Locomotor response to l-DOPA in reserpine-treated rats following central inhibition of aromatic l-amino acid decarboxylase: Further evidence for non-dopaminergic actions of l-DOPA and its metabolites

Abstract

l-DOPA is the most widely used treatment for Parkinson's disease. The anti-parkinsonian and pro-dyskinetic actions of l-DOPA are widely attributed to its conversion, by the enzyme aromatic l-amino acid decarboxylase (AADC), to dopamine. We investigated the hypothesis that exogenous l-DOPA can induce behavioural effects without being converted to dopamine in the reserpine-treated rat-model of Parkinson's disease. A parkinsonian state was induced with reserpine (3 mg/kg s.c.). Eighteen hours later, the rats were administered l-DOPA plus the peripherally acting AADC inhibitor benserazide (25 mg/kg), with or without the centrally acting AADC inhibitor NSD1015 (100 mg/kg). l-DOPA/benserazide alone reversed reserpine-induced akinesia (4158 ± 1125 activity counts/6 h, cf vehicle 1327 ± 227). Addition of NSD1015 elicited hyperactive behaviour that was approximately 7-fold higher than l-DOPA/benserazide (35755 ± 5226, P < 0.001). The hyperactivity induced by l-DOPA and NSD1015 was reduced by the alpha 2C antagonist rauwolscine (1 mg/kg) and the 5-HT 2C agonist MK212 (5 mg/kg), but not by the D2 dopamine receptor antagonist remoxipride (3 mg/kg) or the D1 dopamine receptor antagonist SCH23390 (1 mg/kg). These data suggest that l-DOPA, or metabolites produced via routes not involving AADC, might be responsible for the generation of at least some l-DOPA actions in reserpine-treated rats.