Objective: Levodopa (LD) is the standard treatment for Parkinson’s Disease (PD) despite risk of LD-induced dyskinesia (LID) development within a decade of treatment. Serotonergic (5-HT) compounds reduce LID, however with variable outcomes and hindered LD efficacy. Determining 5-HT targets to reduce LID and maintain LD efficacy is a central goal of the present work.

Background: LID is mutifaceted; however, evidence supports the involvement of dorsal raphe (DRN) 5-HT striatal projecting neurons in conveying LD’s effects whereby 5-HT cells take up LD, convert to dopamine (DA), and release it as a false neurotransmitter, seemingly first to reduce symptoms, but later in an unregulated manner, resulting in motor fluctuations typical of LID. Our prior work has shown that expressing DA-responsive D2 autoreceptor (D2AR) in DRN reduced LID development. Here we examined if interventional expression of D2AR on 5-HT DRN cells reduces established LID.

Method: We used Tryptophan-hydroxylase-2 (TPH2)-Cre+ Long Evans rats who received a unilateral 6-hydroxydopamine medial forebrain bundle lesion, followed by chronic treatment of either LD (6 mg/kg, s.c.) or vehicle for 14 days to establish stable dyskinesia. Abnormal involuntary movements (AIMs) were assessed at days 1, 7, and 14. To target Cre+ 5-HT cells, animals received either a viral Cre-dependent AAV-FLEX-D2AR or AAV-FLEX-GFP infusion into the DRN after day 14. After 4 weeks, rats received their respective treatments of LD or vehicle for another 14 days, where AIMs were observed at 1, 7, and 14. To assess motor performance, the forepaw adjusting steps (FAS) test was used pre- and post-viral intervention.

Results: Following D2AR intervention, animals showed 50% reduction in axial, limb, and orolingual (ALO) AIMs scores across their 14-day treatment compared to pre-D2AR state. This significant reduction was not observed in control rats. Moreover, ectopic expression of D2AR did not affect LD’s efficacy observed by stable, improved forepaw stepping.

Conclusion: These findings suggest that leveraging lesion and LD-induced 5-HT neuroplasticity, we can genetically autoregulate 5-HT DRN derived DA to optimize LD treatment, implicating such strategies as a promising future therapeutic avenue.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-ectopic-dopamine-d2-autoregulation-of-raphe-striatal-projecting-neurons-on-established-l-dopa-mediated-behaviors-in-a-hemiparkinsonian-rat-model/