Tolerance to alpha-methyl-p-tyrosine in rats: studies on the antagonism of amphetamine-induced motor activity and excitatory behaviour.

Rats were treated chronically with alpha-methyl-p-tyrosine methyl-ester HCl (alpha-MT) twice daily for 0--14 days. At 1 h after the (last) alpha-MT injection, d-amphetamine sulphate was given and motor activity was measured in an ANIMEX activity meter for 4 h. Amphetamine-induced excitatory and stereotyped behaviour was scored according to a rating scale in a separate experiment. A single dose of alpha-MT markedly reduced the activity response after amphetamine. After 1--3 days of alpha-MT treatment, tolerance to its amphetamine-antagonistic affect started to develop, reaching a maximal degree after 7--14 days. The pattern of the amphetamine response, monophasic in control rats, became biphasic in the alpha-MT tolerant rats with an early (at 0--1 h) and a late (2--4 h) peak of motor activity. The late peak appeared within 3 days, while the early peak appeared after 7 days of alpha-MT treatment. The results on amphetamine-induced excitatory and stereotyped behaviour in essence agreed with the motor-activity data. It is concluded that tolerance to the amphetamine-antagonistic action of alpha-MT is not complete. Its rate of development varies in a complex pattern, indicating the presence of more than one mechanism of tolerance.