These studies have demonstrated that a number of important and unexpected mechanisms underlie, or can underlie, the rewarding effects of psychostimulant drugs. However, the question remains as to what these studies may tell us about the genetic mechanisms underlying addiction in humans. That manipulation of these genes can alter responses to psychostimulant drugs, or produce behavioral phenotypes that might be expected to be associated with addiction, does not necessarily mean that variation in those genes in humans has an important influence on addiction liability. This may not necessarily be because those genes cannot affect those phenotypes, but rather because the allelic variation simply does not exist in humans for other reasons. Indeed, the most dramatic effects observed in transgenic mouse models are the result of rather extreme alterations in function that are not seen in humans (homozygous deletion of these genes or complete elimination of dopamine). When heterozygous KO mice have been examined, which would roughly model the range of variation of these genes that is observed in humans (approximately a 50% reduction) they have rarely been shown to exhibit the changes that are observed in homozygous KO mice.
