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

Disruption of neuronal chloride ion (Cl-) 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-HT2AR) 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-HT2AR 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- 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- transport in VTA GABA neurons. Critically, in vivo TCB-2 administration normalized Cl- 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- homeostasis that is reversible with agonism of 5-HT(2A)Rs. Our results provide insight into the potential therapeutic action of 5-HT2AR agonists for alcohol abuse.