Adolescent intermittent ethanol exposure produces sex-specific development of functional tolerance to ethanol-induced motor impairment and hypothermia

Adolescent intermittent ethanol (AIE) exposure has been shown to attenuate sensitivity to ethanol effects, suggesting tolerance development. The present studies sought to determine whether AIE-exposed male and female rats would develop tolerance to ethanol-induced motor impairment and hypothermia, and to test the effects of AIE on ethanol-metabolizing enzymes in the brain. Adult rats showed motor impairment at 2 g/kg i.p. ethanol, with intoxicated practice attenuating ethanol-induced motor impairment (Experiments 1 & 2). AIE-exposed males, but not females, showed reduced motor impairment when challenged with 2 g/kg i.p. ethanol 1 day after AIE, suggesting tolerance development (Experiment 3). AIE-exposed males, but not females, became tolerant to ethanol-induced hypothermia during AIE (Experiment 4). Brain and/or blood ethanol levels were not affected by AIE. No tolerance was evident 30 days later. Gene expression of ethanol-metabolizing enzymes was assessed in animals with a history of AIE and challenged with 2.5 g/kg i.p. ethanol in adulthood (Experiment 5). In females, AIE reduced catalase (CAT) and aldehyde dehydrogenase 2 (ALDH2) expression in the amygdala. Males showed increased alcohol dehydrogenase 1 (ADH1) expression in the amygdala following an ethanol challenge. Experiment 6 revealed transient effects of AIE on cell-type-specific expression of ADH1 and ALDH2. One day after AIE, AIE-exposed males showed a reduction in ADH1 colocalized with neurons in the cerebellum, whereas AIE-exposed females showed a reduction in ALDH2, particularly in microglia, in the hippocampus. Together, these findings revealed sex-specific, short-term tolerance to ethanol-induced motor impairment and hypothermia during AIE that was independent of ethanol pharmacokinetics.