Abstract
The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT(2B) receptors. Conversely, direct agonist stimulation of 5-HT(2B) receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT(2B) receptors and (iii) a selective 5-HT(2B) agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT(2B) receptors. The 5-HT(2B) receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT(2B) receptor should be considered as a new tractable target in the combat against depression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Hydroxy-2-(di-n-propylamino)tetralin / adverse effects
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Analysis of Variance
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Animals
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Bromodeoxyuridine / metabolism
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Cell Differentiation / drug effects
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Chromatography, High Pressure Liquid
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Exploratory Behavior / drug effects
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Fluoxetine / pharmacology*
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Gene Expression Regulation / drug effects
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Hippocampus / drug effects
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Hypothermia / chemically induced
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Ki-67 Antigen / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microdialysis
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Neurogenesis / drug effects*
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Reaction Time / drug effects
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Receptor, Serotonin, 5-HT2B / deficiency
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Receptor, Serotonin, 5-HT2B / physiology*
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Selective Serotonin Reuptake Inhibitors / pharmacology*
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Serotonin / metabolism
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Serotonin Plasma Membrane Transport Proteins / deficiency
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Serotonin Plasma Membrane Transport Proteins / metabolism*
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Serotonin Receptor Agonists / adverse effects
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Time Factors
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Transcription Factors / deficiency
Substances
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Fev protein, mouse
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Ki-67 Antigen
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Receptor, Serotonin, 5-HT2B
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists
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Serotonin Uptake Inhibitors
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Transcription Factors
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Fluoxetine
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Serotonin
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8-Hydroxy-2-(di-n-propylamino)tetralin
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Bromodeoxyuridine