Pei Q, Zetterström T S C, Sprakes M, Tordera R, Sharp T
University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK.
Neuroscience. 2003;121(4):975-82. doi: 10.1016/s0306-4522(03)00504-9.
The mechanism underlying the therapeutic effect of antidepressants is not known but neuroadaptive processes akin to long-term potentiation have been postulated. Arc (Activity-regulated, cytoskeletal-associated protein) is an effector immediate early gene implicated in LTP and other forms of neuroplasticity. Recent data show that Arc expression is regulated by brain 5-hydroxytryptamine neurones, a target of many antidepressants. Here in situ hybridisation and immunohistochemistry were used to examine whether Arc expression in rat brain is altered by antidepressant drug treatment. Repeated administration of the monoamine reuptake inhibitors paroxetine, venlafaxine or desipramine induced region-specific increases in Arc mRNA. These increases were greatest in regions of the cortex (frontal and parietal cortex) and hippocampus (CA1 layer) and absent in the caudate putamen. Repeated treatment with the monoamine oxidase inhibitor, tranylcypromine, increased Arc mRNA in a similar fashion to the monoamine reuptake inhibitors. The antidepressant drugs also increased the number of Arc-immunoreactive cells in the parietal cortex. Acute antidepressant injection, and repeated administration of the antipsychotic drug chlorpromazine, produced either limited or no changes in Arc mRNA. The data suggest that chronic treatment with antidepressant drugs induces Arc gene expression in specific regions across the rat forebrain. Up-regulation of Arc expression may be part of the process by which antidepressant drugs achieve long-term changes in synaptic function in the brain.
抗抑郁药治疗效果的潜在机制尚不清楚，但已推测存在类似于长时程增强的神经适应性过程。Arc（活性调节的细胞骨架相关蛋白）是一种效应即刻早期基因，与长时程增强及其他形式的神经可塑性有关。最近的数据表明，Arc表达受脑5-羟色胺神经元调节，而脑5-羟色胺神经元是许多抗抑郁药的作用靶点。在此，我们使用原位杂交和免疫组织化学方法来研究抗抑郁药物治疗是否会改变大鼠脑中Arc的表达。重复给予单胺再摄取抑制剂帕罗西汀、文拉法辛或地昔帕明可诱导Arc mRNA在区域特异性增加。这些增加在皮质（额叶和顶叶皮质）和海马体（CA1层）区域最为显著，而在尾状壳核中则没有。用单胺氧化酶抑制剂反苯环丙胺重复治疗，与单胺再摄取抑制剂类似，可增加Arc mRNA。抗抑郁药物还增加了顶叶皮质中Arc免疫反应性细胞的数量。急性注射抗抑郁药以及重复给予抗精神病药物氯丙嗪，对Arc mRNA产生的变化有限或无变化。数据表明，抗抑郁药物的慢性治疗可诱导大鼠前脑特定区域的Arc基因表达。Arc表达的上调可能是抗抑郁药物在脑中实现突触功能长期变化过程的一部分。
