Positive regulation of raphe serotonin neurons by serotonin 2B receptors

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT_2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT_2B 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-HT_2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT_2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT_2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT_2B-receptor stimulation by BW723C86 counteracted 5-HT_1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT_2B 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-HT_2B 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-HT_1A-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-HT_2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT_2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT_1A-negative autoreceptor.