Effects of Ketogenic Diet on Increased Ethanol Consumption Induced by Social Stress in Female Mice

Stress is a critical factor in the development of mental disorders such as addiction, underscoring the importance of stress resilience strategies. While the ketogenic diet (KD) has shown efficacy in reducing alcohol consumption in male mice without cognitive impairment, its impact on the stress response and addiction development, especially in females, remains unclear. This study examined the KD's effect on increasing ethanol intake due to vicarious social defeat (VSD) in female mice. Sixty-four female OF1 mice were divided into two dietary groups: standard diet (<i>n</i> = 32) and KD (<i>n</i> = 32). These were further split based on exposure to four VSD or exploration sessions, creating four groups: EXP-STD (<i>n</i> = 16), VSD-STD (<i>n</i> = 16), EXP-KD (<i>n</i> = 16), and VSD-KD (<i>n</i> = 16). KD-fed mice maintained ketosis from adolescence until the fourth VSD/EXP session, after which they switched to a standard diet. The Social Interaction Test was performed 24 h after the last VSD session. Three weeks post-VSD, the Drinking in the Dark test and Oral Ethanol Self-Administration assessed ethanol consumption. The results showed that the KD blocked the increase in ethanol consumption induced by VSD in females. Moreover, among other changes, the KD increased the expression of the ADORA1 and CNR1 genes, which are associated with mechanisms modulating neurotransmission. Our results point to the KD as a useful tool to increase resilience to social stress in female mice.