Behavioral sensitization: characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats.

Factors influencing the behavioral sensitization ("reverse tolerance") produced by intermittent amphetamine (AMPH) injections were studied by quantifying rotational behavior in rats that had a unilateral 6-hydroxy-dopamine lesion of the substantia nigra. The results indicate that: a single injection of a low dose of AMPH enhances rotational behavior induced by a second injection of AMPH for up to 12 weeks; multiple, weekly injections of AMPH produce a progressive enhancement in rotational behavior, over-and-above that produced by a single injection; female rats show more robust sensitization than males following single or multiple injections of AMPH; this sex difference may be due to the suppression of sensitization by an androgen, because removal of testicular hormones potentiates sensitization; the long-lasting sensitization of rotational behavior produced by infrequent injections of AMPH is not due to drug-environment conditioning effects, but perhaps to a persistent AMPH-induced change(s) in brain catecholamine systems; and a simple change in DA receptors is probably not involved, because the sensitization produced by infrequent injections of AMPH does not influence the rotation produced by a subsequent injection of apomorphine. The results illustrate an intriguing example of neuroplasticity that may have clinical relevance.