Persistent changes in brain expression after withdrawal

Summary

Principal Investigator: KRISTINE WIREN
Abstract: Chronic ethanol exposure results in the development of physical dependence. After ethanol removal, a withdrawal syndrome is exhibited that can be life threatening. Aspects of the withdrawal syndrome are also influenced by gender. Using microarray analysis, we propose to identify specific genes of importance in modulating the severity of the withdrawal syndrome in both genders by identifying mRNAs regulated by chronic alcohol exposure and withdrawal over an extended time course. We will employ unique models of withdrawal severity, the Withdrawal Seizure- Prone and -Resistant lines (WSP and WSR), that represent alleles from an eight-way cross of inbred mouse lines selectively bred over generations for high or low withdrawal severity. The hypothesis to be tested is that altered brain gene expression that results from withdrawal is a critical factor mediating neuroadaptation and physical dependence. Genes regulated following chronic ethanol exposure might promote withdrawal risk, or exert protection against withdrawal. We also hypothesize that gene profiles will show sex-specific regulation. Due to the inverse genetic relationship between voluntary ethanol drinking and withdrawal severity, comparison between control WSP and WSR animals may identify genes modulating alcohol consumption. Male and female WSP or WSR mice will be exposed to intoxicating levels of ethanol and withdrawn. Prefrontal cortex will be harvested from mice in the presence or absence of severe withdrawal; temporal patterns in gene expression will be identified over an extended time course using microarray analysis. Specific Aim 1 will identify mRNA transcripts that may mediate neuroadaptative processes that underlie risk for the development of physical dependence and aspects of the withdrawal syndrome in both males and females by characterizing differences in mRNA expression in WSP mice. Specific Aim 2 will identify mRNA transcripts that may mediate neuroadaptative processes that protect against the development of physical dependence and aspects of the withdrawal syndrome in both sexes by characterizing differences in mRNA expression in WSR mice. Specific Aim 3 will identify mRNA transcripts that are putative candidates for mediating voluntary alcohol consumption by characterizing differences in mRNA expression between control male and female WSP and WSR. The long-term goal of this research is to understand mechanisms underlying how deleterious responses to chronic ethanol exposure (i.e. physical dependence leading to withdrawal seizures) are regulated at the genetic level. This knowledge may help in the development of new strategies for the treatment of alcohol dependence.
Funding Period: 2001-07-01 - 2005-03-31
more information: NIH RePORT

Top Publications

  1. pmc Neurotoxic consequences of chronic alcohol withdrawal: expression profiling reveals importance of gender over withdrawal severity
    Joel G Hashimoto
    Research Service, Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR, USA
    Neuropsychopharmacology 33:1084-96. 2008
  2. ncbi Elevated testosterone in females reveals a robust sex difference in altered androgen levels during chronic alcohol withdrawal
    Melissa R Forquer
    Portland Veterans Affairs Medical Center, Portland, OR 97239, USA
    Alcohol 45:161-71. 2011
  3. pmc Importance of genetic background for risk of relapse shown in altered prefrontal cortex gene expression during abstinence following chronic alcohol intoxication
    J G Hashimoto
    Research Service, Portland Veterans Affairs Medical Center, Portland, OR 97239, USA
    Neuroscience 173:57-75. 2011
  4. ncbi Alcohol effects on central nervous system gene expression in genetic animal models
    William J McBride
    Indiana University School of Medicine, Indianapolis, Indiana, USA
    Alcohol Clin Exp Res 29:167-75. 2005
  5. ncbi Impact of sex: determination of alcohol neuroadaptation and reinforcement
    Kristine M Wiren
    Oregon Health and Science University, VA Medical Center, Portland, Oregon 97239 2964, USA
    Alcohol Clin Exp Res 30:233-42. 2006

Scientific Experts

Detail Information

Publications5

  1. pmc Neurotoxic consequences of chronic alcohol withdrawal: expression profiling reveals importance of gender over withdrawal severity
    Joel G Hashimoto
    Research Service, Veterans Affairs Medical Center, Oregon Health and Science University, Portland, OR, USA
    Neuropsychopharmacology 33:1084-96. 2008
    ....
  2. ncbi Elevated testosterone in females reveals a robust sex difference in altered androgen levels during chronic alcohol withdrawal
    Melissa R Forquer
    Portland Veterans Affairs Medical Center, Portland, OR 97239, USA
    Alcohol 45:161-71. 2011
    ..Increased androgen signaling in females as a consequence of chronic ethanol exposure may play an important and relatively uncharacterized role in sexually dimorphic responses to alcohol abuse...
  3. pmc Importance of genetic background for risk of relapse shown in altered prefrontal cortex gene expression during abstinence following chronic alcohol intoxication
    J G Hashimoto
    Research Service, Portland Veterans Affairs Medical Center, Portland, OR 97239, USA
    Neuroscience 173:57-75. 2011
    ..Identification of pathways altered in abstinence may aid development of novel therapeutics for targeted treatment of relapse in abstinent alcoholics...
  4. ncbi Alcohol effects on central nervous system gene expression in genetic animal models
    William J McBride
    Indiana University School of Medicine, Indianapolis, Indiana, USA
    Alcohol Clin Exp Res 29:167-75. 2005
    ..Hashimoto and Kristine M. Wiren...
  5. ncbi Impact of sex: determination of alcohol neuroadaptation and reinforcement
    Kristine M Wiren
    Oregon Health and Science University, VA Medical Center, Portland, Oregon 97239 2964, USA
    Alcohol Clin Exp Res 30:233-42. 2006
    ..Devaud; (3) The Influence of Sex on Ethanol Consumption and Reward in C57BL/6 Mice, by Kimber L. Price and Lawrence D. Middaugh; and (4) Sex Differences in Alcohol Self-administration in Cynomolgus Monkeys, by Kathleen A. Grant...