Nutritional ketosis as treatment for alcohol withdrawal symptoms in female C57BL/6J mice

Upon both acute and prolonged alcohol intake, the brain undergoes a metabolic shift associated with increased acetate metabolism and reduced glucose metabolism, which persists during abstinence, putatively leading to energy depletion in the brain. This study evaluates the efficacy of ketogenic treatments to rescue psychiatric and neurochemical alterations during long-term alcohol withdrawal. Female mice were intermittently exposed to alcohol vapor or air for three weeks, during which mice were introduced to either a ketogenic diet (KD), control diet supplemented with ketone ester (KE) or remained on control diet (CD). Withdrawal symptoms were assessed over a period of four weeks followed by re-exposure using several behavioral and biochemical tests. Alcohol-exposed mice fed CD displayed long-lasting depressive-like symptoms measured by saccharin preference and tail suspension, as well as decreased norepinephrine levels and serotonin turnover in the hippocampus. Both KD and KE rescued anhedonia for up to three weeks of abstinence. KD mice showed higher latency to first immobility in the tail suspension test, as well as lower plasma cholesterol levels. Our findings show promising effects of nutritional ketosis in ameliorating alcohol withdrawal symptoms in mice. KD seemed to better rescue these symptoms compared to KE.