McManus Grace, Galfano Ashley, Budrow Carla, Lipari Natalie, Tseng Kuei Y, Manfredsson Fredric P, Bishop Christopher
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, 13902, USA.
Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY, 13902, USA.
Neuropharmacology. 2025 Mar 15;266:110227. doi: 10.1016/j.neuropharm.2024.110227. Epub 2024 Nov 17.
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.
帕金森病（PD）是一种神经退行性疾病，其典型特征是黑质致密部（SNpc）中的多巴胺（DA）神经元丧失，导致运动症状，包括静止性震颤、僵硬、运动迟缓及姿势不稳。左旋多巴（L-DOPA）替代疗法仍是治疗PD运动症状的金标准。不幸的是，长期使用L-DOPA会导致称为L-DOPA诱导的异动症（LID）的副作用。LID的潜在机制是多方面的，但越来越多的研究强烈表明中缝-纹状体5-羟色胺（5-HT）回路内存在适应性不良的神经可塑性。5-HT转运体（SERT）已成为一个引人关注的治疗靶点，因为它在异动症患者和LID动物模型的大脑中上调，并且对SERT的药理学阻断会改变L-DOPA的作用。因此，本研究采用了对SERT进行干预性基因敲低（SERT-KD）的方法，以研究其在LID表达和LID相关转录因子中的作用。为此，对偏侧帕金森病、稳定异动的大鼠（N = 68）在接受表达针对SERT的短发夹RNA（SERT-shRNA）或 scrambled对照shRNA（SCR-shRNA）的腺相关病毒9（AAV9）后，在2周内测定LID恢复情况和运动表现。收集中缝背核和纹状体组织，用于分析已知的帕金森病和LID相关基因的表达。结果表明，SERT-KD显著且持久地降低了LID和L-DOPA诱导的纹状体cFOS mRNA，而不改变L-DOPA的疗效。这些发现表明SERT介导的适应性变化是L-DOPA发挥其作用的5-HT机制以及LID的治疗靶点。
