Because of the early lethality in homozygous VMAT2 KO mice, behavioral studies have examined heterozygous VMAT2 KO mice. Although this might be considered to be problematic, this again depends upon the goal of the study, heterozygous mice being much more near the normal range of variation for the expression of most genes. Heterozygous VMAT2 KO mice are surprisingly normal in terms of motor co-ordination, locomotor activity, weight gain, fertility and some simple forms of learning (Takahashi, et al., 1997). Despite reduced amphetamine-induced striatal dopamine release in heterozygous VMAT2 KO mice (Y. M. Wang, et al., 1997), the acute locomotor stimulant effects of amphetamine and cocaine are increased (Takahashi, et al., 1997; Y. M. Wang, et al., 1997). This is surprising but might be the result of alterations in the affinity states of postsynaptic receptors (Seeman, Hall, & Uhl, 2007). These compensatory changes are not sufficient to normalize all functions however, as heterozygous VMAT2 KO mice do not develop behavioural sensitization to amphetamine (Y. M. Wang, et al., 1997) and exhibit reduced conditioned place preference for amphetamine (Takahashi, et al., 1997).
