Journal Article

5-HT2C Receptor Desensitization Moderates Anxiety in 5-HTT Deficient Mice: From Behavioral to Cellular Evidence

Hamon, Michel, Martin, Vincent S., Lanfumey, Laurence, Martin, Cédric BP, Trigo, José M., Fink, Latham H., Chevarin, Caroline, Maldonado, Rafael, Cunningham, Kathryn A., Mongeau, Raymond

2015

Overview

Background: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.

• Publisher: Oxford University Press
• Subject: Analysis of Variance / Angoixa / Animals / Anxiety / Anxiety - genetics / Anxiety - metabolism / Anxiety - pathology / Behavior, Animal - drug effects / Behavior, Animal - physiology / Brain - drug effects / Brain - metabolism / Cervell / Desensitization (Psychology) / Disease Models, Animal / Feeding Behavior - drug effects / Gene Expression Regulation - drug effects / Gene Expression Regulation - genetics / Interpersonal Relations / Male / Metabolisme / Mice / Mice, Inbred C57BL / Mice, Knockout / Proto-Oncogene Proteins c-fos - genetics / Proto-Oncogene Proteins c-fos - metabolism / Receptor, Serotonin, 5-HT2C - genetics / Receptor, Serotonin, 5-HT2C - metabolism / RNA, Messenger - metabolism / Serotonin Plasma Membrane Transport Proteins - deficiency / Serotonin Plasma Membrane Transport Proteins - genetics / Serotonin Receptor Agonists - pharmacology / Serotonina / Social interaction