LAUSR

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‐HT2ARs. Our results provide insight into the potential therapeutic action of 5‐HT2AR agonists for alcohol abuse.