ACUTE L-DOPA PRETREATMENT POTENTIATES 6-HYDROXYDOPAMINE-INDUCED TOXICEFFECTS ON NIGRO-STRIATAL DOPAMINE NEURONS IN MICE

We have studied the effect of various agents on the decreases in stria tal levels of dopamine (DA) and its metabolites which were observed 14 days after an intracerebroventricular (i.c.v.) administration of 50 m u g 6-hydroxydopamine (6-OHDA) to mice. A pretreatment of mice with ei ther a tyrosine hydroxylase inhibitor (alpha-methyl-p-tyrosine), a D-2 receptor agonist (bromocriptine) or antagonist (haloperidol), or a ve sicular uptake inhibitor (tetrabenazine) did not modify the 6-OHDA-ind uced decreases in DA and metabolites, indicating that DA synthesis, ve sicular storage and neuronal firing rates are not mainly involved in t he 6-OHDA-induced toxicity on the DA neurons. Conversely, a pretreatme nt with L-DOPA + benserazide potentiated the 6-OHDA-induced decreases in striatal levels of DA, homovanillic acid and 3-methoxy-tyramine, Th is effect was not due to an increased 6-OHDA uptake via the neuronal c arrier since a pretreatment with L-DOPA + benserazide, performed 1-1.5 h before sacrifice, decreased the apparent affinity of the uptake, an effect which disappeared when considering the total DA concentration present in incubation medium ([H-3]DA and cold released DA). In conclu sion, potentiation of the 6-OHDA neurotoxicity by L-DOPA rises again t he important problem of the safety of the latter drug in therapeutics.