CHRONIC L-DOPA TREATMENT IN THE UNILATERAL 6-OHDA RAT - EVIDENCE FOR BEHAVIORAL SENSITIZATION AND BIOCHEMICAL TOLERANCE

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronic L-dihydroxyphenylalanine (L-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response for L-DOPA activation of the dopamine denervated striatum. Following 30 daily L-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization to L-DOPA was not reversed by a three-day period of L-DOPA withdrawal. In contrast with the emergence of behavioral sensitization to L-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acute L-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronic L-DOPA treatment produces a partial tolerance in the conversion of L-DOPA to extracellular dopamine. The emergence of L-DOPA sensitization-over-stimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects of L-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion of L-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect of L-DOPA therapy.