The relationship between amphetamine antagonism and depletion of brain catecholamines by alpha-methyl-p-tyrosine in rats.

The time-course and the dose-response relationship for the antagonistic effect of alpha-methyl-p-tyrosine methyl ester HCl H 44/68 (alpha-MT) on d-amphetamine (10.6 mumoles/kg) induced increase in motor activity was studied. The effect of amphetamine was gradually reduced from 30--60 min to a minimum at 1--4 h after the administration of 0.407 mmoles/kg of alpha-MT. From (4--) 8 h the amphetamine response started to reappear and the original response was restored completely at 16 h after alpha-MT. The dose-response curve showed, that between 0.051--0.41 mmoles/kg of alpha-MT, given 1 h before amphetamine, there was a gradual reduction of the amphetamine response; doses above 0.41 mmoles/kg did not cause any further effect. The antiamphetamine action of alpha-MT was compared with its time- and dose-dependent effects of inhibition of synthesis and reduction of stores of brain catecholamines. It was found, that the antiamphetamine action was more closely correlated with the reduction of the levels of brain dopamine, than with the brain noradrenaline levels. Further, the inhibition of catecholamine synthesis per se did not appear to be a sufficient condition for alpha-MT induced antagonism of amphetamine. These findings support the view that amphetamine is dependent on a substantial portion of the brain pool of dopamine and possibly noradrenaline rather than on very small, newly synthesized pools of these neurotransmitters.