Sensitivity of AXB/BXA recombinant inbred lines of mice to the locomotor activating effects of cocaine: a quantitative trait loci analysis.

The present study was conducted in order to characterize putative quantitative trait loci (QTL) for cocaine-induced activation in the AXB/BXA recombinant inbred (RI) lines of mice. Locomotor activity was measured in the AXB/BXA and progenitor A/J and C57BL/6J strains using a computerized open-field apparatus following saline or cocaine (0, 5, 10, 20 mg/kg) administration (i.p.). Analyses were conducted on phenotypes including both novelty (responses under initial saline conditions) and cocaine-induced locomotor activity. Significant differences were observed across RI lines on all measures. Gender differences in sensitivity to the activating effects of cocaine were not observed. The wide and continuous distributions of phenotypic responses in the AXB/BXA RI lines suggested polygenic regulation. Initial basal locomotor activity was significantly correlated with cocaine-induced activation (raw scores) (r = 0.60, P = 0.0021) but not with cocaine difference scores (r = 0.370, P = 0.082). Simple regression and interval mapping were used to initially identify significant gene markers associated with novelty and cocaine-induced activation. Subsequently, composite interval mapping was used to increase the accuracy in mapping individual loci. QTL analysis of cocaine-induced activation (difference scores--20 mg/kg dose) identified significant loci on chromosomes 12 (23 cM), and 15 (46.8 cM). The significant QTLs were identified on chromosomes 12 and 15 map to regions in proximity to genes for the somatostatin 1 (Smstr1 -23 cM) and 3 (Smstr3 -46.3 cM) receptors, respectively. Further research employing AcB/BcA recombinant congenic lines of mice will be employed to confirm the QTL on chromosomes 12 and 15 identified in the present study.