Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors

NEUROPHARMACOLOGY

卷:59

Article

Mombereau, Cedric²  Kawahara, Yukio¹  Gundersen, Brigitta B.²  Nishikura, Kazuko¹  Blendy, Julie A.² 

[1] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

关键词: RNA editing;    5-HT2c receptor;    Anxiety;    Antidepressant;    Transgenic mice;   

DOI  :  10.1016/j.neuropharm.2010.06.009

来源: Elsevier

【 摘 要 】

Serotonin 2C receptors (5-HT2CR) have been shown to undergo post-transcriptional RNA editing. This modification affects the affinity, coupling and constitutive activity of the receptor. In vivo, manipulations such as stress or antidepressant administration dramatically modify the pattern of 5-HT2CR mRNA editing, suggesting that this phenomenon might be involved in the pathophysiology of stress-related disorders. Indeed, alterations of 5-HT2CR mRNA editing have been observed in depressed patients. Thus, the recent development of mice expressing either the non-edited (5-HT2CR-INI) or the fully-edited form of 5-HT2CR (5-HT2CR-VGV) provides a novel opportunity to investigate the relevance of this phenomenon in the context of stress-related disorders. We observed that both 5-HT2CR-INI and 5-HT2CR-VGV mice exhibit exaggerated anxiety-like behaviors in the elevated-plus maze paradigm. This phenotype was observed when the IN! or VGV mutations were present in mice on a BALB/c background, as well as non-significant trends in the same direction in mice on a C57BL/6J background. In animal models of antidepressant-like activity, the absence of editing of 5-HT2CR mRNA (5-HT2CR-INI) induced an increase in the time spent immobile in the forced-swim test (FST) and tail suspension test (TST). Complete editing of 5-HT2C receptor mRNA (5-HT2CR-VGV) induced antidepressant-like behavior in the FST and TST, as reflected by a significant decrease in time spent immobile. These phenotypes were unrelated to alterations in locomotor activity in both 5-HT2CR-INI and 5-HT2CR-VGV. In the TST, these phenotypes were accompanied by a decrease and an increase in response to desipramine in 5-HT2CR-INI and 5-HT2CR-VGV, respectively. These data constitute the first in vivo demonstration of a role for 5-HT2CR mRNA editing in anxiety- and depression-related behaviors. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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