The effect of dopamine D4 receptor density on novelty seeking, activity, social interaction, and alcohol binge drinking in adult mice

The dopamine D₄ receptor has been postulated to play a role in the pathophysiology of alcoholism. This study examined how varying levels of D₄ expression and their associated behaviors in male and female mice correlate with future alcohol intake. We hypothesized that: (1) mice with low (Drd4^+/-) or deficient (Drd4^-/-) in D₄ receptors would show enhanced ethanol consumption compared with control mice (Drd4^+/+), and (2) a specific phenotype in these mice is associated with future vulnerability for alcohol consumption. Individually housed mice were allowed free access to ethanol (20% vv) in the dark (DID). The behaviors measured in male and female mice were: novel object recognition, open-field locomotor activity, and social interaction. Correlation analyses showed that in male Drd4^-/- mice (relative to Drd4^+/+ controls), anxiolytic behavior was significantly correlated with increased alcohol consumption. Also, in male Drd4^-/- mice, there was a significant positive correlation between increased exploratory behavior and increased alcohol consumption. These findings were not observed in females. In conclusion, our data suggest that the dopamine D₄ receptor gene has an important role in increased exploratory and anxiolytic behavior only in males and these behaviors were positively correlated with increased alcohol consumption. This interaction between sex hormones and dopamine D₄ receptor genotype/function predicting future alcohol abuse and correlation with anxiolytic and exploratory behavior in male mice could have important implications for better understanding of vulnerabilities associated with addiction.