Identification of genes and associated neurochemical processes that mediate differences in ethanol sensitivity and acute tolerance will assist in understanding mechanisms underlying alcohol abuse and alcoholism. The proposed research will further test the hypothesis that individual differences in innate sensitivity to ethanol are governed by differences in neurotensin (NT) levels and receptor densities in specific brain regions. These studies will utilize quantitative genetic strategies coupled with pharmacological, biochemical and behavioral approaches.
Specific aims i nclude investigations to determine the effects of altering NT levels on ethanol sensitivity in rats (HAS and LAS) selectively bred for differences in duration of ethanol-induced loss of righting response or sleep time. Two measures of sensitivity will be used, blood ethanol concentrations at regaining righting response (BECST) and BEC at regaining performance on a rotorod (BEC1RR). Various doses of haloperidol (0.5 to 2.0 mg/Kg) will be administered 16 to 20 hours before ethanol to produce dose-dependent changes in NT levels and ethanol responses. Also, the ability of the NT receptor antagonist, SR 48692, to block ethanol responses will be determined in control and haloperidol-treated HAS and LAS rats.
Other aims of this proposal are to identify chromosomal locations, by quantitative trait loci analyses, of genes that regulate brain NT levels and receptor densities and to determine common QTLs for NT measures and measures of ethanol sensitivity and acute functional tolerance in rats. Previous studies indicate common QTLs for NT receptor densities and NT levels in specific brain regions and ethanol-related behaviors in mice. Identification of common QTLs for NT measures and ethanol-related behaviors in rats would significantly strengthen the argument for pleiotropic effects of genes regulating these biochemical and behavioral phenotypes. These studies will utilize a genetically segregating F2 population derived from the HAS and LAS inbred strains; production of all animals will be performed in a separately funded project by Richard A. Deitrich. Studies are funded separately to perform the behavioral phenotyping and approximately 50 percent of the genotyping of the F2 rats. In those studies brains will be dissected and immediately frozen and stored for subsequent assay for NT-ir levels and receptors densities.
| Bergeson, Susan E; Kyle Warren, R; Crabbe, John C et al. (2003) Chromosomal loci influencing chronic alcohol withdrawal severity. Mamm Genome 14:454-63 |
