In female OF1 mice, adolescent exposure to a ketogenic diet did not impair locomotion, anxiety‑like behavior, or aversive memory, but improved spatial memory and lowered ethanol consumption in young adulthood, accompanied by alterations in several neurotransmitter‑related genes.
Study and findings
The authors conducted two experiments in female OF1 mice. In Experiment 1, mice received either a classical ketogenic diet (high fat, low carbohydrate) or a standard control diet from post‑natal day (PND) 25 to PND 48. Behavioral testing showed no differences between groups in open‑field locomotion, elevated‑plus‑maze anxiety‑like measures, or fear‑conditioning aversive memory. In contrast, mice on the ketogenic diet performed better on a hippocampus‑dependent spatial memory task. Gene‑expression analysis of hippocampal tissue identified diet‑related changes in Adora2a, Opmr1, Drd1, Cnr1 and Il‑6. In Experiment 2, the same dietary regimen (PND 39‑82) was followed, after which ethanol intake was measured using the Drinking‑in‑the‑Dark (DID) protocol and an operant self‑administration task. Both paradigms revealed a significant reduction in ethanol consumption in the ketogenic‑diet group. This behavioral effect coincided with altered expression of Crhr1, Drd2, Adora2a and Adora1 in brain regions implicated in reward.
Clinical interpretation
The data suggest that, in female mice, adolescent exposure to a ketogenic diet can attenuate later ethanol drinking without disrupting core developmental behaviors. The preservation of locomotor activity and anxiety‑like responses indicates that the diet does not produce gross neurobehavioral toxicity. Enhanced spatial memory may reflect diet‑induced modulation of hippocampal function, consistent with the observed up‑regulation of genes such as Drd1 and Cnr1 that influence synaptic plasticity. The concurrent down‑regulation of Crhr1 and Drd2, receptors involved in stress and dopaminergic reward pathways, provides a plausible mechanistic link to the reduced ethanol intake. While these findings are preclinical, they support the hypothesis that ketogenic metabolic states could modulate neural circuits governing alcohol‑related reward, particularly in females, a population previously under‑studied.
Limitations and open questions
The study is limited to a single mouse strain and to female subjects; extrapolation to males or to other genetic backgrounds is uncertain. Only behavioral and gene‑expression endpoints were examined; protein levels, neurotransmitter concentrations, and functional circuit activity were not measured. The ketogenic diet was administered continuously, so the relative contribution of macronutrient composition versus ketosis per se remains unresolved. Moreover, the ethanol‑drinking paradigms used model binge‑type intake rather than chronic dependence, limiting relevance to long‑term alcohol use disorders. Future work should test whether the observed effects persist after diet withdrawal, assess dose‑response relationships, and explore translational potential in human adolescent populations.
Source
Torres-Rubio L, Mellado S, Montagud-Romero S, Pascual M, Rodríguez-Arias M. From diet to drinking behavior: Ketogenic diet decreases ethanol intake in young adult female mice. Behav Brain Res. 2026;516:116465. doi: 10.1016/j.bbr.2026.116465. PMID: 42700934.