Divergent gene expression patterns in alcohol and opioid use disorders lead to consistent alterations in functional networks within the Dorsolateral Prefrontal Cortex.

Substance Use Disorders (SUDs) manifest as persistent drug-seeking behavior despite adverse consequences, with Alcohol Use Disorder (AUD) and Opioid Use Disorder (OUD) representing prevalent forms associated with significant mortality rates and economic burdens. The co-occurrence of AUD and OUD is common, necessitating a deeper comprehension of their intricate interactions. While the causal link between these disorders remains elusive, shared genetic factors are hypothesized. Leveraging public datasets, we employed genomic and transcriptomic analyses to explore conserved and distinct molecular pathways within the dorsolateral prefrontal cortex associated with AUD and OUD. Our findings unveil modest transcriptomic overlap at the gene level between the two disorders but substantial convergence on shared biological pathways. Notably, these pathways predominantly involve inflammatory processes, synaptic plasticity, and key intracellular signaling regulators. Integration of transcriptomic data with the latest genome-wide association studies (GWAS) for problematic alcohol use (PAU) and OUD not only corroborated our transcriptomic findings but also confirmed the limited shared heritability between the disorders. Overall, our study indicates that while alcohol and opioids induce diverse transcriptional alterations at the gene level, they converge on select biological pathways, offering promising avenues for novel therapeutic targets aimed at addressing both disorders simultaneously.

MicroRNAs: master regulators of ethanol abuse and toxicity?

Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.