Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects

Abstract

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.

Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

“…The total AIMs score calculated on the final day of L-DOPA priming (day 42 post-lesion) was used to assess the degree of dyskinesia established for each animal. In line with previous studies (Rangel-Barajas et al, 2011;Albarran-Bravo et al, 2019), only L-DOPA-treated animals showing severe dyskinesia, defined as scoring >0.3× maximum possible score (>108 in this case) were selected for further study. Seven of the nine L-DOPA-treated rats met this threshold for classification as severely dyskinetic.…”

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia—Literature Review

“…The deletion of D3R is associated with decreased levels of FosB, ERK and H3 activity. It also causes an attenuation of dyskinesia, with preservation of the therapeutic effect of L-DOPA [ 77 ]. The main locus of D3R, whose levels are elevated in dyskinetic patients, is the GP [ 78 ].…”

“…Another proposed solution to control LID is to affect D1R activity by modulating D3R activity, either with D3 partial agonists or with D3 antagonists. Both receptors are co-expressed in dSPN and together are able to form a heteromeric D1R-D3R complex [ 77 , 199 ]. Overactivity of D3R, which is observed in dyskinesia [ 76 ], increases the membrane binding of D1R, consequently increasing the activity of downstream D1R pathways [ 200 ].…”

Coexistence of D3R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D3nf expression changes

“…), and evaluated rotational behavior (Avalos‐Fuentes et al, 2015). Only rats showing eight or more ipsilateral turns per minute during 60 min were included in this study; this ensures the severity of lesion of at least 85% (Albarran‐Bravo et al, 2019). Brains were removed for slice preparation or animals selected to behavior test 16 days after the 6‐OHDA lesion.…”