5-HT2A receptors shape whole-brain monoaminergic coherence in male mice

Butler, Jasmine Jade, Virgili, Margherita, Di Giovanni, Giuseppe, Chagraoui, Abdeslam, Beyeler, Anna and De Deurwaerdère, Philippe 2025. 5-HT2A receptors shape whole-brain monoaminergic coherence in male mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 141 , 111437. 10.1016/j.pnpbp.2025.111437 Item availability restricted.

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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 2A (5-HT2A) receptors, psychedelics may desynchronize activity between brain regions, however the involvement of the 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences
Publisher:	Elsevier
ISSN:	0278-5846
Date of First Compliant Deposit:	5 August 2025
Date of Acceptance:	3 July 2025
Last Modified:	13 Oct 2025 13:00
URI:	https://orca.cardiff.ac.uk/id/eprint/180263

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