Methamphetamine (METH) is a potent psychomotor stimulant that has high potential for abuse in humans. METH is also a neurotoxin, affecting primarily brain dopamine (DA) and serotonin systems. The abuse potential of METH, together with its neurotoxic effects, make METH an important drug from the standpoint that chronic use by humans may lead to long-term changes in brain neurochemistry. The experiments in this proposal will focus on in vivo changes in presynaptic DA function in the striatum and nucleus accumbens (NAc) of rats treated with neurotoxic doses of METH. The experiments will test the hypotheses that METH will produce long-lasting, functional changes in DA overflow and uptake, that the magnitude and duration of these changes will be dependent on the age of the animals, and that these changes can be prevented or reversed by the recently discovered dopaminergic neurotrophic factor glial cell line derived neurotrophic factor (GDNF). The initial set of experiments will determine the short-term (1 week) effects of METH treatment on DA overflow and uptake in rats. In vivo electrochemistry will be used to map potassium-evoked (calcium dependent) overflow of DA and DA clearance (uptake) in the striatum and NAc of control and METH treated animals. In vivo microdialysis will be carried out to determine basal levels, and potassium-and d-amphetamine-evoked (calcium independent) overflow of DA and DA metabolites to confirm and extend the electrochemical studies. The second set of experiments will use the same techniques to examine the time course (1 week to 1 year) for recovery of DA overflow and uptake in rats following neurotoxic doses of METH. The third set of experiments will examine how the age of the rat during METH treatment affects the magnitude and duration of changes in DA overflow and uptake. The severity of effects and time course for recovery will be followed in young adult (3-4 months old) and middle-aged (12 months old) animals. In the fourth set of experiments GDNF, a potent dopaminergic neurotrophic agent, will be administered directly into the brain of young adult and middle-aged rats at various time points prior to, and after, neurotoxic doses of METH. The ability of GDNF to reduce or prevent METH-induced changes in presynaptic DA function, and the ability to accelerate recovery, will be monitored with in vivo electrochemistry and microdialysis. Tissue DA levels will be determined at the conclusion of all experiments as a measure of the extent of the neurotoxic lesions. It is hoped that the infor-mation derived from these experiments will increase our understanding of possible long-term consequences associated with METH abuse.
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