We focused our Clic genetic studies reported here on the level of response to acute ethanol exposure because there is an intriguing literature indicating that level of response correlates with alcohol abuse or intake. Men with low level of response to acute ethanol are more likely to develop alcohol dependence than those with high level of response (Schuckit, 1994, Schuckit & Smith, 1996). A similar inverse relationship between acute ethanol sensitivity and ethanol drinking behavior is also often seen in several studies with gene-targeted mice. For example, mice with knockout of the A2A adenosine receptor (Naassila et al., 2002), neuropeptide Y (Thiele et al., 1998) or the protein kinase A regulatory subunit RIIβ (Thiele et al., 2000) exhibit decreased sensitivity to ethanol and increased ethanol consumption. Conversely, protein kinase-C epsilon knockout mice have increased sensitivity to the effects of ethanol and decreased ethanol drinking (Hodge et al., 1999). Not all gene-targeted mouse studies, however, show this inverse relationship. In an extensive review of the subject, Crabbe et al. found that 19 out of 48 (40%) genes studied showed opposite effects
