Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain.
Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Universidad de Málaga, Málaga, Spain.
Psychopharmacology (Berl). 2020 Aug;237(8):2419-2431. doi: 10.1007/s00213-020-05544-6. Epub 2020 May 22.
Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson's disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion.
To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour.
Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm.
Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug's antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration.
We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.
冲动控制障碍（ICD）和其他冲动-强迫行为在接受多巴胺能激动剂治疗的帕金森病（PD）患者中经常出现。迄今为止，尚无可用的动物模型来研究其病理生理学，并确定它们是否可以通过改变多巴胺能药物的剂量来诱发。此外，纹状体多巴胺能耗竭的倾向性模式存在一些争议。
研究两种剂量的普拉克索（PPX）对运动冲动性、延迟不耐受和强迫样行为的影响。
采用双侧注射 6-羟多巴胺（6-OHDA）造成背外侧纹状体轻度多巴胺能神经支配损伤的雄性大鼠，给予两种剂量的 PPX（0.25 mg/kg 和 3 mg/kg）治疗，并在可变延迟信号范式中进行测试。
部分（50%）多巴胺能耗竭不会引起运动冲动性或延迟不耐受的显著变化。然而，0.25 mg/kg 的 PPX 增加了运动冲动性，而 3 mg/kg 的 PPX 则增加了运动冲动性和延迟不耐受性。这些作用与药物的抗帕金森作用无关。重要的是，多巴胺能损伤前后的冲动性评分与给予 3 mg/kg 的 PPX 后观察到的冲动性呈正相关。PPX 给药未引起强迫样行为。
我们描述了一种大鼠模型，其背外侧多巴胺能损伤程度中度，类似于早期 PD 患者的损伤，在接受 PPX 治疗时，以剂量依赖的方式产生不同类型的冲动性，与运动获益无关。该模型再现了 PD 中异常冲动性的关键特征，可能有助于深入了解 ICD 的病理生理学。
