L-DOPA does not enhance hydroxyl radical formation in the nigrostriatal dopamine system of rats with a unilateral 6-hydroxydopamine lesion

The debate about the toxicity of L-DOPA to dopaminergic neurons has not bee n resolved. Even though enzymatic and nonenzymatic metabolism of L-DOPA can produce hydrogen peroxide and oxygen free radicals, there has been controv ersy as to whether L-DOPA generates an oxidant stress in vivo. This study d etermined whether acute or repeated administration of L-DOPA caused in vivo production of hydroxyl radicals in striatum and other brain regions in rat s with a unilateral B-hydroxydopamine lesion of the dopaminergic nigrostria tal projections. Salicylate trapping combined with in vivo microdialysis pr ovided measurements of extracellular 2,3-dihydroxybenzoic acid (2,3-DHBA) i n striatum following L-DOPA administration systemically (100 mg/kg, i.p.) o r by intrastriatal perfusion (1 mM, via the microdialysis probe), Tissue co ncentrations of 2,3-DHBA and salicylate were also measured in striatum, ven tral midbrain, and cerebellum following repeated administration of L-DOPA ( 50 mg/kg, i.p., once daily for 16 days). In each instance, treatment with L -DOPA did not increase 2,3-DHBA concentrations, regardless of the nigrostri atal dopamine system's integrity. When added to the microdialysis perfusion medium, L-DOPA resulted in a significant decrease in the striatal extracel lular concentration of 2,3-DHBA. These results suggest that administration of L-DOPA, even at high doses, does not induce hydroxyl radical formation i n vivo and under some conditions may actually diminish hydroxyl radical act ivity. Furthermore, prior damage to the nigrostriatal dopamine system does not appear to predispose surviving dopaminergic neurons to increased hydrox yl radical formation following L-DOPA administration. Unlike L-DOPA, system ic administration of methamphetamine (10 mg/kg, s.c.) produced a significan t increase in the concentration of 2,3-DHBA in striatal dialysate, suggesti ng that increased formation of hydroxyl radicals may contribute to methamph etamine neurotoxicity.