Zhuang Xiaowen, Lemak Julia, Sridhar Sadhana, Nelson Alexandra B
Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA.
Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA.
Brain. 2025 Sep 4. doi: 10.1093/brain/awaf312.
Parkinson's disease (PD) is characterized by progressive neurodegeneration, which is associated with motor and non-motor symptoms. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), characterized by pathological gambling, hypersexuality, and/or compulsive shopping. Approximately 14-40% of all medicated PD patients suffer from ICD. Despite the high prevalence of ICD in medicated PD patients, we know little of its mechanisms, and the main therapeutic strategy is reducing or eliminating dopamine agonist medication. Human imaging studies suggest that the input nucleus of the basal ganglia, the striatum, may be a critical site of circuit dysfunction in ICD. To explore the cellular and circuit mechanisms of ICD, we developed a mouse model in which we administered the dopamine D2/3 agonist pramipexole to parkinsonian and healthy control mice. ICD-like behavior was assessed using a delay discounting task. Delay discounting is a normal cognitive phenomenon, in which the value of a reward decreases according to the time needed to wait for it. Impulsivity is measured as the preference for immediate (small) over delayed (large) rewards. We combined this mouse model with chemogenetics and in vivo optically-identified single-unit recordings to examine how dopamine agonists act on vulnerable striatal circuitry to mediate impulsive decision-making. We found that in parkinsonian mice, therapeutic doses of dopamine D2/3R or D1R agonists drove more pronounced delay discounting, reminiscent of what has been reported in PD/ICD patients on medication. In contrast, healthy mice did not become more impulsive when given the same dose of dopamine agonist. The clinically relevant dopamine D2/3R agonist pramipexole induced marked bidirectional changes in the firing of striatal direct and indirect pathway neurons in parkinsonian mice. Chronic pramipexole treatment potentiated these changes in striatal physiology and decision-making behavior. Furthermore, chemogenetic excitation of direct pathway striatal neurons or inhibition of indirect pathway neurons induced impulsive decision making in the absence of dopamine agonists. These findings indicate that abnormal striatal activity plays a causal role in mediating ICD-like behaviors. Together, they provide a robust mouse model and insights into ICD pathophysiology.
帕金森病（PD）的特征是进行性神经退行性变，这与运动和非运动症状相关。多巴胺替代疗法可以缓解运动症状，但也会导致冲动控制障碍（ICD），其特征为病理性赌博、性欲亢进和/或强迫购物。所有接受药物治疗的PD患者中约有14 - 40%患有ICD。尽管ICD在接受药物治疗的PD患者中患病率很高，但我们对其机制知之甚少，主要治疗策略是减少或停用多巴胺激动剂药物。人体影像学研究表明，基底神经节的输入核团纹状体可能是ICD中回路功能障碍的关键部位。为了探究ICD的细胞和回路机制，我们建立了一种小鼠模型，在帕金森病小鼠和健康对照小鼠中给予多巴胺D2/3激动剂普拉克索。使用延迟折扣任务评估类似ICD的行为。延迟折扣是一种正常的认知现象，其中奖励的价值会根据等待奖励所需的时间而降低。冲动性通过对即时（小）奖励相对于延迟（大）奖励的偏好来衡量。我们将这种小鼠模型与化学遗传学和体内光学识别的单单元记录相结合，以研究多巴胺激动剂如何作用于易损的纹状体回路来介导冲动决策。我们发现，在帕金森病小鼠中，治疗剂量的多巴胺D2/3R或D1R激动剂会导致更明显的延迟折扣，这与服用药物的PD/ICD患者的情况相似。相比之下，给予相同剂量多巴胺激动剂时，健康小鼠并没有变得更冲动。临床上相关的多巴胺D2/3R激动剂普拉克索在帕金森病小鼠中诱导纹状体直接和间接通路神经元放电出现明显的双向变化。慢性普拉克索治疗增强了纹状体生理学和决策行为的这些变化。此外，在没有多巴胺激动剂的情况下，化学遗传学刺激直接通路纹状体神经元或抑制间接通路神经元会诱导冲动决策。这些发现表明，异常的纹状体活动在介导类似ICD的行为中起因果作用。总之，它们提供了一个有力的小鼠模型以及对ICD病理生理学的见解。
