Magnard Robin, Vachez Yvan, Carcenac Carole, Boulet Sabrina, Houeto Jean-Luc, Savasta Marc, Belin David, Carnicella Sebastien
INSERM U1216 and Univ. Grenoble Alpes, Grenoble Institut des Neurosciences (GIN), Grenoble, France.
CIC-INSERM 1402, Service de Neurologie, CHU de Poitiers, Université de Poitiers, Poitiers, France.
Front Behav Neurosci. 2018 Dec 13;12:312. doi: 10.3389/fnbeh.2018.00312. eCollection 2018.
Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson's disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD. We therefore investigated in a preclinical model in rats, specifically designed to study PD-related non-motor symptoms, the effect of nigrostriatal DA denervation on impulsive choice, in relation to pre-existing levels of impulsivity, measured in a Delay Discounting Task (DDT). In this procedure, rats had the choice between responding for a small sucrose reinforcer delivered immediately, or a larger sucrose reinforcer, delivered after a 0, 5, 10 or 15 s delay. In two different versions of the task, the preference for the large reinforcer decreased as the delay increased. However, and in contrast to our initial hypothesis, this discounting effect was neither exacerbated by, or related to, the extent of the substantia nigra pars compacta (SNc) DA lesion, nor it was influenced by pre-existing variability in impulsive choice. These results therefore question the potential implication of the nigrostriatal DA system in impulsive choice, as well as the DA neurodegenerative process as a factor contributing significantly to the development of ICDs in PD.
冲动控制障碍（ICDs）是帕金森病（PD）中多巴胺能（DA）替代疗法（DRTs）常见的行为并发症。冲动选择是指无法忍受强化延迟，已被确定为ICDs的核心病理生理过程。尽管在接受DRTs的ICDs的PD患者中冲动选择会加剧，但一些临床和临床前研究表明，神经退行性过程引起的背侧纹状体DA去神经支配以及先前存在的高冲动性特质，可能都有助于PD中ICDs的出现。因此，我们在专门设计用于研究PD相关非运动症状的大鼠临床前模型中，研究黑质纹状体DA去神经支配对冲动选择的影响，这与在延迟折扣任务（DDT）中测量的先前存在的冲动性水平有关。在此过程中，大鼠可以选择立即获得小蔗糖强化物，或者在延迟0、5、10或15秒后获得大蔗糖强化物。在该任务的两个不同版本中，随着延迟增加，对大强化物的偏好降低。然而，与我们最初的假设相反，这种折扣效应既没有因黑质致密部（SNc）DA损伤的程度而加剧，也与之无关，也不受冲动选择中先前存在的变异性的影响。因此，这些结果质疑了黑质纹状体DA系统在冲动选择中的潜在作用，以及DA神经退行性过程作为PD中ICDs发展的一个重要促成因素的作用。
