The κ-opioid system has been implicated in several effects of ethanol. The effects on ethanol consumption of modulating the κ-opioid system are complex and differ in different species, strains and conditions (6). Stimulation of the KOR reduces voluntary ethanol drinking in rats (7). Blocking the KOR increases voluntary ethanol intake in C57/BL6 mice (8). Although the phenotype of voluntary drinking of ethanol is clearly not the same as alcohol dependence, these results are consistent with our results, which demonstrate that the presence of the indel that reduced gene expression in vitro by half was associated with a higher risk for alcoholism. In a different system, a selective KOR antagonist reduced ethanol self-administration in rats that had been made dependent on ethanol, but not on control rats (9). Mice homozygous for a disruption in Oprk1 drink less ethanol in a two-bottle choice paradigm than either wild-type or heterozygous mice (10), however, suggesting that complete deletion of the KOR reduces drinking in mice, but a 50% reduction in KOR levels may not affect it. Again, alcohol dependence in humans is a much more complex phenotype.
