Quantitative trait loci (QTLs) are sites on a chromosome containing genes that influence a complex trait with multiple determinants. Mapping QTLs is the all-important first step toward identifying the specific underlying a QTL and its mechanism of action. Newly developed statistical methods now make it possible to detect and genetically map the chromosomal location of such QTLs. The mouse appears to be a good model in which to study skeletal genetics. In a panel of recombinant inbred strains of mice derived from the F2 crosses of F1 offspring from C57/BL/6J (B6) and DBA/2J (D2) progenitors (BXD RI), we found bone mass to be highly heritable in mice, and provisionally identified 10 specific chromosomal areas that are tightly linked to the control of bone mass. We propose a genetic mapping approach using the BXD RI strain set as an initial step in the ultimate identification of genes and biochemical factors determining skeletal sensitivity to alcohol. Because the BXD RI strains have been used in numerous gene-mapping studies of other physiologic responses to ethanol, the data from this experiment can be incorporated into the PARC QTL database in a search for common genetic elements controlling different ethanol responses. GRANT6434291;P50AA The proposed project takes an innovative approach toward the motivational effects of alcohol, potentially mediating ethanol (EtOH) consumption, associated with withdrawal severity, by examining differential activation of the kappa opioid (kappa-opioid) system. Activation of kappa-opioid receptors is thought to be involved in the development of aversion in a variety of settings, but little is known about a direct role in influencing motivational responses to alcohol exposure/withdrawal. Data from our laboratory are consistent with the notion that kappa-opioid opioid receptor activation may mediate certain aspects of the aversion syndrome associated with EtOH withdrawal (see APPENDIX MS#10C-1). Specifically, prodynorphin mRNA abundance was increased during withdrawal from chronic EtOH exposure in the selectively bred Withdrawal Seizure-Prone (WSP) LINE, but not in the Withdrawal Seizure-Resistant (WSR) mice. Therefore, we hypothesize that differences between genotypes in the level or region of expression of the kappa-opioid receptor or its ligand prodynorphin following EtOH sensitivity (e.g., EtOH preference drinking conditioned place preference (CPP), conditioned taste aversion (CTA)). Both prodynorphin and the kappa-opioid receptor represent potential candidate genes for QTL regions associated with acute and chronic EtOH withdrawal and with conditioned place preference. Therefore, we propose to confirm the regulation of the endogenous kappa-opioid receptor system in alcohol withdrawal in several genetic animal models of EtOH withdrawal severity. Knowledge regarding the relationship between EtOH withdrawal and the motivational properties of EtOH is important for our understanding of factors contributing to the development, maintenance and relapse of excessive drinking in alcoholics. In addition, information on the contribution of kappa receptor activation in the negative relationship between EtOH motivation and withdrawal ultimately may lead to the development of more effective treatments for alcoholism.
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