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.
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Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095–3105.
Blier P . The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol 2003; 13: 57–66.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28–40.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354.
Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of general psychiatry 2006; 63: 856–864.
Furey ML, Drevets WC . Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 2006; 63: 1121–1129.
Furey ML, Khanna A, Hoffman EM, Drevets WC . Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology 2010; 35: 2479–2488.
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91–95.
Dekeyne A, Mannoury la Cour C, Gobert A, Brocco M, Lejeune F, Serres F et al. S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology 2008; 199: 549–568.
de Boer TH, Nefkens F, van Helvoirt A, van Delft AM . Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan. J Pharmacol Exp Therap 1996; 277: 852–860.
Palvimaki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E et al. Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor. Psychopharmacology 1996; 126: 234–240.
Jenck F, Moreau JL, Mutel V, Martin JR . Brain 5-HT1C receptors and antidepressants. Progr Neuro-Psychopharmacol Biol Psychiatry 1994; 18: 563–574.
Jenck F, Moreau JL, Mutel V, Martin JR, Haefely WE . Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. Eur J Pharmacol 1993; 231: 223–229.
Popoli M . Agomelatine: innovative pharmacological approach in depression. CNS Drugs 2009; 23 (Suppl 2): 27–34.
Sansone RA, Sansone LA . Agomelatine: a novel antidepressant. Innov Clin Neurosci 2011; 8: 10–14.
Kasper S, Hamon M . Beyond the monoaminergic hypothesis: agomelatine, a new antidepressant with an innovative mechanism of action. World J Biol Psychiatry 2009; 10: 117–126.
Dulawa SC, Holick KA, Gundersen B, Hen R . Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 2004; 29: 1321–1330.
Holick KA, Lee DC, Hen R, Dulawa SC . Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 2008; 33: 406–417.
Jiao J, Nitzke AM, Doukas DG, Seiglie MP, Dulawa SC . Antidepressant response to chronic citalopram treatment in eight inbred mouse strains. Psychopharmacology 2011; 213: 509–520.
Shanahan NA, Velez LP, Masten VL, Dulawa SC . Essential role for orbitofrontal serotonin 1B receptors in obsessive-compulsive disorder-like behavior and serotonin reuptake inhibitor response in mice. Biol Psychiatry 2011; 70: 1039–1048.
van der Stelt HM, Breuer ME, Olivier B, Westenberg HG . Permanent deficits in serotonergic functioning of olfactory bulbectomized rats: an in vivo microdialysis study. Bioll Psychiatry 2005; 57: 1061–1067.
Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773.
Sibille E, Wang Y, Joeyen-Waldorf J, Gaiteri C, Surget A, Oh S et al. A molecular signature of depression in the amygdala. Am J Psychiatry 2009; 166: 1011–1024.
Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 2013; 493: 532–536.
Breuer ME, Groenink L, Oosting RS, Westenberg HG, Olivier B . Long-term behavioral changes after cessation of chronic antidepressant treatment in olfactory bulbectomized rats. Biol Psychiatry 2007; 61: 990–995.
Mar A, Spreekmeester E, Rochford J . Fluoxetine-induced increases in open-field habituation in the olfactory bulbectomized rat depend on test aversiveness but not on anxiety. Pharmacol Biochem Behav 2002; 73: 703–712.
Willner P . Chronic mild stress (CMS) revisited: consistency and behavioural–neurobiological concordance in the effects of CMS. Neuropsychobiology 2005; 52: 90–110.
Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S et al. cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 2000; 20: 4030–4036.
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G . Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012; 62: 35–41.
Krishnan V, Nestler EJ . The molecular neurobiology of depression. Nature 2008; 455: 894–902.
Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69: 754–761.
Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 2007; 55: 712–725.
Nestler EJ, Hyman SE . Animal models of neuropsychiatric disorders. Nat Neurosci 2010; 13: 1161–1169.
Dulawa SC, Hen R . Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci Biobehav Rev 2005; 29: 771–783.
Honig G, Jongsma ME, van der Hart MC, Tecott LH . Chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. PLoS One 2009; 4: e6797.
Song C, Leonard BE . The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev 2005; 29: 627–647.
Ibarguen-Vargas Y, Surget A, Vourc'h P, Leman S, Andres CR, Gardier AM et al. Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-like effects in the unpredictable chronic mild stress. Behav Brain Res 2009; 202: 245–251.
Nibuya M, Nestler EJ, Duman RS . Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365–2372.
Malberg JE, Blendy JA . Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci 2005; 26: 631–638.
Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I et al. Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 2008; 1211: 37–43.
Duman RS, Voleti B . Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 2012; 35: 47–56.
Conti AC, Cryan JF, Dalvi A, Lucki I, Blendy JA . cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 2002; 22: 3262–3268.
Duman RS . Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromol Med 2004; 5: 11–25.
Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci USA 2004; 101: 10827–10832.
Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM . Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry 2008; 63: 642–649.
Di Matteo V, Cacchio M, Di Giulio C, Esposito E . Role of serotonin(2C) receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 2002; 71: 727–734.
Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP et al. Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 2000; 36: 205–221.
Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R et al. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 2013 doi:10.1016/j.biopsych.2013.04.025.
Mnie-Filali O, Faure C, Lambás-Señas L, El Mansari M, Belblidia H, Gondard E et al. Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy. Neuropsychopharmacology 2011; 36: 1275–1288.
Lucas G, Debonnel G . 5-HT4 receptors exert a frequency-related facilitatory control on dorsal raphe nucleus 5-HT neuronal activity. Eur J Neurosci 2002; 16: 817–822.
Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E . SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 1999; 38: 1195–1205.
Sotty F, Folgering JH, Brennum LT, Hogg S, Mørk A, Hertel P et al. Relevance of dorsal raphe nucleus firing in serotonin 5-HT(2C) receptor blockade-induced augmentation of SSRIs effects. Neuropharmacology 2009; 57: 18–24.
This work was funded by National Institutes of Health Grants RO1MH079424, T32GM07839, a NARSAD Young Investigator Award to SD and The Geraldi Norton Foundation.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Opal, M., Klenotich, S., Morais, M. et al. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry 19, 1106–1114 (2014). https://doi.org/10.1038/mp.2013.144
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