PMID- 24166413 OWN - NLM STAT- MEDLINE DCOM- 20150806 LR - 20221207 IS - 1476-5578 (Electronic) IS - 1359-4184 (Linking) VI - 19 IP - 10 DP - 2014 Oct TI - Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. PG - 1106-14 LID - 10.1038/mp.2013.144 [doi] AB - 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. FAU - Opal, M D AU - Opal MD AD - 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA. FAU - Klenotich, S C AU - Klenotich SC AD - 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA. FAU - Morais, M AU - Morais M AD - 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/Guimaraes, Portugal. FAU - Bessa, J AU - Bessa J AD - 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/Guimaraes, Portugal. FAU - Winkle, J AU - Winkle J AD - Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA. FAU - Doukas, D AU - Doukas D AD - Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA. FAU - Kay, L J AU - Kay LJ AD - 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. FAU - Sousa, N AU - Sousa N AD - 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/Guimaraes, Portugal. FAU - Dulawa, S M AU - Dulawa SM AD - 1] Committee on Neurobiology, University of Chicago, Chicago, IL, USA [2] Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, IL, USA. LA - eng GR - R01 MH079424/MH/NIMH NIH HHS/United States GR - R01MH079424/MH/NIMH NIH HHS/United States GR - T32GM07839/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131029 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Receptor, Serotonin, 5-HT2C) RN - 0 (Receptors, Dopamine D1) RN - 0 (Serotonin 5-HT2 Receptor Antagonists) RN - 0 (Serotonin Uptake Inhibitors) RN - 0DHU5B8D6V (Citalopram) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.20 (Eef2k protein, mouse) RN - EC 2.7.11.20 (Elongation Factor 2 Kinase) SB - IM MH - Animals MH - Antidepressive Agents/*pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Chronic Disease MH - Citalopram/pharmacology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Depressive Disorder/drug therapy/pathology/physiopathology MH - Disease Models, Animal MH - Elongation Factor 2 Kinase/metabolism MH - Female MH - Mice, Inbred BALB C MH - Olfactory Bulb/physiopathology MH - Prefrontal Cortex/drug effects/pathology/physiopathology MH - Pyramidal Cells/drug effects/pathology/physiopathology MH - Receptor, Serotonin, 5-HT2C/metabolism MH - Receptors, Dopamine D1/antagonists & inhibitors/metabolism MH - Serotonin 5-HT2 Receptor Antagonists/*pharmacology MH - Selective Serotonin Reuptake Inhibitors/pharmacology MH - Stress, Psychological MH - TOR Serine-Threonine Kinases/metabolism MH - Time Factors EDAT- 2013/10/30 06:00 MHDA- 2015/08/08 06:00 CRDT- 2013/10/30 06:00 PHST- 2012/09/12 00:00 [received] PHST- 2013/09/18 00:00 [revised] PHST- 2013/09/24 00:00 [accepted] PHST- 2013/10/30 06:00 [entrez] PHST- 2013/10/30 06:00 [pubmed] PHST- 2015/08/08 06:00 [medline] AID - mp2013144 [pii] AID - 10.1038/mp.2013.144 [doi] PST - ppublish SO - Mol Psychiatry. 2014 Oct;19(10):1106-14. doi: 10.1038/mp.2013.144. Epub 2013 Oct 29.