UNTANGLING THE NEURAL MECHANISMS REGULATING SEX DIFFERENCES IN ALCOHOL USE DISORDERS

The World Health Organization (WHO) estimates 400M people living with alcohol use disorders (AUD). Beyond the classic effects of alcohol use in brain circuitries and behaviour, it is now well accepted that alcohol causes the release of proinflammatory mediators that contribute substantially to the development of AUD. Of interest, there is a clear discrepancy between men and women in AUD. Women experience worse health consequences from chronic alcohol use, presenting higher likelihood of relapse, higher prevalence of alcohol-related cancers and faster progression to liver disease. Using a well-established model of voluntary alcohol intake in mice, and focusing on the prefrontal cortex (PFC) of male and female adults, we identified a number of relevant sex-specific responses. Female, but not male, exhibited reduced astrocyte size and complexity, and enlarged microglial volume and complexity. Males displayed increased inhibitory synapse density and anxiety, while females exhibited increased excitatory synapse density and higher exploratory behaviour. An analysis of the proteomic data obtained from male and female synaptosomes confirmed substantial sex differences, showing that in females alcohol seems to affect mainly fatty-acid metabolism and TCA cycle, impacting on glutamate and GABA function, while in males the most affected terms seem to be related with myelin function. In accordance, a published review of AUD-associated structural changes evidenced reduced gray and white matter volume, plus weaker structural connectivity in men, but not in women. Importantly, the underlying mechanisms explain these sex differences in AUD are largely unknown and may be highly relevant to devise sex-specific therapeutic strategies.