The serotonin 2A receptor agonist TCB‐2 attenuates heavy alcohol drinking and alcohol‐induced midbrain inhibitory plasticity

Abstract

Disruption of neuronal chloride ion (Cl À ) homeostasis has been linked to several pathological conditions, including substance use disorder, yet targeted pharmacotherapies are lacking. In this study, we explored the potential of serotonin 2A receptor (5-HT 2A R) agonism to reduce alcohol consumption in male wild-type C57Bl/6J mice and to ameliorate alcohol-induced inhibitory plasticity in the midbrain. We found that administration of the putative 5-HT 2A R agonist TCB-2 attenuated alcohol consumption and preference but did not alter water or saccharin consumption. We hypothesized that the selective behavioural effects of TCB-2 on alcohol drinking were due, at least in part, to effects of the agonist on ventral tegmental area (VTA) neurocircuitry. Alcohol consumption impairs Cl À transport in VTA GABA neurons, which acts as a molecular adaptation leading to increased alcohol self-administration. Using ex vivo electrophysiological recordings, we found that exposure to either intermittent volitional alcohol drinking or an acute alcohol injection diminished homeostatic Cl À transport in VTA GABA neurons. Critically, in vivo TCB-2 administration normalized Cl À transport in the VTA after alcohol exposure. Thus, we show a potent effect of alcohol consumption on VTA inhibitory circuitry, in the form of dysregulated Cl À homeostasis that is reversible with agonism of 5-HT 2A Rs. Our results provide insight into the potential therapeutic action of 5-HT 2A R agonists for alcohol abuse.

Psilocybin sex-dependently reduces alcohol consumption in C57BL/6J mice

“…An alternative possibility, that non-specific effects on consummatory behaviors might explain reductions in alcohol drinking behaviors observed with classical psychedelics in rodent models has been more extensively investigated. Consistent with the results reported here, studies of classical psychedelics or 5-HT 2A R psychedelic analogs utilizing rodent alcohol drinking paradigms have found modest increases in total fluid or water consumption ( Elsilä et al, 2022 ) or no change ( Maurel et al, 1999a ; Maurel et al, 1999b ; Maurel et al, 2000 ; Alper et al, 2018 ; Oppong-Damoah et al, 2019 ; Meinhardt et al, 2020 ; Cameron et al, 2021 ; Kimmey et al, 2022 ; Serra et al, 2022 ). Additional reports of no reduction in sucrose or saccharin preference ( Maurel et al, 2000 ; Cameron et al, 2021 ; Elsilä et al, 2022 ; Kimmey et al, 2022 ), or change in intracranial self-stimulation current-intensity thresholds ( Elsilä et al, 2022 ), and another study in which psilocybin restored sucrose preference in chronically stressed C57BL/6J mice ( Hesselgrave et al, 2021 ), weigh against the possibility that nonspecific effects on appetitive behavior or reward could explain the reported reductions in alcohol consumption observed with classical psychedelics or 5-HT 2A R psychedelic analogs.…”

“…Table 1 summarizes previously published studies reporting on the effect of the classical psychedelics psilocybin ( Meinhardt et al, 2020 ; Meinhardt et al, 2021 ), LSD ( Alper et al, 2018 ; Elsilä et al, 2022 ), ayahuasca ( Serra et al, 2022 ) or 2,5-dimethoxy-4-iodoamphetamine (DOI) ( Maurel et al, 1999a ; Maurel et al, 1999b ; Maurel et al, 2000 ; Oppong-Damoah et al, 2019 ; Berquist and Fantegrossi, 2021 ) on ethanol self-administration in animal models. The table also includes two serotonin 2A receptor (5-HT 2A R) agonist psychedelic analogs produced by rational pharmaceutical design; Tabernanthalog (TBG) ( Cameron et al, 2021 ), and (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide (TCB-2) ( Kimmey et al, 2022 ). The administered classical psychedelic or 5-HT 2A R agonist psychedelic analog reduced ethanol consumption and/or preference in mice or rats in at least one experimental condition in all of these twelve studies, and the effect appeared dose-related in six of them ( Maurel et al, 1999a ; Maurel et al, 1999b ; Alper et al, 2018 ; Berquist and Fantegrossi, 2021 ; Elsilä et al, 2022 ; Kimmey et al, 2022 ).…”

“…The table also includes two serotonin 2A receptor (5-HT 2A R) agonist psychedelic analogs produced by rational pharmaceutical design; Tabernanthalog (TBG) ( Cameron et al, 2021 ), and (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide (TCB-2) ( Kimmey et al, 2022 ). The administered classical psychedelic or 5-HT 2A R agonist psychedelic analog reduced ethanol consumption and/or preference in mice or rats in at least one experimental condition in all of these twelve studies, and the effect appeared dose-related in six of them ( Maurel et al, 1999a ; Maurel et al, 1999b ; Alper et al, 2018 ; Berquist and Fantegrossi, 2021 ; Elsilä et al, 2022 ; Kimmey et al, 2022 ).…”

Classic psychedelics and alcohol use disorders: A systematic review of human and animal studies

“…[64][65][66] These data are important since this inhibitory plasticity is reversible by 5-HT2 2A receptor agonism via functional enhancement of the potassium-chloride cotransporter KCC2. 62 In that sense, a recent study by Kimmey et al 67 demonstrates that 5-HT 2A receptor agonists reduce alcohol consumption in rodents by restoring VTA Cl-homeostasis.…”

5-HT-dependent synaptic plasticity of the prefrontal cortex in postnatal development

“…They primarily bind 5-HT receptors, but they can partially interact with other receptor types, especially if used at high concentrations 74 . TCB-2, LP-44 and SB-269970 have been reported to bind with high-affinities to their receptor targets [73][74][75][76][77][78] . On the other hand, 8-OH-DPAT, Ketanserin and WAY-100635 were found to also interact with other receptor types.…”