The central nervous system stimulants, methamphetamine (METH) and its congeners, are abused to essentially the same extent as cocaine. In contrast to cocaine, when large, repeated doses of METH are administered to rats, significant neurochemical deficits are observed, which include long-lasting decreases in neostriatal tyrosine hydroxylase (TH) and tryptophan hydroxylase activities and in concentrations of dopamine (DA) and 5-hydroxytryptamine and their metabolites. There is considerable evidence that these responses to METH are DA-mediated. Since these neurochemical deficits are blocked by MK-801, a glutamate antagonist, it appears that glutamate also may play a role in the METH-induced neurochemical response. This resubmission of the grant proposal has been extensively revised. The central theme of the proposal is more focused and will be confined to an investigation of the role of glutamate in causing the METH-induced dopaminergic deficit; a persisting decrease in TH activity will be used as an index of this neurochemical deficit. Glutamate and DA release in selected brain areas will be monitored by employing in vivo microdialysis probes; these substances will be assayed by high performance liquid chromatography coupled with electrochemical detection. In preliminary studies, we observed a dramatic and abrupt rise in extracellular concentrations of glutamate after multiple doses of METH. This METH- induced glutamate release will first be characterized, the relationship between DA and glutamate release will then be studied, and the role of glutamate and dopamine in mediating the dopaminergic deficit will be determined. The possible influence of gamma-aminobutyric acid (GABA) on METH-induced glutamate and DA release, and the subsequent dopaminergic deficit, will be studied. Whether molecular messengers (calcium, calmodulin, nitric oxide and/or cyclic GMP) participate in these responses will be determined. The results of these studies are relevant to clinical conditions that occur in those individuals who abuse central nervous system stimulants, such as METH. Moreover, because schizophrenia-like symptoms are often observed in individuals who abuse METH, these findings could also be relevant to understanding this psychotic disorder. Finally, because toxic doses of METH decrease dopaminergic parameters in brain areas that are similarly compromised in Parkinson's disease, the results of these studies could be of value in elucidating mechanisms responsible for degeneration of dopaminergic neurons in this clinical condition.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Drug Abuse Biomedical Research Review Committee (DABR)
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University of Utah
Schools of Pharmacy
Salt Lake City
United States
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