Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
J Pharmacol Exp Ther. 2011 Feb;336(2):423-30. doi: 10.1124/jpet.110.169532. Epub 2010 Oct 21.
Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (L-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 ± 0.3-, 7.8 ± 0.2-, and 1.8 ± 0.1-fold (mean of URB597 groups ± S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with L-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after L-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total L-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of L-DOPA or L-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma L-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing L-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of L-DOPA treatment.
多巴胺能疗法仍然是治疗帕金森病（PD）最有效的症状治疗方法，但与运动并发症相关，包括运动障碍，以及非运动并发症，如精神病、冲动控制障碍（ICD）和多巴胺调节障碍综合征（DDS）。内源性大麻素系统等非多巴胺能神经递质系统可能对这些并发症的发展至关重要。在 1-甲基-4-苯基-1,2,3,6-四氢吡啶损伤的狨猴 PD 模型中，研究了脂肪酸酰胺水解酶（FAAH）在介导 L-3,4-二羟基苯丙氨酸（L-DOPA）诱导行为中的作用。通过生物分析（液相色谱-串联质谱）和行为观察方法评估了选择性 FAAH 抑制剂[3-（3-氨甲酰基苯基）苯基] N-环己基氨基甲酸酯（URB597）的药效学和运动效应。URB597（3、10、30 或 60 mg/kg po）与载体相比，分别使 FAAH 底物 N-花生四烯酰乙醇酰胺（花生四烯酸酰胺）、N-油酰乙醇酰胺和 N-棕榈酰乙醇酰胺的血浆水平增加 10.3±0.3、7.8±0.2 和 1.8±0.1 倍（URB597 组的平均值±S.E.M.），所有差异均有统计学意义（均 P<0.001），给药后 4 小时。L-DOPA（20 mg/kg sc）治疗可缓解帕金森病，但可引起运动障碍、精神病样行为和多动，这可能与 ICD 和 DDS 相关。在 L-DOPA 后 2 至 4 小时（相当于 URB597 给药后 4 至 6 小时），URB597 使总 L-DOPA 诱导的活动和多动的幅度分别减少 32%和 52%，使其达到正常动物的水平。URB597（10 mg/kg po）治疗不会改变 L-DOPA 的抗帕金森作用或 L-DOPA 诱导的运动障碍和精神病。URB597 单独给药时不改变血浆 L-DOPA 水平，也无行为作用。抑制 FAAH 可能是一种减少 L-DOPA 诱导的副作用的新方法，例如 ICD 和 DDS，同时保持 L-DOPA 治疗的抗帕金森益处。
