Abstract
We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.
Highlights
Alcohol use disorder (AUD) is a clinical problem of great significance that cost the United States $249 billion in 2010, with 3/4 of the cost related to binge drinking or a pattern of drinking that brings blood alcohol concentration ≥ 80 mg/dL
The results indicated that there was a largely divergent regulation of genes by binge drinking in males and females, reflecting different neuroadaptive responses in the nucleus accumbens (NAc) that would result in dysregulation of distinct biological pathways between the sexes
Stage of the estrous cycle was not monitored during this study, based on evidence that binge ethanol consumption was not affected by estrous cycle phase in female C57BL/6J mice and that 6 weeks of binge ethanol drinking did not affect the length or pattern of the estrous cycle (Satta et al, 2018)
Summary
Alcohol use disorder (AUD) is a clinical problem of great significance that cost the United States $249 billion in 2010, with 3/4 of the cost related to binge drinking or a pattern of drinking that brings blood alcohol concentration ≥ 80 mg/dL (or 0.8 mg/mL; NIAAA, 2004). The functional implication of the changes was confirmed by the demonstration that intra-NAc rapamycin, which inhibits mammalian target of rapamycin (mTOR) in the PI3K signaling cascade, significantly decreased binge ethanol drinking in male but not in female mice (Cozzoli et al, 2016). Taken in conjunction with evidence that rapamycin (see Neasta et al, 2014 and references therein) and newly developed mTOR complex 1 inhibitors (Morisot et al, 2018) significantly reduce high ethanol drinking in male rodents, the results by Cozzoli et al (2016) highlight sex differences in the influence of binge drinking on signaling cascades downstream of PI3K and presumably, metabotropic Group 1 glutamate receptors (mGluR1)
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