Department of Pathology, University of Otago, Christchurch, New Zealand.
J Psychopharmacol. 2010 Aug;24(8):1243-51. doi: 10.1177/0269881109102786. Epub 2009 Apr 3.
Antidepressant drugs can exert significant effects on the mood of a patient suffering major depression and other disorders. These drugs generally have pharmacological actions on the uptake or metabolism of the neurotransmitters serotonin, noradrenaline and, to a lesser extent, dopamine. However, there are many aspects of antidepressant action we do not understand. We have applied proteomic analysis in a rat hippocampal model in an attempt to identify relevant molecules that operate in pathways functionally relevant to antidepressant action. Rats were administered either 5 mg/kg daily of the antidepressant paroxetine or vehicle for 12 days, then hippocampal protein was recovered and resolved by 2-D gel electrophoresis. After antidepressant exposure, we observed increased expression or modification of cytochrome c oxidase, subunit Va, cyclin-dependent kinase inhibitor 2A interacting protein, dynein, axonemal, heavy polypeptide 3 and RHO GDP-dissociation inhibitor alpha. Decreased expression or modification was observed for complexin 1 (CPLX1), alpha-synuclein, parvalbumin, ribosomal protein large P2, prohibitin, nerve growth factor, beta subunit (NGFB), peroxiredoxin 6 (PRDX6), 1-acylglycerol-3-phosphate O-acyltransferase 2_predicted, cystatin B (CYTB) and lysosomal membrane glycoprotein 1. CPLX1, the most strongly regulated protein observed, mediates the fusion of cellular transport vesicles with their target membranes and has been implicated in the pathophysiology of mood disorders, as well as antidepressant action. CPLX1 and the other proteins identified may represent links into molecular processes of importance to mood dysregulation and control, and their respective genes may represent novel candidates for studies of antidepressant pharmacogenetics.
抗抑郁药对患有重度抑郁症和其他疾病的患者的情绪有显著影响。这些药物通常对神经递质 5-羟色胺、去甲肾上腺素的摄取或代谢具有药理作用，在较小程度上也对多巴胺具有药理作用。然而，我们对抗抑郁药作用的许多方面并不了解。我们应用蛋白质组学分析大鼠海马模型，试图鉴定与抗抑郁作用相关的功能途径中的相关分子。将大鼠每天给予 5mg/kg 的抗抑郁药帕罗西汀或载体 12 天，然后回收海马蛋白并通过二维凝胶电泳分离。在抗抑郁药暴露后，我们观察到细胞色素 c 氧化酶亚基 Va、细胞周期蛋白依赖性激酶抑制剂 2A 相互作用蛋白、动力蛋白、轴突重链 3 和 RHO GDP 解离抑制剂α的表达或修饰增加。复合物 1 (CPLX1)、α-突触核蛋白、副甲状腺蛋白、核糖体蛋白大 P2、抑制素、神经生长因子、β亚基 (NGFB)、过氧化物还原酶 6 (PRDX6)、1-酰基甘油-3-磷酸 O-酰基转移酶 2_预测、胱抑素 B (CYTB)和溶酶体膜糖蛋白 1 的表达或修饰减少。CPLX1 是观察到的调节最明显的蛋白质，介导细胞运输囊泡与靶膜的融合，并且与心境障碍的病理生理学以及抗抑郁作用有关。CPLX1 和鉴定的其他蛋白质可能代表与情绪失调和控制的重要分子过程的联系，它们各自的基因可能代表抗抑郁药药物遗传学研究的新候选基因。
