Mechanism of an exaggerated locomotor response to a low-dose challenge of methamphetamine.

Previous studies using phenylethylamine psychostimulants such as amphetamine (AMPH) have demonstrated that pretreatment with a high-dose of drug followed by a low-dose challenge injection (3 h later) results in an exaggerated behavioral response. In order to explore the mechanism of this exaggerated or what has been suggested to be a "sensitized" response, we investigated the effects of methamphetamine (METH) in a similar treatment paradigm. The current study found that, as suggested by previous studies, a low-dose challenge with METH substantially increased the locomotor response in animals that received a high-dose pretreatment (3.5 h prior to challenge). We also observed that rats displayed an increase in the concentrations of METH and its metabolite AMPH in the striatum following the low-dose challenge of METH if they were pretreated with METH versus saline. A similar pattern for METH and AMPH levels was measured in the plasma. Taken together, these results suggest that the accumulation of drug in animals pretreated with high-dose METH contributes to the overall enhanced behavioral response following challenges with low-doses of METH.