5-HT_2A receptors shape whole-brain monoaminergic coherence in male mice

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-HT_2A) 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-HT_2A 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-HT_2A receptors.