Long Sleep (LS) and Short Sleep (SS) mice were selectively bred for differential initial sensitivity to the sedative-hypnotic effects of ethanol. The inbred strains ILS and ISS have been obtained from the LS and SS lines. Similar differences in the behavioral effects of ethanol and NMDAR antagonists have been noted in the ILS and ISS strains of mice. This has led to the hypothesis that differences in the N-methyl-D- aspartate receptor (NMDAR) may be responsible, at least in part, for the differential ethanol sensitivities of these two strains of mice.
The specific aims of this research are as follows. First that the NMDARs functionally expressed at the membrane surface in the hippocampus and/or nucleus accumbens will differ in the subunit composition between ILS and ISS mice. Second there will be differences in basal or ethanol stimulated , tyrosine phosphorylation of NMDAR2 subunits between the ILS and ISS mice. In order to accomplish these goals we propose to use chymotrypsin digestion and crosslinking agents differentiate surface expressed receptors from intracellularly stored receptors. NMDAR protein level, receptor subunit stoichiometry, and receptor phosphorylation state will be examined by quantitative western blots and co-immunoprecipitation. We hope these studies will contribute to the understanding of alcoholism by enhancing our understanding of the differential ethanol sensitivity of the ILS and ISS mice .
