Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels
Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels
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DOI：
10.1016/j.neuint.2011.07.013
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发表时间：
2011-11-01
影响因子：
4.2
通讯作者：
Barlati, Sergio
中科院分区：
文献类型：
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作者：
Barbon, Alessandro;Caracciolo, Luca;Barlati, Sergio
越来越多的证据表明谷氨酸能神经传递在重度抑郁症的病理生理学和抗抑郁药的作用中发挥着关键作用。本研究的主要目的是阐明长期接受两种不同抗抑郁药：氟西汀（FLX）和瑞波西汀（RBX）治疗的大鼠前额叶/额叶皮层（P/FC）和海马（HC）中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体表达的时间分布及其功能调节。大鼠组用两种药物治疗 1、2 或 3 周，在其他组中，治疗后进行 1 周的药物清除 (3 + 1)。我们发现这两种药物都能诱导 AMPAR 亚基蛋白表达的强烈增加，这种增加具有时间依赖性和亚基特异性。尤其是在P/FC中，FLX主要作用于GluA2和GluA4亚基，药物洗脱后达到5倍的增加； RBX主要影响GluAl和GluA3，在治疗结束时达到4倍的增加。此外，在 HC 中，两种药物诱导亚基蛋白水平出现时间特异性增加，其中 GluA3 和 GluA4 呈现主要变化，尽管动力学不同。此外，我们的数据表明，抗抑郁药可能会改变 GluA2 的 RIG 编辑水平，尽管变化很小，主要是在 P/FC 中，反过来可能会诱导谷氨酸神经传递的微调。总的来说，我们表明抗抑郁药治疗会引起 AMPA 受体亚基表达的显着变化，其时间依赖性效应与这些药物的治疗效果的起效一致。这些数据证实了谷氨酸神经传递参与这些药物的作用，并进一步表明以 AMPA 受体为目标作为治疗抑郁症的治疗方法。 (C) 2011 Elsevier B.V. 保留所有权利。
Growing evidence suggests a pivotal role for glutamatergic neurotransmission in the pathophysiology of major depressive disorder and in the action of antidepressants. The main aim of this study was to elucidate the temporal profile of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors expression and their functional regulation in prefrontal/frontal cortex (P/FC) and hippocampus (HC) of rats chronically treated with two different antidepressants: fluoxetine (FLX) and reboxetine (RBX). Rat groups were treated for 1, 2 or 3 weeks with the two drugs and, in additional groups, the treatments were followed by 1 week of drug washout (3 + 1). We found that both drugs induced strong increases in AMPAR subunit protein expression that were time dependent and subunit specific. Especially in P/FC, FLX had the main effect on GluA2 and GluA4 subunits, reaching a 5-fold increase after the drug washout; RBX mostly affected GluAl and GluA3, reaching a 4-fold increase at the end of the treatment. Furthermore, in HC, the two drugs induced a time specific increase in subunit protein levels, with GluA3 and GluA4 presenting the main changes, albeit with different kinetics. In addition, our data indicate that antidepressants might alter, though by small changes, the RIG editing levels for GluA2, mostly in P/FC, and in turn may induce fine-tuning of glutamate neurotransmission.Overall, we showed that antidepressant treatments induced marked changes in AMPA receptor subunits expression, with time-dependent effects that are consistent with the onset of therapeutic effect of these drugs. These data confirm the involvement of glutamate neurotransmission in the effects of these drugs and further suggest the targeting of AMPA receptors as a therapeutic approach for the treatment of depression. (C) 2011 Elsevier B.V. All rights reserved.