ADOLESCENT ALCOHOL ABUSE ARRESTS ELECTROPHYSIOLOGICAL PHENOTYPE OF NUCLEUS ACCUMBENS MEDIUM SPINY NEURONS IN A LATE DEVELOPMENTAL STATE

Adolescence represents a critical window of late brain development characterized by an imbalance between early-maturing reward-sensitive circuits that promote risk-seeking behavior and the delayed maturation of cortical control systems regulating impulsivity. This developmental mismatch increases vulnerability to harmful exposures, including excessive alcohol consumption. To further elucidate the mechanisms underlying the increased vulnerability of the adolescent brain and the long-term consequences of heavy adolescent alcohol consumption, we performed whole-cell recordings from medium spiny neurons (MSNs) of the nucleus accumbens (NAc) shell in brain slices prepared from alcohol-naïve adolescent and adult mice, and from adult mice exposed to an established drinking-in-the-dark (DID) paradigm during adolescence (PND 32-45). Current-clamp recordings from MSNs of alcohol-naïve mice revealed a characteristic decrease in intrinsic MSN excitability from adolescence to adulthood. In striking contrast, such attenuation of firing propensity with late brain maturation was precluded by heavy adolescent drinking. Likewise, the remarkable increase in the strength of acutely applied ethanol (30 mM) to inhibit MSN firing, that accompanied maturation of alcohol-naïve mice, was abrogated by prior DID experience. In fact, most MSNs from these mice showed even enhanced firing upon acute alcohol when tested in adulthood. Thus, despite later abstinence, DID at young ages perpetuates the putatively risk-entailing alcohol response observed during adolescence and also locks MSNs in a high-excitable state. Both these persistent effects of adolescent DID on a major neuronal player in the brain´s reward circuitry may contribute to the detrimental consequences of heavy drinking later in life.