ABSTRACT: Repeated excessive alcohol consumption is a risk factor for alcohol use disorder (AUD). Although AUD has been more common in men than women, women develop more severe behavioral and physical impairments. However, relatively few new therapeutics targeting development of AUD have been validated. Here, to gain a better understanding of molecular mechanisms underlying alcohol intake, we conducted a genome-wide RNA-sequencing analysis in female mice exposed to different modes (acute vs chronic) of ethanol drinking. We focused on transcriptional profiles in amygdala including the central and basolateral subnuclei, brain areas previously implicated in alcohol drinking and seeking. We found distinct gene expression patterns and canonical pathways induced by both acute and chronic intake. Surprisingly, both drinking modes triggered similar transcriptional changes, including up-regulation of ribosome-related/translational pathways and myelination pathways, and down-regulation of chromatin binding and histone modification. Notably, multiple genes that were significantly altered with alcohol drinking, including Atp2b1, Hspa4, Slc4a7, Sbno1, Ubxn2b, Nfkb1, Nts, and Hdac2, had previously been associated with human AUD via GWAS or other genomic studies. In addition, subsequent analyses of hub genes and upstream regulatory pathways predicted that voluntary ethanol consumption affects epigenetic changes via histone deacetylation pathways, oligodendrocyte and myelin function, and the oligodendrocyte-related transcription factor, Sox17. Overall, our results suggest that the expression of oligodendrocyte-related genes in the central and basolateral subnuclei of the amygdala is sensitive to voluntary alcohol drinking. These findings suggest potential molecular targets for future therapeutic approaches to prevent the development of AUD, particularly in women, due to repeated excessive alcohol consumption
