Division of Behavioral Neuropharmacology, International Center for Brain Science (ICBS), Fujita Health University, Toyoake 470-1192, Aichi, Japan.
Department of Neurology, School of Medicine, Fujita Health University, Toyoake 470-1192, Aichi, Japan.
Int J Mol Sci. 2024 Aug 14;25(16):8849. doi: 10.3390/ijms25168849.
In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.
在帕金森病（PD）患者中，多巴胺 D2/D3 受体激动剂替代疗法会导致决策受损，包括病理性赌博。这些不良反应的神经生物学机制仍不清楚。在这里，我们在 PD 小鼠模型中研究了多巴胺 D3 受体（D3R）优先激动剂普拉克索（PPX）对决策的影响。通过将毒素 6-羟多巴胺双侧注射到背外侧纹状体来生成 PD 模型小鼠。随后用 PPX 处理会增加基于触摸屏的爱荷华赌博任务中的不利选择，其特征是高风险/高回报。这一效应被选择性 D3R 拮抗剂 PG-01037 阻断。在接受 PPX 治疗的模型小鼠中，外苍白球（GPe）中 c-Fos 阳性细胞的数量增加，表明皮质丘脑-基底神经节回路中的间接通路失调。相应地，GPe 的化学遗传抑制恢复了正常的 c-Fos 激活，并挽救了 PPX 诱导的不利选择。这些发现表明，间接通路中 GPe 神经元的过度激活会损害 PD 模型小鼠的决策能力。研究结果为 PD 患者 D2/D3 受体药物治疗期间观察到的病理性赌博提供了候选机制和治疗靶点。
