ROLE OF DOPAMINE IN THE DEVELOPMENT OF DRUG-INDUCED NEUROTOXICITY

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The possible involvement of dopamine in the neurotoxicity of a number of centrally acting drugs is being examined. The hypothesized role of dopamine in the selective toxicity of the parkinsonism-inducing compound 1-MPTP was investigated using mice pretreated with agents which alter endogenous dopamine synthesis in a defined manner. Treatment with the competitive inhibitor of tyrosine hydroxylase, alpha-methy-p-tyrosine, did not alter the dopaminergic neurotoxicity of l-MPTP nor did treatment with large doses of the dopamine precursor L-DOPA. In related experiments, the mechanism behind the requirement for dopamine synthesis in the sesrotonergic neurotoxicity of central stimulants such as methamphetamine was studied. Serotonergic neurons were shown to take up dopamine via their high affinity uptake system. This uptake was facilitated by ascorbic acid just as the neurotoxicity of methamphetamine requires normal levels of ascorbic acid in vivo. More recently we have also demonstrated that dopamine release induced by drug stimulation in vivo does enter serotonergic neurons where it displaces endogenous stores of serotonin.