The firing of mesolimbic dopamine neurons is important for druginduced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca 2+ -dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2 −/− mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2 −/− mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I A potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.I A current | neuroimaging genetic reward-anticipation preference T he reinforcing properties of addictive drugs are dependent on the activity of mesolimbic dopamine (DA) neurons in the ventral tegmental area (VTA) and their projections to the ventral striatum (VS) and prefrontal cortex (PFC) (1). Microdialysis studies using rodent models have shown that acute administration of addictive drugs, including alcohol, results in elevated DA levels in the VS (2). This effect results from local inhibition of DA reuptake, stimulation of its release, or an increase in firing rate of DA neurons in the VTA (3-5). PET studies have shown a similar effect in the VS of humans as evidenced by decreased competitive binding of a DA receptor antagonist [ 11 C] raclopride (6, 7). Illustrating the importance of DA signaling in the regulation of alcohol-induced reinforcement, rats are known to self-administer ethanol in the nucleus accumbens (8) and posterior VTA (9). These studies and other animal studies suggest that midbrain DA neurons are involved in the acquisition of primary alcohol reinforcement (review in ref. 1).Although the neurobiological and molecular mechanisms controlling DA neuron activity by different ...