5-HT2A receptors shape whole-brain monoaminergic coherence in male mice.
Jasmine Jade Butler, Margherita Virgili, Giuseppe Di Giovanni, Abdeslam Chagraoui, Anna Beyeler, Philippe De Deurwaerdère
Progress in Neuro-Psychopharmacology and Biological Psychiatry July 13, 2025 DOI: 10.1016/j.pnpbp.2025.111437 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | TCB-2 MDL-100 907 |
| Dose | TCB-2: 0.3, 3, and 10 mg/kg; MDL-100,907: 0.2 mg/kg |
| Topics | Serotonin |
| Keywords | Correlations Exploratory behavior Mdl-100,907 Neurochemistry complex neurochemistry Whole-brain monoamines Neurochemical organization Psychedelics psychedelic compound Specific receptor Precise modulation Connections |
| Citations | 5 |
| Key findings | Both activation and blockade of 5-HT2A receptors disrupt the organized pattern of correlations among monoamine concentrations across brain regions in mice during exploratory behavior. |
Abstract
The mechanism of action of serotonergic psychedelics is increasingly explored worldwide due to their clinical benefits in various psychiatric conditions. Beyond the stimulation of serotonin 2 A (5-HT2A) receptors, psychedelics may desynchronize activity between brain regions, however the involvement of corresponding neurotransmission systems has been largely overlooked. Given that monoaminergic systems target virtually all brain regions and play a role in exploratory behavior, we hypothesized that psychedelics disrupt the coherence of monoamine systems across brain regions during forced exploratory behavior in mice. Using post-mortem tissue quantification of serotonin (5-HT), dopamine (DA), noradrenaline (NA), and their metabolites in 28 distinct brain regions, we observed a dense and highly organized pattern of correlations within and between monoamines in vehicle-treated mice. This organization was disrupted by both the psychedelic 5-HT2A receptor agonist TCB-2 (0.3, 3 and 10 mg/kg) and the antagonist MDL-100,907 (0.2 mg/kg), both of which decreased correlations between regional neurochemical concentrations. Interestingly, the combination of MDL-100,907 and TCB-2 partially restored correlations. Quantitatively, TCB-2 dose-dependently decreased 5-HT turnover (metabolite/5-HT) across all brain regions, and DA turnover (3-methoxytyramine/DA) in the striatum. TCB-2 also enhanced markers of the DA and NA systems in certain brain regions, notably including the anterior cingulate cortex. MDL-100,907, which had minimal impact on monoamine levels when administered alone, reduced TCB-2 (3 mg/kg)-induced head twitches and increased monoamine concentrations in the anterior cingulate cortex, but did not affect the TCB-2-induced decrease 5-HT turnover across the brain. These data suggest that the functional connectivity of monoaminergic systems during exploration is highly sensitive to modulation through either activation or blockade of 5-HT2A receptors.
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 2
- From network destabilisation to adaptive reconfiguration: A hippocampal longitudinal axis model of psychedelic therapy. Progress in Neuro-Psychopharmacology and Biological Psychiatry August 20, 2026
- Thalamic 5-HT2A receptor activation reduces GABA uptake, increases tonic GABAA inhibition and induces absence seizures in Wistar rats. Neuropharmacology June 11, 2026
Cites 40
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
and 35 more in the library