ROLE OF ENDOGENOUS GLUTATHIONE IN THE OXIDATION OF DOPAMINE

Intrastriatal injection of dopamine causes the selective degeneration of tyrosine hydroxylase-containing terminals and an increase in conten t of cysteinyl-catechols, an index of dopamine oxidation, Both of thes e effects can be attenuated by coadministration of antioxidants such a s glutathione. Therefore, we investigated the effects of decreased end ogenous glutathione on the neurotoxic potential of dopamine. We observ ed that pretreatment with either L-buthionine sulfoximine, a specific inhibitor of glutathione synthesis, or diethyl maleate, which forms ad ducts with glutathione, caused significant decreases in endogenous glu tathione levels at the time of dopamine injection. Pretreatment with L -buthionine sulfoximine potentiated the formation of protein cysteinyl -dopamine after intrastriatal injection of 1.0 mu mol of dopamine. We also observed that intrastriatal injection of 1.0 mu mol of dopamine d ecreased striatal glutathione content in all pretreatment conditions. However, injection of a low dose (0.05 mu mol of dopamine) caused a de crease in striatal glutathione levels only in the L-buthionine sulfoxi mine-pretreated rats, Diethyl maleate pretreatment was not effective i n potentiating either cysteinyl-catechol formation or glutathione loss after dopamine injection. We conclude that dopamine contributes to ce llular oxidative stress and that this can be exacerbated, or at least unmasked, if glutathione synthesis is compromised.