5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence

Int J Neuropsychopharmacol. 2014 Oct 31;18(3):pyu056. doi: 10.1093/ijnp/pyu056.


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.

Keywords: antidepressant drugs; c-fos mRNA; editing; frontal cortex; serotonin2C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anxiety* / genetics
  • Anxiety* / metabolism
  • Anxiety* / pathology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Brain / drug effects
  • Brain / metabolism*
  • Disease Models, Animal
  • Feeding Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Interpersonal Relations
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / metabolism
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / deficiency*
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Receptor Agonists / pharmacology


  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptor, Serotonin, 5-HT2C
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Slc6a4 protein, mouse