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

Belmer A,Quentin E, Diaz SL, Guiard BP, Fernandez SP, Doly S,Banas SM,Pitychoutis PM, Moutkine I,Muzerelle M, Tchenio A,Roumier A,Mameli M, Maroteaux M.
2018 Neuropsychpharmacology sous presse hal-01703916, doi:10.1038/s41386-018-0013-0,

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-HT2Breceptor
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 wildtype
mice. By a conditional genetic ablation that eliminates 5-HT2B-receptor expression
specifically and exclusively from Pet1-positive serotonin neurons (Htr2b5-HTKO mice), we
demonstrated that behavioral and sensitizing effects of MDMA, as well as acute behavioral
and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B-receptor
expression in serotonergic neurons. In Htr2b5-HTKO mice, dorsal raphe serotonin neurons
displayed a lower firing frequency compared to control Htr2blox/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 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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