Metabolic and experimental factors in the behavioral response to repeated amphetamine.

Previous studies have shown that repeated administration of d-amphetamine results in a progressive augmentation of locomotor activity and stereotypy. The present studies demonstrate that rats also exhibit an enhanced behavioral response following multiple daily injections of l-amphetamine and methylphenidate. Furthermore, behavioral augmentation is shown to persist for at least six days after a single injection of d-amphetamine. These results demonstrate the generality of the reverse tolerance phenomenon and indicate that metabolic factors, such as the formation of false neurotransmitters, do not account for the enhanced behavioral responsiveness observed with multiple injections of these drugs. The role of experiential factors in the behavioral augmentation was studied by (1) varying the amount of continuous exposure to the experimental environment prior to d-amphetamine administration, and (2) examining the effects of repeated injections of saline or d-amphetamine in different environments prior to testing in the experimental chambers. The results, which revealed a behavioral augmentation independent of pretreatment condition, indicate that neither acclimation to the test chamber nor state-dependent conditioning to external stimuli accounts for the enhanced locomotor activity and stereotypy observed with repeated administration of psychomotor stimulants.