EARLY L-DOPA TREATMENT INITIALLY RETARDS BUT LATER ENHANCES DOPAMINE-RECEPTOR SUPERSENSITIVITY FOLLOWING UNILATERAL DOPAMINE DENERVATION

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriat al dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 m g/kg carbidopa once or twice per day or saline in sepal-ate treatment groups for 13 days. Treatment was initiated within 18-20 h postoperati ve, well-before the onset of denervation supersensitivity. Contralater al rotation emerged as a response to L-DOPA on day 7 postoperative fir st in the L-DOPA once/day group and then on day 9 for the L-DOPA twice /day group. Thus, early postoperative L-DOPA treatment retarded but di d not prevent the development of dopamine receptor supersensitivity. F ollowing a 14-day withdrawal period, these same L-DOPA treated groups exhibited substantially higher rates of contralateral rotation to an L -DOPA challenge as compared to a drug-naive group with comparable 6-OH DA lesions. HPLC-EC measurements of L-DOPA in striatal and cortical ti ssue samples showed no differences in concentration across the L-DOPA treatment groups. There were several differences, however, in the neur ochemical impact of L-DOPA on frontal cortex vs. striatum. In the stri atum but not the cortex, L-DOPA concentrations were higher in the 6-OH DA than the intact hemisphere and, L-DOPA increased dopamine concentra tions in cortex but not in the striatum. Behaviorally, L-DOPA exerted two diametrically opposite effects linked to the stare of dopamine rec eptors. Prior to the onset of dopamine receptor supersensitivity L-DOP A suppressed locomotor behavior and delayed the emergence of denervati on supersensitivity. Once denervation supersensitivity developed, howe ver, the L-DOPA engaged sensitization mechanisms and enhanced locomoto r behavior and dopamine receptor supersensitivity. These findings sugg est that the initiation of antiparkinsonian treatment prior to the ons et of denervated dopamine receptor supersensitivity in the 6-OHDA mode l is a valuable strategy to determine if a drug treatment retards or f acilitates the development of dopamine receptor supersensitivity.