Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales, UK.
Neuropharmacology. 2012 Oct;63(5):818-28. doi: 10.1016/j.neuropharm.2012.06.011. Epub 2012 Jun 18.
Foetal cell transplantation in patients with Parkinson's disease can induce motor complications independent of L-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson's disease, post-transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although L-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing L-DOPA-induced dyskinesia against post-transplantation amphetamine-induced dyskinesia. Agents include: dopaminergic antagonists (D₁: CP94253; D₂: SCH-22390; D₃: nafadotride), serotonergic agonists (5-HT(1A): 8-OH-DPAT; 5-HT(1B): CP94253), opioid antagonist (μ: naloxone), cannabinoid agonist (CB₁: WIN55, 212-2), adrenergic antagonist (α₁ and α₂: yohimbine) and glutamatergic antagonists (NMDA: amantadine and MK-801; mGluR5: MTEP; AMPA: IEM1460). Abnormal involuntary movements in response to amphetamine were decreased by SCH-22390, raclopride, CP94253 and 8-OH-DPAT, yet were unaltered by naloxone, WIN55, 212-2, yohimbine, amantadine, MTEP and IEM1460. Unusually, MK-801 increased the appearance of amphetamine-induced dyskinesia. The results suggest that dopaminergic, serotoninergic and glutamatergic systems are likely to have a fundamental role in the development of graft-induced dyskinesias, which are mechanistically distinct from L-DOPA-induced behvaviours. Importantly, the expression of D₁ and D₂ receptors was unrelated to the severity of AIMs.
胎细胞移植治疗帕金森病可引起运动并发症，与左旋多巴无关，称为移植物诱导运动障碍。在帕金森病 6-羟基多巴胺损伤大鼠模型中，移植后异常运动可对安非他命刺激产生反应，该行为用于模拟移植物诱导运动障碍。虽然左旋多巴诱导的运动障碍在药理学上已有很好的描述，但我们缺乏对移植后安非他命诱导运动障碍的调节的了解，这可能有助于阐明移植物诱导运动障碍的机制。我们评估了一系列对减少左旋多巴诱导运动障碍有效的药物对移植后安非他命诱导运动障碍的作用。这些药物包括：多巴胺能拮抗剂（D₁：CP94253；D₂：SCH-22390；D₃：nafadotride），5-羟色胺能激动剂（5-HT1A：8-OH-DPAT；5-HT1B：CP94253），阿片受体拮抗剂（μ：纳洛酮），大麻素激动剂（CB₁：WIN55,212-2），肾上腺素能拮抗剂（α₁和α₂：育亨宾）和谷氨酸能拮抗剂（NMDA：金刚烷胺和 MK-801；mGluR5：MTEP；AMPA：IEM1460）。安非他命刺激引起的异常不自主运动减少，受 SCH-22390、氯丙嗪、CP94253 和 8-OH-DPAT 的影响，但不受纳洛酮、WIN55,212-2、育亨宾、金刚烷胺、MTEP 和 IEM1460 的影响。不同寻常的是，MK-801 增加了安非他命诱导运动障碍的出现。结果表明，多巴胺能、5-羟色胺能和谷氨酸能系统可能在移植物诱导运动障碍的发展中起着根本性的作用，其机制与左旋多巴诱导的行为不同。重要的是，D1 和 D2 受体的表达与 AIMs 的严重程度无关。
