This project proposes to continue the selective breeding program, designed to develop lines of rats, expressing sensitivity and resistance to the acute central nervous system depressant effects of ethanol. The animal model produced will aid further in elucidation of the mechanism by which alcohol depresses the central nervous system, as well as provide a tool for studying how gene action mediates the response to alcohol effects. These studies may serve further in understanding the biological factors contributing to human alcoholism. Rats, originating from a large genetically heterogeneous base population, are being selected to have either prolonged or shortened """"""""sleep times"""""""" (i.e., duration of loss of the righting response) following a standard intraperitoneal dose of alcohol. Six lines, with two replicates in each direction, are maintained, two high sensitivity (long sleep), two low sensitivity (short sleep) and two control (unselected) lines. The relative effects of ethanol metabolism are assessed by measurement of blood alcohol levels upon recovery of the righting response. Within family selection is used and a minimum of ten families per line are maintained. Periodic monitoring of the lines as selection proceeds is being done to measure ethanol effects on related electrophysiological and biochemical phenotypes to determine the extent of genetic correlation of the behavioral response with these phenotypes. The species generality of these correlation studies are determined by comparison with the ethanol responses in the mouse model. Eventually, after maximum genetic response in both directions has been obtained (empirically, this has been found to be at least 20 generations of selection) inbred and recombinant inbred lines will be developed from the selected rat lines.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA005868-04
Application #
3109144
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1983-04-01
Project End
1991-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Draski, L J; Bice, P J; Deitrich, R A (2001) Developmental alterations of ethanol sensitivity in selectively bred high and low alcohol sensitive rats. Pharmacol Biochem Behav 70:387-96
Draski, L J; Deitrich, R A; Menez, J F (1997) Phenobarbital sensitivity in HAS and LAS rats before and after chronic administration of ethanol. Pharmacol Biochem Behav 57:651-7
Kiefer, S W; Badia-Elder, N E (1997) Taste reactivity in high-alcohol-sensitive and low-alcohol-sensitive rats. Alcohol 14:225-9
Pearson, B J; Donatelli, D P; Freund, R K et al. (1997) Differential development and characterization of rapid acute neuronal tolerance to the depressant effects of ethanol on cerebellar Purkinje neurons of low-alcohol-sensitive and high-alcohol-sensitive rats. J Pharmacol Exp Ther 280:739-46
Erwin, V G; Draski, L J; Deitrich, R A (1996) Neurotensin levels and receptors in HAS and LAS rat brains: effects of ethanol. Pharmacol Biochem Behav 54:525-32
Zimatkin, S M; Deitrich, R A (1995) Aldehyde dehydrogenase activities in the brains of rats and mice genetically selected for different sensitivity to alcohol. Alcohol Clin Exp Res 19:1300-6
Liu, Y; Fay, T; Deitrich, R A (1995) Behavioral effects and pharmacokinetics of propofol in rats selected for differential ethanol sensitivity. Alcohol Clin Exp Res 19:874-8
Deitrich, R A; Draski, L J; Baker, R C (1994) Effect of pentobarbital and gaseous anesthetics on rats selectively bred for ethanol sensitivity. Pharmacol Biochem Behav 47:721-5
Deitrich, R A (1993) Selective breeding for initial sensitivity to ethanol. Behav Genet 23:153-62
Menez, J F; Machu, T K; Song, B J et al. (1993) Phosphorylation of cytochrome P4502E1 (CYP2E1) by calmodulin dependent protein kinase, protein kinase C and cAMP dependent protein kinase. Alcohol Alcohol 28:445-51

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