Pharmacological Role of 3-O-Methyldopa in the Central Nervous System-Mediated Behavioral Effects of L-DOPA in Rats

Long-term l-3,4-dihydroxyphenylalanine (l-DOPA) therapy for Parkinson's disease increases plasma concentrations of 3-O-methyldopa (3-OMD), a major metabolite of l-DOPA. This study aimed to investigate the role of 3-OMD in the central nervous system (CNS)-mediated behavioral effects associated with chronic l-DOPA treatment in rats. The effects of 3-OMD on CNS function were examined using two rat models: repeated oral co-administration of l-DOPA/benserazide and single or repeated intraperitoneal (i.p.) administration of 3-OMD. Behavioral assessments included spontaneous locomotor activity, spontaneous alternation behavior (SAB), spatial learning, and depression-like behavior. Plasma and brain concentrations of 3-OMD were also measured. Repeated oral administration of l-DOPA/benserazide maintained plasma 3-OMD concentrations at 1.57-3.50 μg/mL and brain concentrations at 1.68-3.23 μg/g. This treatment reduced SAB by up to 30% and showed a trend toward reduced spatial learning, whereas locomotor activity was unaffected. Repeated i.p. administration of 3-OMD produced comparable plasma and brain concentrations of 3-OMD, reduced SAB, and showed a trend toward reduced spatial learning, without affecting other behaviors. The reduction in SAB was reversed after a 7-d washout period. In contrast, a single administration of 3-OMD had no detectable behavioral effects. In conclusion, sustained, but not transient, exposure to 3-OMD may contribute to reduced working memory performance during chronic l-DOPA therapy.