Sex Differences in Photic Entrainment and Sensitivity to Ethanol-Induced Chronodisruption in Adult Mice After Adolescent Intermittent Ethanol Exposure

BACKGROUND: Evidence supports a role for the circadian system in alcohol use disorders, but the impact of adolescent alcohol exposure on circadian timing later in life is unknown. Acute ethanol attenuates circadian photic phase-resetting in adult, but not adolescent, rodents. However, nearly all studies have focused on males and it is unknown whether this adolescent-typical insensitivity to ethanol persists into adulthood after adolescent drinking. METHODS: Circadian activity was monitored in C57BL6/J mice receiving adolescent intermittent ethanol (AIE) exposure (15% ethanol and water every other day throughout adolescence) or water alone followed by 24 days wherein ethanol was not available (washout). Mice then received a challenge dose of ethanol (1.5 g/kg, i.p.) or saline 15 min prior to a 30-min phase-delaying light pulse, then were released into constant darkness (DD). To control for possible phase-shifting by ethanol challenge alone, a separate group of mice underwent AIE exposure (or water-only) and washout, then received an ethanol or saline injection, but did not receive a light pulse prior to DD. RESULTS: Striking sex differences in nearly all measures of circadian photic entrainment were observed during adolescence but AIE effects were subtle and few. Only ethanol-naïve adult male mice showed attenuated photic phase-shifts with ethanol challenge, while all other groups showed normal phase-resetting responses to light. AIE-exposed females showed a persistent delay in activity offset. CONCLUSIONS: Adult male AIE-exposed mice retained adolescent-like insensitivity to ethanol-induced suppression of photic phase-resetting, suggesting AIE-induced ‘lock-in’ of an adolescent behavioral phenotype. Adult AIE-exposed females showed delayed initiation of the rest phase. Our results also indicate that intermittent ethanol drinking has subtle effects on circadian activity in mice during adolescence that differ from previously reported effects on adult males. The observed sex differences in circadian activity, ethanol consumption and preference, and responses to ethanol challenge merit future mechanistic study.