title: 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence.
abstract: 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.
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Cédric Bp
authors.initials: CB
authors.lastname: Martin
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Martin
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: José M
authors.initials: JM
authors.lastname: Trigo
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Caroline
authors.initials: C
authors.lastname: Chevarin
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Latham H
authors.initials: LH
authors.lastname: Fink
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Cunningham
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham).
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.affiliation: Paris Descartes, Univ Paris 05, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); UPMC, Univ Paris 06, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); INSERM UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France (Drs CBP Martin, VS Martin, Chevarin, Hamon, Lanfumey, and Mongeau); Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain (Drs Trigo and Maldonado); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX (Drs Fink and Cunningham). raymond.mongeau@parisdescartes.fr.
authors.forename: Raymond
authors.initials: R
authors.lastname: Mongeau
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044405:Receptor, Serotonin, 5-HT2C; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse
keywords: antidepressant drugs; c-fos mRNA; editing; frontal cortex; serotonin2C