The Long-Term Effects of Adolescent and Postnatal Ethanol Exposure on the Adult Mouse Brain: A Multidisciplinary Approach

Studies on the effects of alcohol on adolescent and fetal development find developing tissues are particularly sensitive to alcohol toxicity. Since, during adolescence, brain regions associated with cognitive function, decision making, and intelligence mature to adulthood, ethanol exposure during adolescence and early postnatal life may have persistent effects. Long-term effects of alcohol exposure (P7 or P28-37) on the adult brain (P60-P110) were examined using magnetic resonance imaging (MRI), immunohistochemistry (IHC), and behavior. On postnatal day seven (P7), the effects of ethanol (2.5 g/kg s.c., two hours apart) which blocks NMDA receptors, was compared to dizocilpine, another NMDA antagonist. Mice receiving P7 ethanol treatment and studied at P82, had a 4% reduction in adult brain volume, reduced numbers of parvalbumin (PV) immunoreactive (IR) cells in the frontal cortex (18-31%), as well as a reduction in cux1 IR layer II pyramidal neurons. Dizocilpine (MK801) administered on P7 also reduced frontal cortical PV interneurons (50%) and layer V pyramidal neurons (42%) in adulthood. Interestingly, P7 ethanol treatment resulted in a 52% increase in adult hippocampal neurogenesis in males, but not in females. Two models of underage drinking were employed: adolescent continuous ethanol (ACE) and adolescent intermittent ethanol (AIE). Both showed changes in adult behaviors, regional brain volumes, and cellular architecture. Mice treated with ACE (5g/kg/day, i.g., P28-37) showed adult deficits including: altered neurotransmitter gene expression, a reversal learning deficit in the Morris water maze, olfactory bulb and basal forebrain volume reductions (7.8% and 4.6% respectively), and a 7.5% reduction in numbers of choline-acetyltransferase (ChAT) IR cholinergic neurons in the basal forebrain. AIE (5g/kg, i.g., P28-37, 2 days on-2 days off) also caused an adulthood deficit in reversal learning in a different test, the Barnes Maze. AIE also resulted in increased anxiety-like behavior in adults, evidenced by a 43% reduction in time spent in the center of the open field. There were no significant adult regional brain volume reductions at P110 as a result of this treatment. The orbitofrontal cortex, a region critical for reversal learning, showed increased volume. Thus, alcohol exposure during adolescent or postnatal life can cause persistent changes in adult brain