A SYNERGISTIC NEUROTROPHIC RESPONSE TO I-DIHYDROXYPHENYLALANINE AND NERVE GROWTH-FACTOR

The catecholamine precursor l-dihydroxyphenylalanine (L-DOPA) is the p rimary therapeutic intervention for Parkinson's disease. Although shor t-term exposure (30 min) potentiates dopamine (DA) release by elevatin g quantal size, longer term exposure to L-DOPA (48 hr) promotes neurit e outgrowth from midbrain DA neurons in culture. To characterize long term effects of L-DOPA, we used a pheochromocytoma (PC12) line that ex tends neurites on exposure to nerve growth factor (NGF). L-DOPA potent iated the outgrowth of processes elicited by NGF. This response did no t require conversion of L-DOPA to DA, was not caused by agonist effect s at DA receptors, and was not blocked by the tyrosine kinase inhibito r genistein. However, similar results were found after exposure to l-n -acetylcysteine or apomorphine, a DA receptor agonist that produces a quinone metabolite, and seemed to correlate with glutathione synthesis . Long-term process elaboration was blocked by L-buthionine sulfoximin e, consistent with mediation by an antioxidant mechanism. L-DOPA poten tiation of NGF response was important functionally as seen by increase d quantal neurotransmitter release from the L-DOPA/NGF-treated neurite varicosities, which displayed both P-fold greater quantal size and fr equency of quantal release. These results demonstrate potentiation by L-DOPA of morphological and physiological responses to neurotrophic fa ctors as well as synergistic induction of antioxidant pathways. Togeth er with effects on transmitter synthesis, these properties seem to pro vide a basis for the compound's long term presynaptic potentiation of DA release and therapeutic actions.