BackgroundLaw doses of theN‐methyl‐D‐aspartate receptor (NMDAR) antagonist 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 have fewer brain (3H]MK‐801 binding sites than SS mice. In this study, LSXSS recombinant inbred (RI) mice were used to investigate whether different NMDAR densities contribute to differential MK‐801 activation and whether common genes are involved in initial sensitivity to MK‐801‐ and ethanol‐induced activation.MethodsLocomotor activity was measured for 90 min after saline or MK‐801 injection. Quantitative autoradiographic analysis of [3H]MK‐801 binding was used to measure densities of NMDARs in seven brain regions. The ethanol (1–2 gkg) activation scores from Erwin and colleagues (1997) were used for correlational analysis, as was their method for quantitative trait loci (QTL) analysis.ResultsBoth saline and MK‐801 (0.3 mgkg, given intraperitoneally) induced 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, respectively. Dose‐response experiments with these two strains confirmed that 0.3 mgkg MK‐801 produced significant activation, similar to previous results with LS and SS mice. However, unlike previous LS/SS results, lower densities of NMDARs were not observed in the RI 9 than in the RI 4 mouse brains. No significant genetic correlations were observed between MK‐801‐induced and ethanol‐induced responses in the LSXSS RI mice. Two provisional MK‐801 activation QTLs were identified (p< 0.01) on chromosomes 11 and 19, neither in common with those mapped for ethanol activation.ConclusionsDifferent densities of brain NMDARs are unlikely to account for 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 ethanol‐induced locomotor responses or the overlapping subset of genes controlling these two behaviors is small (≤ 10%).