The long-range goals of this proposal are to better understand the molecular neurobiological events that underlie the development of excessive alcohol drinking, and contribute to the long-range consequences of excessive alcohol drinking. The overall hypothesis to be tested is that changes in the expression of genes involved in neurotransmission, neuroplasticity, and intracellular signaling pathways within discrete regions of the extended amydala (E-AMYG) contribute to the development of excessive alcohol drinking. Excessive drinking is defined as sustainable blood alcohol concentrations (BACs) in the range of 100-150 mg% that are repeatedly attained over a chronic period. The overall hypothesis will be tested using selectively bred alcohol-preferring (P) and high-alcohol-drinking (HAD) rats. Micro-punch techniques will be used to obtain samples containing the nucleus accumbens shell (ACB-sh) and central nucleus of the amygdala (CeA). Changes in gene expression will be determined using Affymetrix microarrays. RT-PCR and in situ hybridization will be used to verify key findings from the microarray experiments. The excessive alcoholdrinking paradigm to be used will be the 'drinking in the dark multiple scheduled access' (DID-MSA) procedure. Time-course changes in gene expression will be determined following a drinking episode, and during the development of excessive alcohol drinking.
The specific aims will be designed to determine changes in gene expression within the ACB-sh and CeA of P and HAD rats prior to, during initiation of, and following development of excessive alcohol drinking. The effects of chronic alcohol exposure and the development of excessive alcohol drinking are influenced by multiple genetic and environmental factors. This project will provide important molecular neurobiological information in discrete regions of the E-AMYG of genetically vulnerable subjects that could more comprehensively describe the complex inter- and intracellular events leading to the development, maintenance, and consequences of excessive alcohol drinking. Such information would be critically important for developing pharmacotherapeutic strategies to treat alcoholism and alcohol abuse. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016652-03
Application #
7493077
Study Section
Special Emphasis Panel (ZAA1-DD (70))
Program Officer
Reilly, Matthew
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$185,031
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
McBride, William J; Kimpel, Mark W; McClintick, Jeanette N et al. (2014) Changes in gene expression within the extended amygdala following binge-like alcohol drinking by adolescent alcohol-preferring (P) rats. Pharmacol Biochem Behav 117:52-60
McBride, William J; Kimpel, Mark W; McClintick, Jeanette N et al. (2013) Gene expression within the extended amygdala of 5 pairs of rat lines selectively bred for high or low ethanol consumption. Alcohol 47:517-29
McBride, William J; Kimpel, Mark W; McClintick, Jeanette N et al. (2013) Changes in gene expression within the ventral tegmental area following repeated excessive binge-like alcohol drinking by alcohol-preferring (P) rats. Alcohol 47:367-80
McBride, William J; Kimpel, Mark W; McClintick, Jeanette N et al. (2012) Gene expression in the ventral tegmental area of 5 pairs of rat lines selectively bred for high or low ethanol consumption. Pharmacol Biochem Behav 102:275-85
McBride, William J; Kimpel, Mark W; Schultz, Jonathan A et al. (2010) Changes in gene expression in regions of the extended amygdala of alcohol-preferring rats after binge-like alcohol drinking. Alcohol 44:171-83
McBride, William J; Schultz, Jonathan A; Kimpel, Mark W et al. (2009) Differential effects of ethanol in the nucleus accumbens shell of alcohol-preferring (P), alcohol-non-preferring (NP) and Wistar rats: a proteomics study. Pharmacol Biochem Behav 92:304-13
Bell, Richard L; Kimpel, Mark W; McClintick, Jeanette N et al. (2009) Gene expression changes in the nucleus accumbens of alcohol-preferring rats following chronic ethanol consumption. Pharmacol Biochem Behav 94:131-47
Rodd, Zachary A; Kimpel, Mark W; Edenberg, Howard J et al. (2008) Differential gene expression in the nucleus accumbens with ethanol self-administration in inbred alcohol-preferring rats. Pharmacol Biochem Behav 89:481-98
Kimpel, Mark W; Strother, Wendy N; McClintick, Jeanette N et al. (2007) Functional gene expression differences between inbred alcohol-preferring and -non-preferring rats in five brain regions. Alcohol 41:95-132
Bell, R L; Kimpel, M W; Rodd, Z A et al. (2006) Protein expression changes in the nucleus accumbens and amygdala of inbred alcohol-preferring rats given either continuous or scheduled access to ethanol. Alcohol 40:3-17