Mpdz was identified as a modulator of ethanol and barbiturate withdrawal seizures using classical genetic techniques. A quantitative trait locus (QTL) for withdrawal seizures was initially identified using recombinant inbred lines (Buck et al. 1997, 1999), and was subsequently fine mapped using successively smaller congenic strains to a 1.8-Mb interval that contained just 16 genes. Mpdz was identified as the causal gene because it was expressed in brain, contained coding SNPs and was differentially expressed in the relevant two inbred strains. Based on these findings, Mpdz was identified as the most likely gene to cause the QTL (Fehr et al. 2002; Shirley et al. 2004). Withdrawal seizures are relevant to substance abuse because the propensity to seizures and other negative symptoms may stem from a common mechanism corresponding to Stage 5 in Table 1. In humans, two candidate gene association studies have subsequently found modest evidence that SNPs in MPDZ were associated with risk for alcoholism but interestingly, not alcohol withdrawal seizures (Karpyak et al. 2009, 2011). The failure to demonstrate an association with withdrawal seizures in particular could reflect
