It has been well known that 3-O-methyldopa (3-OMD) is a metabolite of L-3,4-dihydroxyphenylalanine (L-DOPA) formed by catechol O-methyltransferase (COMT), and 3-OMD blood level often reaches higher than physiological level in Parkinson's disease (PD) patients receiving long term L-DOPA therapy. However, the physiological role of 3-OMD has not been well understood. Therefore, in order to clarify the effects of 3-OMD on physiological function, we examined the behavioral alteration in rats based on locomotor activity, and measured dopamine (DA) and its metabolites levels in rats at the same time after 3-OMD subchronic administration. The study results showed that repeated administrations of 3-OMD increased its blood and the striatum tissue levels in those rats, and decreased locomotor activity in a dose dependent manner. Although 3-OMD subchronic administration showed no significant change in DA level in the striatum, DA metabolite levels, such as 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were significantly decreased. After 3-OMD washout period (7 d), locomotor activity and DA turnover in those rats returned to normal levels. Furthermore, locomotor activity and DA turnover decreased by 3-OMD administration were recovered to normal level by acute L-DOPA administration. These results suggested that 3-OMD affect to locomotor activity via DA neuron system. In conclusion, 3-OMD itself may have a disadvantage in PD patients receiving L-DOPA therapy.Key words 3-O-methyldopa; L-3,4-dihydroxyphenylalanine; locomotor activity; dopamine turnover; rat Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra region of the basal ganglia, which results in movement-related symptoms. Current treatment for PD includes dopamine replacement therapy in the form of L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor to dopamine (DA) in its synthesis pathway that has been the gold standard of care for decades. More recently, DA receptor agonists, such as pramipexole, pergolide, and ropinirole, have become more commonly prescribed for the treatment of PD. Approximately 50% of PD patients, when treated with L-DOPA for more than 5 years, experience motor fluctuations such as the "wearing-off" phenomenon or the "no-on" phenomenon. 1) L-DOPA is commonly administered with aromatic amino acid decarboxylase (AADC) inhibitor, such as carbidopa or benserazide. 3-O-methyldopa (3-OMD) is a major metabolite of L-DOPA. 3-OMD is formed by catechol O-methyltransferase (COMT) in many organs including blood, peripheral tissues and brain.2) 3-OMD easily accumulates in several tissues (liver, kidney, brain, blood) because 3-OMD has much longer half-life (approximately 15 h) than L-DOPA. 2,3)It is reported that L-DOPA upregulates the expression and activity of COMT. 4) Therefore, blood level of 3-OMD is continually high and 3-OMD accumulates in PD patients receiving long term L-DOPA therapy.5) COMT inhibitor, such as entacapone, increases the area under ...