Alteration of striatal dopaminergic functions implicated in methamphetamine-induced reverse tolerance in rats

Rats were injected repeatedly with methamphetamine (6 mg/kg per day, for 14 days). The effects of the repeated treatment on the change of behaviors and striatal DA metabolism induced by challenge with DA agonists were studied 10 days after the last injection. Repeated methamphetamine administration decreased the sedative effect of low dose apomorphine, and enhanced apomorphine-induced stereotyped behavior but reduced in after pretreatment with tetrabenazine. Striatal DA, HVA and DOPAC contents, and striatal gamma-butyrolactone-induced DA or DOPA accumulation were not altered by repeated methamphetamine treatment. The effect of apomorphine to decrease DA metabolite content and DA or DOPA accumulation was not changed either. As evidenced by experiments using alpha-MT, repeated methamphetamine administration increased DA utilization after methamphetamine or low dose apomorphine challenge, although it did not change DA utilization at the steady state (without drug challenge). These findings suggest that methamphetamine-induced reverse tolerance is accompanied by an increase of DA utilization resulting from the subsensitivity of DA utilization-modulating autoreceptors.