Positive regulation of raphe serotonin neurons by serotonin 2B receptors.
Arnauld Belmer, Emily Quentin, Silvina L Diaz, Bruno P. Guiard, Sebastian P Fernandez, Stéphane Doly, Sophie M. Banas, Pothitos M Pitychoutis, Imane Moutkine, Aude Muzerelle, Anna Tchenio, Anne Roumier, Manuel Mameli, Luc Maroteaux
Neuropsychopharmacology June 2018 DOI: 10.1038/s41386-018-0013-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice (wild-type, Htr2b lox/lox controls, conditional Htr2b 5-HTKO mutants) |
| Interventions | BW723C86 MDMA (3 4-methylenedioxy-methamphetamine) fluoxetine DOI (2 5-dimethoxy-4-iodoamphetamine) |
| Topics | Serotonin |
| Key findings | The authors report that 5-HT2B receptor stimulation increases firing of serotonin Pet1-positive neurons and that 5-HT2B expression in these neurons is required for MDMA's behavioral and sensitizing effects and for fluoxetine's acute behavioral and chronic neurogenic effects. They propose that the 5-HT2B receptor acts as a direct positive modulator of serotonin neurons, opposing the 5-HT1A negative autoreceptor. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 5
- Effects of psychedelics on neurogenesis and broader neuroplasticity: a systematic review. Mol Med December 19, 2024
- LSD: Mechanisms and relevance to the treatment of depression Neuroscience & Biobehavioral Reviews October 10, 2025
- Effects of psychedelics on neurogenesis and brain plasticity: A systematic review bioRxiv (Cold Spring Harbor Laboratory) July 20, 2023
- Of mice and men on MDMA: a translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy'). Brain Research November 14, 2019
- 2-Aminoindan and its Ring-Substituted Derivatives Interact with Plasma Membrane Monoamine Transporters and α2-Adrenergic Receptors Psychopharmacology March 1, 2019
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