Behavioral Neuroscience Program, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY, 13902, USA.
Psychopharmacology (Berl). 2020 Jan;237(1):155-165. doi: 10.1007/s00213-019-05353-6. Epub 2019 Aug 21.
In the majority of Parkinson's disease (PD) patients, long-term dopamine (DA) replacement therapy leads to dyskinesia characterized by abnormal involuntary movements (AIMs). There are various mechanisms of dyskinesia, such as the sensitization of striatal DA D1 receptors (DR) and upregulation of DA D3 receptors (DR). These receptors interact physically and functionally in DR-bearing medium spiny neurons to synergistically drive dyskinesia. However, the cross-receptor-mediated effects due to DR-DR cooperativity are still poorly understood. In pursuit of this, we examined whether or not pharmacological DR or DR stimulation sensitizes the dyskinetic response to the appositional agonist, a process known as cross-sensitization. First, we established DR-DR behavioral synergy in a cohort of 6-OHDA-lesioned female adult Sprague-Dawley rats. Then, in a new cohort, we tested for cross-sensitization in a between-subject design. Five groups received a sub-chronic regimen of either saline, the DR agonist SKF38393 (1.0 mg/kg), or the DR agonist PD128907 (0.3 mg/kg). For the final injection, each group received an acute injection of the other agonist. AIMs were monitored following each injection. Sub-chronic administration of both SKF38393 and PD128907 induced the development of dyskinesia. More importantly, cross-agonism tests revealed reciprocal cross-sensitization; chronic treatment with either SKF38393 or PD128907 induced sensitization to a single administration of the other agonist. This reciprocity was not marked by changes to either DR or DR striatal mRNA expression. The current study provides key behavioral data demonstrating the role of D3R in dyskinesia and provides behavioral evidence of D1R and D3R functional interactions.
在大多数帕金森病（PD）患者中，长期多巴胺（DA）替代疗法会导致以异常不自主运动（AIMs）为特征的运动障碍。运动障碍有多种机制，例如纹状体 DA D1 受体（DR）的敏化和 DA D3 受体（DR）的上调。这些受体在携带 DR 的中脑多巴胺能神经元中物理和功能相互作用，协同驱动运动障碍。然而，由于 DR-DR 协同作用，交叉受体介导的影响仍知之甚少。为了研究这一点，我们检查了药理学 DR 或 DR 刺激是否会使阿朴吗啡激动剂的运动障碍反应敏感，这个过程称为交叉敏感化。首先，我们在一组 6-OHDA 损伤的成年雌性 Sprague-Dawley 大鼠中建立了 DR-DR 行为协同作用。然后，在一个新的队列中，我们在一个被试间设计中测试了交叉敏感化。五组接受了亚慢性盐水、DR 激动剂 SKF38393（1.0mg/kg）或 DR 激动剂 PD128907（0.3mg/kg）治疗方案。对于最后一次注射，每组接受另一种激动剂的急性注射。每次注射后监测 AIMs。亚慢性给予 SKF38393 和 PD128907 均可诱导运动障碍的发展。更重要的是，交叉激动剂测试显示出相互交叉敏感化；慢性给予 SKF38393 或 PD128907 诱导对另一种激动剂单次给药的敏感化。这种互惠性并不以 DR 或 DR 纹状体 mRNA 表达的变化为标志。本研究提供了关键的行为数据，证明了 D3R 在运动障碍中的作用，并提供了 D1R 和 D3R 功能相互作用的行为证据。
