From diet to drinking behavior: Ketogenic diet decreases ethanol intake in young adult female mice

The normalization of ethanol consumption in Western societies represents a major public health concern, particularly when drinking begins during adolescence. The ketogenic diet (KD) has demonstrated therapeutic potential in various conditions, including substance use disorders. This, together with evidence showing that the diet does not significantly affect locomotor activity or aversive and spatial memory in adolescent male mice, makes it an interesting tool for addressing ethanol consumption during a critical developmental period: the transition from adolescence to young adulthood. However, the lack of evidence in females highlights an important gap in current research. This study aimed to evaluate the effects of a KD during adolescence on behavioral profile and ethanol consumption during young adulthood in female OF1 mice. In Experiment 1, behavioral profile was assessed after administration of a KD or control diet from postnatal day (PND) 25 to PND 48. Motor activity, anxiety-like behavior, memory, and learning were evaluated. In Experiment 2, ethanol consumption was assessed using the Drinking in the Dark and operant self-administration paradigms following dietary intervention from PND 39 to PND 82. The KD did not alter locomotion, anxiety-like behavior, or aversive memory, but enhanced hippocampus-dependent spatial memory. Molecular analyses revealed changes in gene expression, including Adora2a, Opmr1, Drd1, Cnr1, and Il-6. Additionally, KD significantly reduced ethanol consumption, which was associated with altered expression of Crhr1, Drd2, Adora2a, and Adora1. These findings support the potential of KD as a therapeutic strategy for reducing ethanol intake in females without negatively impacting behavioral development during adolescence.