Between- and Within-Family Association Test of the Dopamine Receptor D2 Taqia Polymorphism and Alcohol Abuse and Dependence in a General Population Sample of Adults * (Report‪)‬

SINCE THE OBSERVATION by Olds and Milner (1954), extensive research has implicated dopamine as an etiological factor in the rewarding and motivating effects of alcohol. Findings from human and animal studies have refined this observation further, suggesting that the increased release of dopamine within the mesolimbic pathway constitutes the primary "reward pathway" that influences alcohol intake and alcohol-use disorders (Boileau et al., 2003). The mesolimbic pathway begins in the ventral tegmental area and includes the nucleus accumbens and striatum, brain regions that mediate the reinforcing effects of ethanol. Dysregulated dopaminergic transmission within this pathway is thought to underlie many of the cognitive, emotional, and locomotor behaviors observed with alcohol and drug intake (Koob and Le Moal, 1997). Its etiology has therefore been a major research priority for the past decade. Synaptic levels of dopamine are regulated through an interconnected process involving two presynaptic receptors, the dopamine transporter (DAT) and the D2 auto-receptor (DRD2). Whereas the transporter determines the magnitude and duration of dopaminergic transmission, the D2 receptor inhibits the rate-limiting enzyme of dopamine synthesis, tyrosine hydroxylase. Reduced levels of the DRD2 receptor are a widely observed risk factor associated with increased alcohol consumption (Heinz et al., 2004; Tupala et al., 2003; Volkow et al., 1996) and have been correlated with greater levels of alcohol craving (Self, 1998). Heightened brain activation within the orbital-frontal and medial prefrontal cortices and the anterior cingulate has been associated with low D2 receptor expression (Volkow and Fowler, 2000), with differences in alcohol-cue processing and compulsive, uncontrolled drug use (Heinz et al., 2004). Experimental studies have implicated the D2 receptor in goal-directed behavior (Goto and Grace, 2005), and overexpression of D2 receptor levels reduces alcohol intake (Thanos et al., 2001). Taken together, these findings implicate differences in presynaptic receptor functioning and expression in the etiology of alcohol-use disorders.