Towards understanding the influence of age and gender on the neurobiological consequences of binge ethanol consumption

Although -85% of the USA population who drink socially never become alcoholics, adolescents who engage in binge drinking are at a-4-fold increased risk of developing alcoholism early in adulthood (Early Onset Alcoholism, EOA). A minority of adult social drinkers lose control over drinking and develop alcoholism later in life (Late Onset Alcoholism- LOA) suggesting that the pattern of development of alcoholism may be different between adolescents and adults. With the objective of determing the unknown molecular determinants of excessive alcohol consumption in adolescents and adults, microarray analyses were conducted on mRNA from brain samples of Fl hybrid (FVB/NJ x C57BL/6J) mice after subjecting them to a four-day Drinking-in- Dark (DID) paradigm of voluntary ethanol consumption (binge exposure). Bioinformatics analysis of the binge ethanol-mediated, unique gene expression revealed evidence for an age-differential regulation of neuroimmune pathways and generated the hypothesis that treatments directed at the neuroimmune system would reduce drinking in adult animals only. Consistent with the hypothesis, modulation of the neuroimmune system using minocycline, an FDA approved antibiotic with known neuroimmune modulation properties, reduced ethanol drinking in adult, but not adolescent male and female Fl and C57Bl/6J (B6) mice. Minocycline pretreatment had no effect on ethanol metabolism, suggesting a pharmacodynamic, rather than pharmacokinetic mode of action. Genomic screens for epigenetic changes upon binge ethanol exposure revealed modulation of microRNAs, DNA methylation, histone acetylation and histone H3.3 variant replacement in an age-divergent manner, suggesting a predominant age effect in response to ethanol. These studies highlighted complex and inter-related roles in the regulation of various epigenetic mechanisms as a result of ethanol exposure. Of particular interest are microRNAs, miR-590-Jp in particular, as possible neuroadaptive mechanisms underlying the increased risk for alcoholism in adolescents. Epigenetic changes at the molecular level may help researchers to understand the long-term neurobehavioral alterations leading to high alcohol drinking, and potentially alcoholism. Overall, the current research findings should enable a better understanding of alcohol's age-differential actions at of the basic molecular and cellular level and suggests the neuroimmune system as a potential target for the development of future pharmacotherapeutic agents (or LOA, but perhaps not for EOA treatment.