Genetic Variability in Adenosine Deaminase‐Like Contributes to Variation in Alcohol Preference in Mice

Background A substantial part of the risk for alcohol use disorder is determined by genetic factors. We previously used chromosome substitution (CSS) mice, to identify a quantitative trait loci (QTL) for alcohol preference on mouse chromosome 2. The aim of this study was to identify candidate genes within this QTL that confer the risk for alcohol preference. Methods In order to delineate the neurobiological underpinnings of alcohol consumption, we expanded on the QTL approach to identify candidate genes for high alcohol preference in mice. We narrowed down a QTL for alcohol preference on mouse chromosome 2, that we previously identified using CSS mice, to 4 candidate genes in silico. Expression levels of these candidate genes in prefrontal cortex, amygdala, and nucleus accumbens—brain regions implicated in reward and addiction—were subsequently compared for the CSS‐2 and the C57BL/6J host strain. Results We observed increased expression of adenosine deaminase‐like (Adal) in all 3 regions in CSS‐2 mice. Moreover, we found that the adenosine deaminase inhibitor EHNA reduced the difference in alcohol preference between CSS‐2 and C57BL/6J mice. Conclusions This study identifies Adal as a genetically protective factor against alcohol consumption in mice, in which elevated Adal levels contribute to low alcohol preference. Mice from the chromosome substitution strain 2 (CSS‐2) consume less alcohol and with a lower preference compared to C57BL/6J mice. Following up on a previously identified QTL to explain the phenotypic difference between these two mouse strains, this study identified adenosine deaminase‐like (Adal) as a quantitative trait gene for their difference in alcohol preference. Expression of Adal was enhanced in CSS‐2 mice (A) and pharmacological inhibition of adenosine deaminase using EHNA selectively increased alcohol preference in CSS‐2 mice (B).