Pharmacological Reversal of Adolescent Alcohol‐Induced Perturbation to Mesolimbic Dopamine Network Dynamics Rescues Maladaptive Decision Making in Adulthood

Alcohol is the most commonly used and abused substance among adolescents, promoting the development of substance use disorders and compromised decision‐making in adulthood. Using a preclinical model we have demonstrated that adolescent alcohol use results in maladaptive adult risk‐taking behavior that positively correlates with increased mesolimbic phasic dopamine transmission in response to risky options, but the underlying mechanisms remain unknown. Here we show that increased phasic dopamine after adolescent alcohol use is attributable to a selective perturbation of midbrain circuitry. Indeed, we demonstrate that VTA dopamine neurons exhibit enhanced IPSCs, but not EPSCs, leading to decreased basal dopamine levels in adulthood that negatively correlate with risk‐taking. We conclude that a novel disinhibitory mechanism in midbrain circuitry mediates the effects of alcohol in a model where increased inhibitory tone on dopamine neurons leads to a persistent decrease in basal dopamine and promotes a potentiation in stimulus‐evoked phasic dopamine release that drives maladaptive choice behavior. Based on these findings we employ a selective GABA(A) receptor agonist to pharmacologically reverse risk‐taking in adulthood in parallel with normalization of phasic dopamine. Together these results isolate the underlying circuitry involved in maladaptive decision‐making and identify a potential therapeutic target. Support or Funding Information R01AA021121 and T32AA07455