminol were very similar in their abilities to inhibit DA-accumulation. In contrast to the results with striatal tissues, with cortical homogenates, the dextrorotatory isomer of amphetamine was only slightly more potent in inhibiting the uptake of NE (0.5 pM) and DA (0.2 ,uM) than the (-)-enantiomer. By varying the concentration of either the catecholamine or amphetamine, kinetic analysis by two methods indicated that the &-value for levoamphetamine was less than twice that of dextroamphetamine.