Abstract
Background
Alcohol is the leading cause of death globally for people aged 15-49 years. Rates of alcohol use disorder (AUD) are rising, especially in women, with an 80% increase in the last 15 years compared to 35% in men. Emerging research suggests sex differences in treatment response, but this remains poorly understood as historical research has focused solely on males. Neurosteroids, synthesised within the brain from precursor sex hormones or de novo from cholesterol, are promising treatments for neuropsychiatric disorders. Zuranolone, a synthetic form of the neurosteroid allopregnanolone, was recently FDA-approved for postpartum depression. Successful preclinical studies could therefore fast-track zuranolone’s repurposing for AUD treatment, offering a novel therapeutic intervention; however, its safety and efficacy remain unknown.
Aims & Objectives
Here, we investigate zuranolone’s efficacy and safety on alcohol-related behaviours in preclinical rodent models.
Method
Male and female C57BL/6J mice underwent a drinking-in-the-dark binge drinking protocol (n=12/sex). Zuranolone’s effect on locomotor behaviour within activity chambers was also evaluated in an alcohol-naive cohort of mice (n=8/sex). Mice received vehicle or zuranolone (0.3, 1, 3 mg/kg; i.p) 30 minutes prior to testing. Data were analysed using two-way repeat- or mixed-measures ANOVA with Bonferroni post-hoc analysis where appropriate.
Results
Zuranolone (3 mg/kg) initially decreased binge drinking in male (p<0.05), but not female (p>0.05) mice; however, no effect on total alcohol consumption was observed in either sex. Zuranolone increased locomotor activity in a dose-related manner in both males (p<0.0001) and females (p<0.01), with males more sensitive to locomotor effects (p<0.01).
Discussion & Conclusions
Zuranolone demonstrates sex-dependent effects on binge drinking and locomotor activity. Future research should explore potential benefits of neurosteroid treatments for AUD and their mechanism(s) of action, which may accelerate development of sex-specific treatments. Further, these findings underscore the importance of considering sex as a biological variable in the development of tailored, effective therapies for AUD.