Vol. 54, Issue 4, 678-686, October 1998

A Synergistic Neurotrophic Response to l-Dihydroxyphenylalanine and Nerve Growth Factor

M. A. Mena,¹ Viviana Davila, Joanna Bogaluvsky, and David Sulzer

Departments of Neurology (M.A.M, V.D., J.B., D.S.) and Psychiatry (D.S.), Columbia University and Department of Neuroscience (D.S.), New York State Psychiatric Institute, New York, NY 10032

The catecholamine precursor l-dihydroxyphenylalanine (LDOPA) is the primary therapeutic intervention for Parkinson's disease. Although short-term exposure (30 min) potentiates dopamine (DA) release by elevating quantal size, longer term exposure to L-DOPA (48 hr) promotes neurite outgrowth from midbrain DA neurons in culture. To characterize long term effects of L-DOPA, we used a pheochromocytoma (PC12) line that extends neurites on exposure to nerve growth factor (NGF). L-DOPA potentiated the outgrowth of processes elicited by NGF. This response did not require conversion of L-DOPA to DA, was not caused by agonist effects at DA receptors, and was not blocked by the tyrosine kinase inhibitor 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 sulfoximine, consistent with mediation by an antioxidant mechanism. L-DOPA potentiation of NGF response was important functionally as seen by increased quantal neurotransmitter release from the L-DOPA/NGF-treated neurite varicosities, which displayed both 2-fold greater quantal size and frequency of quantal release. These results demonstrate potentiation by L-DOPA of morphological and physiological responses to neurotrophic factors as well as synergistic induction of antioxidant pathways. Together with effects on transmitter synthesis, these properties seem to provide a basis for the compound's long term presynaptic potentiation of DA release and therapeutic actions.