Circuitry and Molecular Mechanisms Underlying Maladaptive Decision Making Following Chronic Adolescent Alcohol Intake

Abstract

Alcohol is the most commonly abused substance among adolescents and shows the highest liability of all abused drugs. Using a probability discounting task and fast-scan cyclic voltammetry (FSCV) we previously demonstrated that chronic voluntary consumption of alcohol by adolescent rats results in maladaptive risk-taking behavior and increased phasic dopamine (DA) release within the nucleus accumbens (NAc) during adulthood. In order to investigate the underlying mechanisms, electrical stimulation of discrete neuronal populations in anesthetized rats was used to measure phasic NAc DA release in adulthood following adolescent alcohol intake. Stimulation of the pedunculopontine nucleus (PPT) resulted in enhanced DA release in animals that consumed alcohol during adolescence. Conversely, stimulation of the medial forebrain bundle (MFB) or bed nucleus of the stria terminalis (BNST) resulted in DA release that did not differ between alcohol or control animals, suggesting that increased DA release following adolescent alcohol intake occurs via changes within the VTA in a pathway specific manner. Systemic administration of L-838,417, a GABA(A) receptor α2, 3, and 5 subunit allosteric agonist, normalized the increased PPT-stimulated DA release seen in rats that consumed alcohol during adolescence, suggesting a potential therapeutic target for future studies. Together, these results provide unique insight into the potential circuitry and molecular mechanisms underlying the maladaptive risk-taking behavior seen following adolescent alcohol intake and highlights new potential therapeutic targets.