L-DOPA EXACERBATES AMPHETAMINE-INDUCED DOPAMINE DEPLETION

Administration of L-DOPA to Parkinson patients has been suggested to e xacerbate ''functional denervation'' of the nigrostriatal system. Ther efore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride ) would potentiate amphetamine-induced neurotoxicity. Mice received tw o injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) i nterspersed with four injections of amphetamine (15.0 mg/kg) at 2-h in tervals. Significant depletion of striatal dopamine, DOPAC, and HVA wa s evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to in creased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal system s of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ben serazide depleted 5-HT to 82% of control values. No changes were evide nt in the frontal cortex following amphetamine with or without concurr ent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.