Noradrenergic antidepressant responses to desipramine in聽vivo are reciprocally regulated by arrestin3 and spinophilin

详细信息	查看全文 | 推荐本文 |

• 作者：Christopher Cottingham^a ; Xiaohua Li^b ; ¹ ; Qin Wang^a ; ^{qinwang@uab.edu}
• 关键词：伪2 Adrenergic receptor ; Arrestin ; Depression ; Desipramine ; Forced swim test ; Spinophilin
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：June, 2012
• 卷：62
• 期：7
• 页码：2354-2362
• 文件大小：635 K

摘要

Many antidepressant drugs, including the tricyclic antidepressant desipramine (DMI), are broadly understood to function by modulating central noradrenergic neurotransmission. 伪₂ adrenergic receptors (伪₂ARs) are key regulators of the noradrenergic system, and previous work has implicated 伪₂ARs in mediating the antidepressant activity of DMI in the rodent forced swim test (FST). However, little is known about intracellular regulators of antidepressant drug action. 伪₂AR function is tightly regulated by its intracellular interacting partners arrestin and the dendritic protein spinophilin. We have previously established the competitive and reciprocal nature of these interacting proteins at the 伪₂AR in the context of classic agonist effects, and have shown DMI to be a direct arrestin-biased ligand at the receptor. In the present study, we report that mice deficient in the 伪_2AAR subtype lack DMI-induced antidepressant behavioral effects in the FST. As well, mice deficient in arrestin3 lack antidepressant response to DMI, while spinophilin-null mice have enhanced antidepressant response to DMI compared with wild-type controls, indicating that this 伪_2AAR-mediated response is reciprocally regulated by arrestin and spinophilin. The characteristic of 伪_2AAR-dependence and arrestin3 involvement was shared by the antidepressant effect of the classic 伪₂AR agonist clonidine but not the non-tricyclic norepinephrine reuptake inhibitor reboxetine, supporting a model whereby DMI exerts its antidepressant effect through direct engagement of the 伪_2AAR and arrestin3. Our results implicate arrestin- and spinophilin-mediated regulation of the 伪_2AAR in the pharmacology of the noradrenergic antidepressant DMI, and suggest that manipulation of this mode of receptor regulation may represent a novel and viable therapeutic strategy.