5-HT_2C receptor desensitization moderates anxiety in 5-HTT deficient mice: From behavioral to cellular evidence

Background: Desensitization and blockade of 5-HT_2C receptors (5-HT_2CR) 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-HT_2CR 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-HT_2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT_2CR-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-HT_2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT_2CR-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-HT_2CR stimulation were associated neither with altered levels of 5-HT_2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT_2CR 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-HT_2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT_2CR 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.