The high success rate (6 out of 6) of our validation raises the question of whether a global KO of any gene with a significant brain function will result in behavioral disturbance that would to, at least, some degree affect alcohol consumption. This is not consistent with the literature as a review of 93 null mutants tested for alcohol responses noted that only about 1/3 showed a decrease in alcohol consumption (Crabbe et al., 2006), A more specific test of this hypothesis is whether negative microarray findings would be followed by negative behavioral results. Our data and results of others indicate that this is indeed the case. For example, genetic deletion of some key brain receptors, such as the beta2 subunit of GABAA receptors or metabotropic glutamate receptors (mGluR4, mGluR5) did not change alcohol consumption (Blednov et al., 2003; Blednov et al., 2004; Blednov and Harris, 2008;) and none of these genes passed the statistical threshold of significant regulation in Mulligan et al. (2006). On the other hand, genetic differences in GABAA alpha2 subunit expression were found (Mulligan et al., 2006) and these differences corresponded to the altered drinking in Gabra2 null mutants (Boehm et al., 2004).
