Trichostatin A Modulates Ethanol Consumption and Reveals Dose- and Sex-Specific Transcriptomic Signatures in the Nucleus Accumbens Shell

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on ethanol consumption remain poorly understood. Method: We collected the nucleus accumbens shell (NAcSh) of HAD1 rats, which has been used to investigate the impact of TSA treatment on ethanol consumption. RNA-seq profiling of NAcSh followed by IPA and GSEA analysis were conducted. Results: Gene profiling identified differentially expressed genes (DEGs) with sex- and dose-specific effects, with some genes demonstrating high fold change (FC). Males showed significantly increased Oxt and decreased Ttr expression following 1 mg/kg TSA treatment. In females, Pmch expression significantly decreased following 1 mg/kg TSA treatment, whereas Tmem179 expression increased following 2 mg/kg TSA treatment. Pathways centered on Hdac and Fkbp5 in males, and Bdnf and estrogen receptor in females were significantly enriched following TSA treatment, with distinct pathways identified at the 1 mg/kg and 2 mg/kg doses. IL1β and β-estradiol are common upstream regulators among all groups. Unexpectedly, some common DEGs between male and female comparisons have opposite responses to the same dose of TSA. GSEA analysis has identified additional gene sets, hallmark genes and microRNAs, and functions including immune response, metabolism, and estrogen response significantly associated with TSA treatment. Conclusions: This study successfully identified gene expression evidence that TSA treatment is sex- and dose-specific, underscoring the importance of considering both variables in the development of HDAC-targeted therapies for alcohol use disorders.