Peripherally administered arginine vasopressin (AVP) affects tolerance to EtOH hypothermia in mice chronically administered EtOH. Such effects of AVP are mediated by the central nervous system and are not due to changes in EtOH metabolism. These effects of AVP may depend upon intact serotonergic projections from the median raphe nucleus to the hippocampus and may be mediated through VI receptors. Sensitivity and tolerance to the hypothermic effect of EtOH are known to be influenced markedly by genotype. In a panel of 20 inbred strains of mice, both qualitative and quantitative differences were seen, for some strains developed no tolerance over the 8 day treatment period. An AVP analog without peripheral hormonal effects influenced the pattern of genetic control over hypothermic sensitivity and tolerance in a panel of recombinant inbred (RI) mice. The proposed research will attempt to link these two areas of research which have been independently investigated. It is hypothesized that the genetic differences in EtOH sensitivity and tolerance development may be in part due to differences in AVP systems. The proposed research will attempt to test this hypothesis employing molecular genetic tools for studying AVP gene expression in the same panel of inbred strains of mice. Dr. Crabbe, the Visiting Researcher, will learn to employ the techniques of RNA extraction, Northern blotting, cDNA library development, cDNA clone development and characterization, solution hybridization, and RFLP development and analysis with Southern blotting during a 6 month stay in the laboratory of Dr. Milner, the Host. These techniques will be used to characterize brain AVP gene activity in the panel of 20 inbred strains of mice which Dr. Crabbe has previously characterized for sensitivity and tolerance development to EtOH-induced hypothermia. The potential relationship between AVP gene activity and EtOH hypothermia will be assessed by genetic correlational analysis. cDNA clones for the gene in mice will be developed, and an attempt will be made to map the gene in mice.
