The critical impact of sex on preclinical alcohol research - insights from zebrafish

Sex is an important biological variable widely recognized in alcohol use and drinking patterns, as well as alcohol-related diseases (White, 2020). In a recent review article in Frontiers in Neuroendocrinology; Li and colleagues (Li et al., 2021) highlight the sex bias in alcohol research for the past 20 years. Complementing clinical and preclinical (e.g., rodent) studies, the zebrafish (Danio rerio) is the second (after mice) most used laboratory species, and a powerful model organism in biomedicine (Kalueff et al., 2014, Stewart et al., 2014). Like clinical and rodent models, zebrafish demonstrate overt sex differences in alcohol-related responses, as, for example, females acutely exposed to 0.5% alcohol perform more rapid investigation of the novel object (Souza et al., 2021), and are more sensitive to behavioral (e.g., aggregating) effects of chronic ethanol than males (Dlugos et al., 2011). In contrast, chronic exposure to ethanol reduces hyperactivity only in zebrafish males (Devaud et al., 2019), whereas its early-life (developmental) exposure increases the consumption of alcohol-containing gelatin and promotes freezing behavior in adult females, but increases aggression in adult males (Collier et al., 2021). Collectively, this strongly supports zebrafish as a sensitive model to further probe in-depth sex differences in alcohol-related neurobehavioral traits.Fig 1.

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