MK-801-induced locomotor activity in long-sleep x short-sleep recombinant inbred mouse strains: Correlational analysis with low-dose ethanol and provisional quantitative trait loci

Background: Low doses of the N-methyl-D-aspartate receptor (NMDAR) antagoni st MK-801 (dizocilpine) or ethanol increase locomotor activity to a lesser extent in long-sleep (LS), than in short-sleep (SS), mice. LS mice also hav e fewer brain [H-3]MK-801 binding sites than SS mice. In this study, LSXSS recombinant inbred (RI) mice were used to investigate whether different NMD AR densities contribute to differential MK-801 activation and whether commo n genes are involved in initial sensitivity to MK-801- and ethanol-induced activation. Methods: Locomotor activity was measured for 90 min after saline or MK-801 injection. Quantitative autoradiographic analysis of [H-3]MK-801 binding wa s used to measure densities of NMDARs in seven brain regions. The ethanol ( 1-2 g/kg) activation scores from Erwin and colleagues (1997) were used for correlational analysis, as was their method for quantitative trait loci (QT L) analysis. Results: Both saline and MK-801 (0.3 mg/kg, given intraperitoneally) induce d a continuum of locomotor responses across the LSXSS RI strains. There was a 4-fold range of MK-801 difference scores (MK-801 score-saline baseline), with the RI 9 and RI 4 strains representing low and high responders, respe ctively. Dose-response experiments with these two strains confirmed that 0. 3 mg/kg MK-801 produced significant activation, similar to previous results with LS and SS mice. However, unlike previous LS/SS results, lower densiti es of NMDARs were not observed in the RI 9 than in the RI 4 mouse brains. N o significant genetic correlations were observed between MK-801-induced and ethanol-induced responses in the LSXSS RI mice. Two provisional MK-801 act ivation QTLs were identified (p < 0.01) on chromosomes 11 and 19, neither i n common with those mapped for ethanol activation. Conclusions: Different densities of brain NMDARs are unlikely to account fo r the differential activation of LSXSS RI mice by MK-801. Additionally, in the RI mice either separate sets of genes regulate low dose MK-801- and eth anol-induced locomotor responses or the overlapping subset of genes control ling these two behaviors is small (less than or equal to 10%).