Ketone Supplements and Alcohol‐Related Responses in Rodents

While alcohol use disorder can be treated with pharmacological interventions, ketosis is a recently proposed treatment option. Ketosis, defined by elevated concentrations of ketone bodies such as β-hydroxybutyrate (BHB), can be induced by a ketogenic diet or by supplements. As a supplement, both the salt and ester formulation of BHB rapidly increase blood ketone levels. Although preclinical studies have revealed that a ketogenic diet or a mix of ketone supplements reduces alcohol intake and alleviates withdrawal symptoms, the impact of BHB supplements on alcohol-related responses remains to be defined. We first assessed the efficacy of BHB in ester versus salt formulation on general locomotor activity, exogenous ketosis and alcohol-induced locomotor stimulation in male mice. We then investigated the impact of the BHB salt on alcohol intake in male and female rats. In attempts to define mechanisms influenced by the BHB salt, monoamines and their metabolites were measured in the nucleus accumbens (NAc), a brain region associated with alcohol reward. Initial results indicate that the BHB salt had a greater impact on ketone levels, glucose-ketone index and inhibition of alcohol-induced locomotor stimulation compared to the BHB ester, without altering the general locomotor activity. We further found that BHB salt dose-dependently lowered alcohol intake in rats of both sexes and that females responded to lower doses than males. Moreover, BHB salt elevated dopamine and noradrenaline and their metabolites in the NAc of male mice. Overall, this study provides insight into the role of BHB salt in modulating rodent alcohol-related behaviours.