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

Abstract

Serotonin 2C receptors (5-HT 2C R) 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-HT 2C R mRNA editing, suggesting that this phenomenon might be involved in the pathophysiology of stress-related disorders. Indeed, alterations of 5-HT 2C R mRNA editing have been observed in depressed patients. Thus, the recent development of mice expressing either the non-edited (5-HT 2C R-INI) or the fully-edited form of 5-HT 2C R (5-HT 2C R -VGV) provides a novel opportunity to investigate the relevance of this phenomenon in the context of stress-related disorders. We observed that both 5-HT 2C R-INI and 5-HT 2C R-VGV mice exhibit exaggerated anxiety-like behaviors in the elevated plus maze paradigm. This phenotype was observed when the INI 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-HT 2C R mRNA (5-HT 2C R-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-HT 2C R-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-HT 2C R-INI and -VGV. In the TST, these phenotypes were accompanied by a decrease and an increase in response to desipramine in 5-HT 2C R-INI and -VGV, respectively. These data constitute the first in vivo demonstration of a role for 5-HT 2C R mRNA editing in anxiety-and depression-related behaviors.

Enhancement of alcohol drinking in mice depends on alterations in RNA editing of serotonin 2C receptors

“…This suggests that alterations in RNA editing of 5-HT 2C R in the ACC is crucial for determining alcohol drinking behaviour. INI-mice bred on a C57BL/6 background exhibit no significant differences from WT littermates in anxiety-like and feeding behaviours (Mombereau et al, 2010). Thus, our observation would not be attributed to another behavioural phenotype.…”

A-to-I editing of coding and non-coding RNAs by ADARs

“…However, the mutant mice lacked certain PWS-associated symptoms such as obesity, and thus the relevance of over-editing of 5-HT 2C R mRNA to PWS needs further investigation. The 5-HT 2C R mRNA-editing mutant mice (both over- and under-edited) exhibit anti-depressive and exaggerated anxiety- like behaviours, indicating a relevance of 5-HT 2C R mRNA editing to psychiatric disorders 89 . An association of altered editing patterns of 5-HT 2C R with several psychiatric disorders, including anxiety, depression, bipolar disorder, schizophrenia and suicide, as well as with autism, has been reported, although the findings have often been inconsistent owing to the difficulty of analysing post-mortem human brain samples 28,29,90 .…”

Optimization of 2-Phenylcyclopropylmethylamines as Selective Serotonin 2C Receptor Agonists and Their Evaluation as Potential Antipsychotic Agents

“…3–7 One of the many advantages of the 5-HT 2C receptor as a CNS drug target stems from the fact that it is found almost exclusively in the CNS, 8,9 and thus compounds that selectively activate this receptor should have limited impact on peripheral tissues. However, the activation of two other closely related 5-HT 2 subtypes, namely the 5-HT 2A and 5-HT 2B receptors, has been reported to be associated with hallucinations and cardiac valvulopathy, respectively.…”