Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson's disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [3H]-gamma-aminobutyric acid ([3H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [3H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation.
Keywords: Basal ganglia; Dopamine 1 receptors; Dopamine 3 receptors; Dyskinesia; Parkinson’s disease; Substantia nigra pars reticulata.