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TitleSerotonin 2C receptor antagonists induce fast-onset antidepressant effects
Author(s)Opal, M. D.
Klenotich, S. C.
Morais, M.
Bessa, J.
Winkle, J.
Doukas, D.
Kay, L. J.
Sousa, Nuno
Dulawa, S. M.
Antidepressive Agents
Brain-Derived Neurotrophic Factor
Chronic Disease
Cyclic AMP Response Element-Binding Protein
Depressive Disorder
Disease Models, Animal
Elongation Factor 2 Kinase
Mice, Inbred BALB C
Olfactory Bulb
Prefrontal Cortex
Pyramidal Cells
Receptor, Serotonin, 5-HT2C
Receptors, Dopamine D1
Serotonin 5-HT2 Receptor Antagonists
Serotonin Uptake Inhibitors
Stress, Psychological
TOR Serine-Threonine Kinases
Time Factors
Neuronal remodeling
Issue dateOct-2014
JournalMolecular Psychiatry
Abstract(s)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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Appears in Collections:ICVS - Artigos em revistas internacionais / Papers in international journals

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