Orexin system inhibition attenuates stress-induced alcohol preference and relapse in adolescent mice

Underage drinking is a significant global public health concern, with stress identified as a major contributing factor. While the orexin system is known to be involved in both alcohol addiction and stress response pathways, its specific role in adolescent populations remains underexplored. Current interventions for Alcohol Use Disorder often have limited efficacy, particularly in preventing stress-induced relapse. Understanding the orexin system's involvement could unveil new targets for preventing stress-induced alcohol addiction in vulnerable youth.

Researchers first constructed protein-protein interaction (PPI) networks to confirm connections between orexin receptors and genes related to stress and alcohol dependence. For experimental validation, adolescent mice were subjected to a conditioned place preference (CPP) paradigm combined with a foot-shock stress model. The study investigated the effects of chronic and acute stress on alcohol-seeking behavior. Orexin concentrations in specific brain regions were measured using ELISA. The core intervention involved the pharmacological inhibition of orexin receptors to assess its impact on alcohol addiction-like behaviors.

Bioinformatics analysis confirmed significant interactions among proteins of the orexin system, chronic/acute stress, and alcohol dependence. Experimentally, chronic stress was found to increase the animals' vulnerability to alcohol addiction-related behavior. Acute foot-shock stress specifically promoted alcohol-seeking behavior reinstatement and significantly facilitated orexin concentrations in brain regions associated with reward and addiction.

Inhibition of orexin receptors attenuated both the formation and reinstatement of alcohol addiction-like behavior among adolescent mice. These findings collectively highlight the orexin system's pivotal role in modulating stress-induced alcohol responses.