Inserm, U1216, F- 38000 Grenoble, France.
Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000 Grenoble, France.
Sci Rep. 2017 Jan 30;7:41589. doi: 10.1038/srep41589.
Beyond classical motor symptoms, motivational and affective deficits are frequently observed in Parkinson's disease (PD), dramatically impairing the quality of life of patients. Using bilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats, we have been able to reproduce these neuropsychiatric/non-motor impairments. The present study describes how bilateral 6-OHDA SNc lesions affect the function of the main striatal dopaminergic (DA) receptor subtypes. Autoradiography was used to measure the levels of striatal DA receptors, and operant sucrose self-administration and neuropharmacological approaches were combined to investigate the causal implication of specific DA receptors subtypes in the motivational deficits induced by a dorsostriatal DA denervation. We found that D3 receptors (DR) exclusively are down-regulated within the dorsal striatum of lesioned rats. We next showed that infusion of a DR antagonist (SB-277011A) in non-lesioned animals specifically disrupts preparatory, but not consummatory behaviors. Our findings reveal an unexpected involvement of dorsostriatal DR in motivational processes. They strongly suggest an implication of dorsostriatal DR in the neuropsychiatric symptoms observed in PD, highlighting this receptor as a potential target for pharmacological treatment.
除了经典的运动症状外，帕金森病（PD）患者还经常出现动机和情感缺陷，极大地影响了患者的生活质量。我们使用双侧 6-羟多巴胺（6-OHDA）损毁大鼠黑质致密部（SNc），成功复制了这些神经精神/非运动障碍。本研究描述了双侧 6-OHDA SNc 损伤如何影响主要纹状体多巴胺（DA）受体亚型的功能。放射自显影用于测量纹状体 DA 受体水平，并结合操作性蔗糖自我给药和神经药理学方法，研究了特定 DA 受体亚型在背侧纹状体 DA 去神经支配引起的动机缺陷中的因果关系。我们发现，DR 仅在损伤大鼠的背侧纹状体中下调。我们接下来表明，在非损伤动物中输注 DR 拮抗剂（SB-277011A）特异性破坏预备行为，但不破坏摄取行为。我们的发现揭示了背侧纹状体 DR 在动机过程中的意外参与。它们强烈表明背侧纹状体 DR 参与了 PD 中观察到的神经精神症状，突出了该受体作为药物治疗的潜在靶点。
