Martin, Cedric B.P.Martin, Vincent S.Trigo i Rodríguez, Josep M.Chevarin, CarolineMaldonado, Rafael, 1961-Fink, Latham H.Cunningham, Kathryn A.Hamon, MichelLanfumey, LaurenceMongeau, Raymond2016-12-152016-12-152015Martin CB, Martin VS, Trigo JM, Chevarin C, Maldonado R, Fink LH et al. 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence. Int J Neuropsychopharmacol. 2015 Oct 31; 18(3):[12 p.]. DOI: 10.1093/ijnp/pyu0561461-1457http://hdl.handle.net/10230/27769BACKGROUND: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. METHODS: Mice lacking the 5-HT reuptake carrier (5-HTT(-/-)) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR-induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos-induced expression) levels. RESULTS: Although 5-HTT(-/-) mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR-mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT(-/-) mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT(-/-) mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT(-/-) mutants. CONCLUSIONS: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT(-/-) mice.application/pdfeng© Cédric BP Martin [et al.] 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of a Creative Commons Attribution LicenseAngoixaCervell -- MetabolismeSerotoninainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1093/ijnp/pyu056info:eu-repo/semantics/openAccess