BINGE-LIKE ALCOHOL EXPOSURE ALTERS TRANSCRIPTIONAL REGULATION OF ENDOGENOUS OPIOID SYSTEM GENES IN PREADOLESCENT RATS

Alcohol is one of the most commonly used recreational substances worldwide, with adolescents making up a substantial portion of consumers. However, alcohol has neurotoxic properties and can modify various brain structures and neural pathways, particularly those in the mesocorticolimbic and striatal systems. Notably, during adolescence, crucial changes occur in brain circuits responsible for stress management and emotional processing, which are especially susceptible to the effects of alcohol exposure.Given the fundamental role of the endogenous opioid system in alcohol's rewarding properties and evidence emphasizing the importance of epigenetic mechanisms in alcohol's effects, this research investigated the transcriptional regulation of genes linked to this system in specific brain regions of pre-adolescent rats exposed to an intermittent binge-like drinking protocol. qRT-PCR and Pyrosequencing were performed to assess gene/miRNA expression and DNA methylation, respectively. The findings revealed a significant reduction in mRNA levels of Kop in the ventral tegmental area and of Pdyn and Mop in the prefrontal cortex of alcohol-exposed rats, while no alterations were observed in hippocampus and amygdala. Sex-stratified analyses showed significant modifications only in male rats. Epigenetic analyses showed a consistent increase in DNA Methylation levels at Kop gene regulatory region, in particular in male rats wiich showed an inverse correlation with gene expression. Moreover we observed alterations in Pdyn DNA methylation levels and an interesting pattern in miR-339-5p expression in the prefrontal cortex. These findings, by clarifying ethanol's molecular mechanism, may contribute to better understanding its behavioral effects and support development of novel treatments for alcohol use disorders.