Parkinson’s disease is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations following neurodegeneration or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops. This study investigated the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity, and markers of synaptic plasticity. Bilateral nigrostriatal degeneration was induced by viral-mediated expression of human mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the dorsomedial striatum (DMS) were performed, and spike probability in response to OFC stimulation was measured before and after high-frequency stimulation (HFS). Post-mortem analysis included stereological assessment of nigral neurodegeneration, BDNF and TrkB protein levels. Nigrostriatal neurodegeneration led to altered firing patterns of OFC neurons that were restored by PPX. HFS of the OFC led to an increased spike probability in the DMS, while dopaminergic loss had the opposite effect. PPX led to a decreased spike probability following HFS in control rats and failed to counteract the effect of dopaminergic neurodegeneration. These alterations were associated with decreased levels of BDNF and TrkB in the DMS. This study demonstrates that nigral dopaminergic loss and PPX both contribute to alter frontostriatal transmission, precluding adequate information processing in associative basal ganglia loops as a gateway for the development of non-motor symptoms or non-motor side effects of DRT.

帕金森病的特征是黑质致密部(SN c ) 多巴胺能神经元变性，导致运动和认知症状。神经退行性疾病或多巴胺替代疗法（DRT）后的许多细胞和分子适应已在运动网络中被描述，但对于联合基底神经节环路知之甚少。本研究调查了黑质纹状体变性和普拉克索 (PPX) 对眶额皮质 (OFC) 神经元活动、额纹状体可塑性和突触可塑性标志物的影响。双侧黑质纹状体变性是由病毒介导的 SNc 中人类突变 α-突触核蛋白表达诱导的。在麻醉大鼠中进行近细胞记录以评估 OFC 中的神经元活动。对背内侧纹状体 (DMS) 进行记录，并在高频刺激 (HFS) 之前和之后测量 OFC 刺激响应的尖峰概率。尸检分析包括黑质神经变性、BDNF 和 TrkB 蛋白水平的体视学评估。黑质纹状体神经变性导致 OFC 神经元的放电模式发生改变，而 PPX 可以恢复这些放电模式。 OFC 的 HFS 导致 DMS 中的尖峰概率增加，而多巴胺能损失则产生相反的效果。 PPX 导致对照大鼠 HFS 后峰值概率降低，并且未能抵消多巴胺能神经变性的影响。这些改变与 DMS 中 BDNF 和 TrkB 水平的降低有关。 这项研究表明，黑质多巴胺能损失和 PPX 都会导致额纹状体传递的改变，从而妨碍关联基底神经节环路中充分的信息处理，作为 DRT 的非运动症状或非运动副作用发展的门户。