Effects of genetic knockdown of the serotonin transporter on established L-DOPA-induced dyskinesia and gene expression in hemiparkinsonian rats

Document Type

Article

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder typified by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) leading to motor symptoms including resting tremor, rigidity, akinesia, and postural instability. DA replacement therapy with levodopa (L-DOPA) remains the gold-standard treatment for the motor symptoms of PD. Unfortunately, chronic use of L-DOPA leads to the development of side effects known as L-DOPA-induced dyskinesia (LID). The mechanisms underlying LID are multifaceted, but accumulating research has strongly implicated maladaptive neuroplasticity within the raphe-striatal serotonin (5-HT) circuit. The 5-HT transporter (SERT) has emerged as an intriguing therapeutic target as it is upregulated in the brains of dyskinetic patients and animal models of LID, and pharmacological blockade of SERT alters L-DOPA's effects. Therefore, the current study employed an interventional genetic knockdown of SERT (SERT-KD) to investigate its role in LID expression and LID-associated transcription factors. To do so, hemiparkinsonian, stably dyskinetic rats (N = 68) received adeno-associated virus 9 (AAV9) expressing either a short-hairpin RNA against SERT (SERT-shRNA) or a scrambled control shRNA (SCR-shRNA) after which LID reinstatement and motor performance were assayed over 2 weeks. Dorsal raphe and striatal tissue were collected for the expression analyses of known parkinsonian and LID-associated genes. Results demonstrated that SERT-KD significantly and durably reduced LID and L-DOPA-induced striatal cFOS mRNA without altering L-DOPA efficacy. Such findings point to SERT-mediated adaptations as a 5-HT mechanism by which L-DOPA exerts its actions and therapeutic target for LID.

Keywords

Dopamine, Dorsal raphe nucleus, Levodopa-induced dyskinesia, Parkinson's disease, Serotonin transporter, Short-hairpin RNA, Striatum

Medical Subject Headings

Animals; Levodopa (adverse effects, toxicity); Dyskinesia, Drug-Induced (genetics, metabolism); Serotonin Plasma Membrane Transport Proteins (genetics, metabolism); Male; Antiparkinson Agents (adverse effects, toxicity); Parkinsonian Disorders (drug therapy, metabolism, genetics); Rats; Oxidopamine (toxicity); Rats, Sprague-Dawley; Gene Knockdown Techniques; Proto-Oncogene Proteins c-fos (metabolism, genetics); Corpus Striatum (metabolism, drug effects); Disease Models, Animal; Gene Expression (drug effects)

Publication Date

3-15-2025

Publication Title

Neuropharmacology

E-ISSN

1873-7064

Volume

266

First Page

110227

PubMed ID

39561852

Digital Object Identifier (DOI)

10.1016/j.neuropharm.2024.110227

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