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Neuropsychopharmacology. 2018 Jun;43(7):1623-1632. doi: 10.1038/s41386-018-0013-0. Epub 2018 Feb 5.

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

Belmer A1,2,3,4, Quentin E1,2,3, Diaz SL1,2,3,5, Guiard BP6,7,8, Fernandez SP1,2,3,9, Doly S1,2,3,10, Banas SM1,2,3, Pitychoutis PM1,2,3,11, Moutkine I1,2,3, Muzerelle A1,2,3, Tchenio A1,2,3,12, Roumier A1,2,3, Mameli M1,2,3,12, Maroteaux L13,14,15.

Author information

INSERM UMR-S 839, 75005, Paris, France.
Sorbonne Universités, UPMC Univ Paris 6, 75005, Paris, France.
Institut du Fer à Moulin, 75005, Paris, France.
Translational Research Institute, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
Instituto de Biología Celular y Neurociencia, Fac. de Cs. Exactas, Químicas y Naturales, Universidad de Morón, UBA-CONICET - Paraguay 2155, 3° piso, C1121ABG, Buenos Aires, Argentina.
Research Center on Animal Cognition, Center for Integrative Biology, 31062, Toulouse, France.
Université Paul Sabatier, 31062, Toulouse, France.
UMR5169 CNRS, 31062, Toulouse, France.
IPMC - CNRS UMR7275 660 Route des Lucioles Sophia-Antipolis, 06560, Valbonne, France.
Université Clermont Auvergne, INSERM, NEURO-DOL, 63000, Clermont-Ferrand, France.
Department of Biology and Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA.
Dept. Fundamental Neurosciences (DNF) The University of Lausanne, Lausanne, Switzerland.
INSERM UMR-S 839, 75005, Paris, France.
Sorbonne Universités, UPMC Univ Paris 6, 75005, Paris, France.
Institut du Fer à Moulin, 75005, Paris, France.


Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT2B-receptor stimulation by BW723C86 counteracted 5-HT1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT1A-negative autoreceptor.

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