METHAMPHETAMINE TOXICITY AND CORTICOSTRIATAL GLUTAMATE

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Methamphetamine (MA) is a drug of abuse with pronounced effects on the CNS including psychomotor stimulation and mood elevation. These effects have contributed to its high abuse liability. Furthermore, prolonged use has produced a behavioral pattern resembling paranoid schizophrenia. These behavioral side effects and abuse potential suggest that MA produces long-lasting neurotoxic effects in the CNS. Recent studies have implicated an excitatory amino acid involvement in MA-induced depletions of striatal dopamine (DA) and serotonin (5HT). No studies to date however, have directly measured brain excitatory amino acids such as the excitotoxin, glutamate, during the time course of repeated MA administration. The manner in which MA selectively destroys DA and 5HT neurons is unknown although a dopaminergic mechanism has been proposed. This proposal will examine a potential cortical-subcortical mechanism of enhanced corticostriatal glutamate release and NMDA receptor activation following MA administration. The primary objective of these studies will be to establish that the neurotoxic effects of MA on DA and 5HT neurons in striatum are mediated in part by glutamate. It is posited that the striatal neurotoxicity to repeated MA injections is partially due to a cumulative increase in striatal glutamate release via increased corticostriatal glutamatergic transmission. In vivo microdialysis will be used to simultaneously measure extracellular levels of glutamate and biogenic amines in both the striatum and frontal cortex of awake-behaving rats during the repeated systemic and intracortical administrations of MA. Striatal tissue content of DA and 5HT will be measured one week after the termination of MA treatment as an index of toxicity. Systemic and local perfusions of specific NMDA receptor antagonists will be used to determine the contribution of the NMDA receptor and the brain region(s) involved in mediating the MA-induced changes in striatal glutamate release and neurotoxicity. The modulatory role of the rat adrenal glucocorticoid, corticosterone will also be examined with regard to the mechanism through which MA increases extracellular glutamate. It is hoped that specific information derived from these experiments will provide basic insight into the neural mechanisms responsible for the neurotoxicity to MA and other psychostimulant drugs.