The importance of genotypic differences in the susceptibility to alcoholism in man, and their influence on ethanol sensitivity, tolerance, and withdrawal severity in animals, is achieving ever greater recognition. While we know that susceptibility to almost all aspects of alcohol's effects in animals is to some degree inherited, we have little idea yet what specifically is inherited. The proposed research will provide an animal genetic model for an unique biochemical and behavioral response to ethanol that will allow us to unravel some of the genetic relationships among different aspects of ethanol responsiveness. The proposed project will develop lines of mice that differ genetically in their sensitivity to ethanol's effect to stimulate activity in an open field. Using within-family selective breeding, two Activity Prone (ACP) and two Activity Resistant (ACR) lines will be developed. The existence of replicate lines will allow clear differentiation of correlated responses to selection from those arise between the given pair of ACP and ACR lines by chance. Methods will be adopted to insure that the lines differ in activity sensitivity to the same brain level of ethanol. The major long-term goal of the proposed selective breeding study is to shed light on an ubiquitous, easily assessed response to ethanol (activity) that potentially mimics biochemical and behavioral indices of the euphoriant response in man. Previous research has identified ethanol-induced activity as a key response that is: (1) easily measured; (2) has clear dose-effect and temporal characteristics; (3) is genetically mediated; (4) may serve as a biochemical and behavioral model for ethanol's behavioral stimulant and euphoriant effects in man; and (5) does not appear to display tolerance development. The successful selection of the proposed lines will provide a unique genetic model for the behaviorally-stimulating effects of ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA006498-03
Application #
3109662
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1985-05-01
Project End
1988-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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Shen, E H; Harland, R D; Crabbe, J C et al. (1995) Bidirectional selective breeding for ethanol effects on locomotor activity: characterization of FAST and SLOW mice through selection generation 35. Alcohol Clin Exp Res 19:1234-45
Shen, E H; Crabbe, J C; Phillips, T J (1995) Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice. Psychopharmacology (Berl) 118:28-36
Phillips, T J (1993) Use of genetically distinct mouse populations to explore ethanol reinforcement. Alcohol Alcohol Suppl 2:451-5
Phillips, T J; Burkhart-Kasch, S; Gwiazdon, C C et al. (1992) Locomotor responses of FAST and SLOW mice to several alcohols and drugs of abuse. Ann N Y Acad Sci 654:499-501
Phillips, T J; Burkhart-Kasch, S; Gwiazdon, C C et al. (1992) Acute sensitivity of FAST and SLOW mice to the effects of abused drugs on locomotor activity. J Pharmacol Exp Ther 261:525-33
Kosobud, A E; Cross, S J; Crabbe, J C (1992) Neural sensitivity to pentylenetetrazol convulsions in inbred and selectively bred mice. Brain Res 592:122-8
Crabbe, J C; Phillips, T J; Cunningham, C L et al. (1992) Genetic determinants of ethanol reinforcement. Ann N Y Acad Sci 654:302-10
Crabbe, J C; Merrill, C; Belknap, J K (1991) Acute dependence on depressant drugs is determined by common genes in mice. J Pharmacol Exp Ther 257:663-7
Feller, D J; Crabbe, J C (1991) Effect of neurotransmitter-selective drugs in mice selected for differential sensitivity to the hypothermic actions of ethanol. J Pharmacol Exp Ther 256:954-8

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