Department of Neurology, University of Arizona College of Medicine, Tucson, AZ, United States of America.
Department of Neurology, University of Arizona College of Medicine, Tucson, AZ, United States of America; Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, United States of America.
Exp Neurol. 2021 Jun;340:113670. doi: 10.1016/j.expneurol.2021.113670. Epub 2021 Mar 2.
L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.
左旋多巴诱导的运动障碍（LID）是帕金森病（PD）多巴胺替代疗法多年治疗后出现的衰弱性运动症状。虽然有大量关于 LID 的细胞和突触起源的研究，但对于 LID 如何影响系统水平的回路和神经同步、同步性如何受到 L-DOPA 暴露剂量和持续时间的影响，以及潜在的新型 LID 治疗方法（如亚麻醉剂量的氯胺酮）如何改变这种活动，知之甚少。最近的研究表明，亚麻醉剂量的氯胺酮治疗可以减少 LID，而且氯胺酮已知会影响神经同步。为了研究这些问题，我们测量了临床前 PD 和 LID 啮齿动物模型的运动皮层（M1）和纹状体的运动和局部场电位（LFP）活动。在第一个实验中，我们研究了 LID 引发程序和 L-DOPA 剂量对 LID 神经特征的影响。比较了两种常见的引发程序：一种是高剂量程序，将单侧 6-羟多巴胺损伤的大鼠暴露于 12mg/kg L-DOPA 7 天；另一种是低剂量程序，将大鼠暴露于 7mg/kg L-DOPA 21 天。与其他小组的报告一致，12mg/kg L-DOPA 引发了 LID 和 80Hz 振荡；然而，尽管明显存在 LID，但在给予 7mg/kg 后并未观察到这些 80Hz 振荡，表明 80Hz 振荡不是 LID 的唯一特征。我们还发现，数周的低剂量引发导致纹状体中出现非振荡宽带伽马活动（>30Hz）和 M1 中θ到高伽马交叉频率耦合（CFC）。在第二组实验中，我们研究了氯胺酮暴露如何影响低剂量 L-DOPA 引发的光谱特征。在每次神经记录过程中，通过 5 次注射（20mg/kg，ip）每隔 2 小时给予氯胺酮。我们发现，氯胺酮暴露抑制了与 LID 相关的纹状体宽带伽马，但增强了 M1 宽带活动。我们还发现，与 LID 开启状态相关的 M1 θ到高伽马 CFC 被氯胺酮抑制。这些结果表明，氯胺酮的治疗效果是区域特异性的。我们的发现也具有临床意义，因为我们是第一个报告与帕金森病个体中多巴胺替代疗法更密切相关的常见低剂量 LID 引发程序的新型振荡特征的人。我们还确定了亚麻醉剂量氯胺酮治疗抗运动障碍活性的神经相关性。
