Treatment of Parkinson’s disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients’ quality of life. Here we replicate DDS in a PD mouse model based on a bilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. Administration of L-Dopa induced locomotor sensitization and conditioned place preference in 6-OHDA lesion, but not in control mice, indicative of the acquisition of addictive-like properties following nigrostriatal dopamine depletion. These behavioral effects were accompanied by abnormal dopamine D1 receptor (D1R) signaling in the medium spiny neurons of the dorsal striatum, leading to hyperactivation of multiple signaling cascades and increased expression of ΔFosB, a stable transcription factor involved in addictive behavior. Systemic administration of the D1R antagonist, SCH23390, abolished these effects and the development of place preference, thereby counteracting the psychostimulant-like effect of L-Dopa. The rewarding properties of L-Dopa were also prevented by chemogenetic inactivation of D1R-expressing neurons in the dorsal striatum. Our results indicate the association between abnormal D1R-mediated transmission and DDS in PD and identify potential approaches for the treatment of this disorder.

帕金森病 (PD) 的治疗基于使用多巴胺能药物，例如左旋多巴和多巴胺受体激动剂。这些物质可以抵消运动症状，但服用它们会伴有运动和非运动并发症。在后一种情况中，一种类似于药物滥用的神经行为障碍，称为多巴胺失调综合征（DDS），因其对患者生活质量的深远负面影响而引起越来越多的关注。在这里，我们通过向背侧纹状体双侧注射 6-羟基多巴胺 (6-OHDA) 在 PD 小鼠模型中复制 DDS。给予左旋多巴可在 6-OHDA 损伤中诱导运动敏化和条件性位置偏好，但在对照小鼠中则不然，这表明黑质纹状体多巴胺耗竭后获得了类似成瘾的特性。这些行为效应伴随着背侧纹状体中型多棘神经元中异常的多巴胺 D1 受体 (D1R) 信号传导，导致多个信号级联的过度激活和 ΔFosB（一种参与成瘾行为的稳定转录因子）的表达增加。全身给予 D1R 拮抗剂 SCH23390，消除了这些作用和位置偏好的发展，从而抵消了左旋多巴的精神兴奋剂样作用。背侧纹状体中表达 D1R 的神经元的化学遗传学失活也阻止了左旋多巴的有益特性。我们的结果表明异常 D1R 介导的传播与 PD 中的 DDS 之间存在关联，并确定了治疗这种疾病的潜在方法。