It is proposed to conduct investigations to utilize and further characterize newly developed genetic lines of mice which have been selectively-bred for either increased or decreased handling- induced convulsions (HIC) following withdrawal from ethanol (WSP and WSR lines). It is planned to determine if these genetically- based differences in susceptibility to HIC associated with physical dependence on ethanol are genetically related to susceptibility (cross-susceptibility) to HIC and other withdrawal signs associated with physical dependence on benzodiazepines, barbiturates, acetaldehyde, anesthetic gases, t-butanol, and several other sedative-hypnotic drugs. If so, then this would suggest that the mechanisms responsible for the intensity of HIC following ethanol withdrawal are also operative with these other drugs and/or withdrawal signs. Conversely, if ethanol HIC susceptibility does not generalize to these other drugs and/or withdrawal signs monitored, then independent controlling mechanisms are implicated. The development of these selected lines allows a novel approach to be utilized to determine the degree of commonality that exists among a number of drug dependencies with respect to alcohol. Additional studies are proposed to assess the role of the GABA and benzodiazepine receptors in the genesis of the alcohol withdrawal syndrome, utilizing in vitro receptor binding and receptor autoradiography in the WSP, WSR mice. The latter technique in particular will allow the detection of very small changes in receptor density caused by chronic intoxication and subsequent withdrawal from ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
7R01AA006243-05
Application #
3109448
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1988-09-01
Project End
1990-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
5
Fiscal Year
1988
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
Metten, Pamela; Iancu, Ovidiu D; Spence, Stephanie E et al. (2014) Dual-trait selection for ethanol consumption and withdrawal: genetic and transcriptional network effects. Alcohol Clin Exp Res 38:2915-24
Metten, Pamela; Sorensen, Michelle L; Cameron, Andy J et al. (2010) Withdrawal severity after chronic intermittent ethanol in inbred mouse strains. Alcohol Clin Exp Res 34:1552-64
Crabbe, John C; Phillips, Tamara J; Belknap, John K (2010) The complexity of alcohol drinking: studies in rodent genetic models. Behav Genet 40:737-50
Metten, Pamela; Crabbe, John C; Belknap, John K (2009) Genetic correlates of morphine withdrawal in 14 inbred mouse strains. Drug Alcohol Depend 99:123-31
Chen, Gang; Reilly, Matthew T; Kozell, Laura B et al. (2009) Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice. Alcohol 43:411-20
Kozell, L; Belknap, J K; Hofstetter, J R et al. (2008) Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3. Genes Brain Behav 7:560-7
Belknap, John K; Metten, Pamela; Beckley, Ethan H et al. (2008) Multivariate analyses reveal common and drug-specific genetic influences on responses to four drugs of abuse. Trends Pharmacol Sci 29:537-43
Hofstetter, J R; Hitzemann, R J; Belknap, J K et al. (2008) Characterization of the quantitative trait locus for haloperidol-induced catalepsy on distal mouse chromosome 1. Genes Brain Behav 7:214-23
Metten, Pamela; Buck, Kari J; Merrill, Catherine M et al. (2007) Use of a novel mouse genotype to model acute benzodiazepine withdrawal. Behav Genet 37:160-70
Peirce, Jeremy L; Li, Hongqiang; Wang, Jintao et al. (2006) How replicable are mRNA expression QTL? Mamm Genome 17:643-56

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