Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Vanderbilt Brain Institute, Department of Psychology, Vanderbilt University, Nashville, TN 37232, USA.
Brain. 2022 Oct 21;145(10):3488-3499. doi: 10.1093/brain/awab487.
Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson's disease population. Here, we applied 18F-fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson's disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty patients with Parkinson's disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with 18F-fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson's disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson's disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours.
冲动-强迫行为在很大一部分帕金森病患者中表现出来。患有这些症状的患者的腹侧纹状体多巴胺受体可用性降低，多巴胺释放增加。先前关于冲动性的研究表明，中脑 D2 自身受体以反馈抑制的方式调节纹状体多巴胺的释放，在健康人群中，更高的冲动性与这种抑制作用的熟练程度较差有关。这在帕金森病患者人群中尚未得到评估。在这里，我们应用 18F-氟丙嗪 PET 研究来评估安慰剂对照口服右旋苯丙胺序列中纹状体和纹状体外 D2 样受体的摄取。我们假设，具有冲动-强迫行为的帕金森病患者对右旋苯丙胺的腹侧纹状体多巴胺反应更大，并且中脑 D2 自身受体无法减弱腹侧纹状体多巴胺的释放是这种反应的基础。20 名患有帕金森病（平均年龄=64.1±5.8 岁）的患者，有（n=10）和没有（n=10）冲动-强迫行为，在多巴胺脱状态下接受单次盲口服右旋苯丙胺挑战（0.43mg/kg）。所有患者均完成了 18F-氟丙嗪的 PET 成像，这是一种高亲和力的 D2 样受体配体，在安慰剂和右旋苯丙胺状态下。基于体素和感兴趣区分析均显示右旋苯丙胺诱导的内源性多巴胺释放定位于腹侧纹状体和尾侧中眶额皮质。在腹侧纹状体中观察到的内源性多巴胺释放与患者报告的参与基于奖励的行为呈正相关，该行为由帕金森病自我报告冲动性评定量表量化。在没有冲动-强迫行为的参与者中，基线中脑 D2 受体可用性与腹侧纹状体多巴胺释放呈负相关；然而，在有冲动-强迫行为的参与者中，这种关系不存在。这些发现强调了帕金森病中基于奖励的行为受腹侧纹状体多巴胺释放的调节，并表明从中脑自身受体丧失抑制性反馈可能是冲动-强迫行为表现的基础。
