title: Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.
abstract: Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.
authors.affiliation: 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Opal
authors.affiliation: 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Klenotich
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Morais
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Bessa
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Winkle
authors.affiliation: Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Doukas
authors.affiliation: 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Institute for Mind and Body, University of Chicago, Chicago, IL, USA [3] Department of Psychology, University of Chicago, Chicago, IL, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Kay
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: N
authors.initials: N
authors.lastname: Sousa
authors.affiliation: 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Dulawa
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002908:Chronic Disease; D015283:Citalopram / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D005260:Female; D008807:Mice, Inbred BALB C; D009830:Olfactory Bulb / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013315:Stress, Psychological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D015283:Citalopram; D017362:Cyclic AMP Response Element-Binding Protein; D054736:Elongation Factor 2 Kinase; D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D058570:TOR Serine-Threonine Kinases; C492004:Creb1 protein, mouse; C546843:mTOR protein, mouse; C517690:Eef2k protein, mouse