Abstract

The chronic administration of DL-α-methyl-para-tyrosine(α-MT, 100 mg/kg i.p.) every 12 hours, together with α-MT methyl ester (0.6 mg/ml) in the drinking water. to male rats for periods up to 13 days resulted in tolerance to the spontaneous motor activity depressant and antiamphetamine (motor stimulant) effects of α-MT. This tolerance developed while brain levels of catecholamines remained maximally depressed. Increased sensitivity to the hyperthermic effect of d-amphetamine sulfate (1 mg/kg s.c.) and increased spontaneous motor activity were observed in rats 30 hours after withdrawal of α-MT after a 13-day treatment. At this time brain amine levels remained significantly depressed. The increased sensitivity to d-amphetamine was not the result of an alteration in amphetamine disposition since brain and plasma levels of amphetamine were identical in α-MT-treated and control animals. On withdrawal from a 13-day α-MT treatment, rats also exhibited enhanced sensitivity to the hypothermic effect of intraventnicularly administered norepinephrine but not to the hypothermic effect of intraventricularly administered amphetamine. It is concluded that the chronic administration of α-MT to the rat results in an increased sensitivity of noradrenergic systems to both amphetamine (systemic hyperthermic effect) and norepinephrine (central hypothermic effect) and that the study of increased sensitivity of the central nervous system to such compounds may be a valuable tool in the delineation of central noradrenergic functions such as thermoregulation and the mechanism of action of centrally active drugs.