This proposal utilizes lines of rats that have been selected for differential initial sensitivity to ethanol. These lines will be used to discover which genes control the molecular mechanisms of action of ethanol in the brain. This information will be compared with similar data from mice and the results extrapolated to humans. Identification of genes responsible for the genetic risk of development of alcoholism is the ultimate goal of these studies. These rats, High Alcohol Sensitive, (HAS) and Low Alcohol Sensitive (LAS) and the control lines (CAS) have been selectively bred for 24 generations. The criteria for selection is """"""""sleep time"""""""" and blood ethanol at awakening following a standard dose of ethanol. There is essentially no overlap between blood ethanol at awakening between the HAS and LAS lines. Replicate lines, started from separate stocks of the N/Nih heterogeneous stock of rats, are maintained. A Quantitative Trait Loci project is underway and depends upon this proposal for the phenotypic testing of parents, F1 and F2 animals from a cross of both outbred lines and inbred strains. In the current proposal, we undertake to more closely define the actions of ethanol at the GABA receptor and the role of glutamate in the actions of ethanol. We will also investigate very rapid acute tolerance, acute functional tolerance and rapid tolerance. We will investigate the actions of dehydroepiandrosterone and its sulfate derivative on the metabolism and actions of ethanol. Other neurosteroids have been found to have differential effects on ethanol responses in these lines of rats.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011464-04
Application #
6371418
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Program Officer
Twombly, Dennis
Project Start
1998-09-18
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
4
Fiscal Year
2001
Total Cost
$284,763
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Deng, Xin-sheng; Deitrich, Richard A (2008) Putative role of brain acetaldehyde in ethanol addiction. Curr Drug Abuse Rev 1:3-8
Deitrich, Richard A; Petersen, Dennis; Vasiliou, Vasilis (2007) Removal of acetaldehyde from the body. Novartis Found Symp 285:23-40;discussion 40-51, 198-9
Deng, Xin-Sheng; Deitrich, Richard A (2007) Ethanol metabolism and effects: nitric oxide and its interaction. Curr Clin Pharmacol 2:145-53
Radcliffe, Richard A; Bludeau, Pequita; Deng, Xin-Sheng et al. (2007) Short-term selection for acute ethanol tolerance and sensitization from an F2 population derived from the high and low alcohol-sensitive selectively bred rat lines. Alcohol 41:557-66
Radcliffe, Richard A; Bludeau, Pequita; Asperi, William et al. (2006) Confirmation of quantitative trait loci for ethanol sensitivity and neurotensin receptor density in crosses derived from the inbred high and low alcohol sensitive selectively bred rat lines. Psychopharmacology (Berl) 188:343-54
Radcliffe, Richard A; Erwin, V Gene; Draski, Laura et al. (2004) Quantitative trait loci mapping for ethanol sensitivity and neurotensin receptor density in an F2 intercross derived from inbred high and low alcohol sensitivity selectively bred rat lines. Alcohol Clin Exp Res 28:1796-804
Deitrich, Richard A (2004) Acetaldehyde: deja vu du jour. J Stud Alcohol 65:557-72
Freund, Ronald K; Gerhardt, Greg A; Marshall, Kriste E et al. (2003) Differences in norepinephrine clearance in cerebellar slices from low-alcohol-sensitive and high-alcohol-sensitive rats. Alcohol 30:9-18
McBride, William J; Li, Ting-Kai; Deitrich, Richard A et al. (2002) Involvement of acetaldehyde in alcohol addiction. Alcohol Clin Exp Res 26:114-9
Dahchour, A; Hoffman, A; Deitrich, R et al. (2000) Effects of ethanol on extracellular amino acid levels in high-and low-alcohol sensitive rats: a microdialysis study. Alcohol Alcohol 35:548-53

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