Abstract
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.
Footnotes
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Send reprint requests to: Dr. David Sulzer, Black Building #305, 650 W 168th St., Columbia University, New York, NY 10032. E-mailds43{at}columbia.edu
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↵1 Current affiliation: Dept. de Investigación, Hospital Ramón y Cajal, Madrid 28034, Spain.
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This work was supported by the Parkinson’s Disease Foundation, Spanish MEC (PR-95–098 and SAF 96–1099; MAM), and National Instititue on Drug Abuse Grants DA10154 and DA07418 (D.S.).
- Abbreviations:
- L-DOPA
- l-dihydroxyphenylalanine
- BSO
- l-buthionine sulfoximine
- DA
- dopamine
- DCF
- 2,7-dichlorofluorescin diacetate
- GSH
- glutathione (reduced form)
- LNAC
- l-N-acetylcysteine
- NGF
- nerve growth factor
- ANOVA
- analysis of variance
- Received December 17, 1997.
- Accepted July 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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