Haplotype-based computational genetic mapping was used to analyze data from this study [11,12]. The distribution of the naloxone-induced withdrawal behavior was compared with the pattern of genetic variation across the 18 strains analyzed. Interestingly, the two most highly correlated haplotype blocks (P value < 5 × 10−6) were in close proximity on chromosome 9 and corresponded to the 5′ and 3′ regions of the Htr3a gene (Figs 1 and 2). There are seven haplotype blocks covering this gene though the dependence-associated blocks account for the majority of SNPs. The remaining small noncorrelated blocks are located between the second and forth exons. None of the SNPs in the associated blocks alter the predicted amino acid sequence of the protein. This gene encodes the 5-HT3a receptor, which has well-established roles in modulating nausea, anxiety, and pain [32]. Although more speculative, it has also been postulated that this receptor could also affect opioid tolerance and dependence [33].
