Administration of methamphetamine to several species of animals results in long-lasting injury of the monoaminergic (dopaminergic and serotonergic) inputs to the striatum. These findings indicate that the health concerns associated with repeated methamphetamine self-administration in human extend beyond those related to the acute sympathomimetic effects of stimulant abuse. In particular, long-lasting injury to striatal dopaminergic nerve terminals may increase the risk of development of motoric disorders, especially in later life. Studies using animals suggest that the methamphetamine-induced neurotoxicity depends upon the release of DA from mesostriatal terminals. In this proposal, a key to studying these transmitter interactions in methamphetamine-induced neurotoxicity lies in the ability to measure the striatal extracellular levels of DA and its metabolites in rats using microdialysis perfusion during the entire period of repeated methamphetamine intoxication. The proposal discusses recent evidence from this laboratory indicating that neurotoxic regimens of methamphetamine treatment induce a dramatic rise in striatal dopamine efflux. Further, the neuroprotective effects of several pharmacological agents, including the noncompetitive N-methyl-D-aspartate antagonist MK-801 and the dopamine antagonists eticlopride and SCH 23390, correspond with the ability of these drugs to attenuate the massive release of DA otherwise seen after neurotoxic regimens of methamphetamine. The current proposal has three objectives: (i) to test further the relationship between DA release by m-AMPH and this stimulant's neurotoxic effects on striatal DA terminals, (ii) to examine the characteristics of striatal dopamine terminals at the time that they are susceptible to massive dopamine overflow by methamphetamine, and (iii) to determine the acute and long-term consequences for sensorimotor function of the dopamine terminal injury induced by methamphetamine.
