Chronic ethanol exposure has been shown to increase NMDA receptors and the levels of receptor subunit proteins in mouse and rat brain. The increase in hippocampal NMDA receptors has been suggested to be related to the occurrence of ethanol withdrawal seizures, and could also be related to changes in cognition, as well as in the reinforcing effects of ethanol. In the amygdala, chronic ethanol and withdrawal-induced increases in NMDA receptor function may be associated with the anxiogenic effect of ethanol withdrawal, while evidence suggests that altered NMDA receptor function in the nucleus accumbens could be associated with changes in ethanol reinforcement. However, changes in NMDA receptors in the amygdala and nucleus accumbens during chronic ethanol exposure and during a period of withdrawal have not been examined. Furthermore, little attention has been given to ethanol-induced alterations in non-NMDA (AMPA) glutamate receptors. Long-term adaptive changes in NMDA and/or non-NMDA glutamate receptors may involve not only increases in receptor subunit protein levels, but also altered cell surface expression and/or cellular localization of the receptors. We propose to assess these adaptations in NMDA and non-NMDA glutamate receptors following the chronic ethanol treatment and withdrawal paradigm that produces the alcohol deprivation effect. Such receptor changes (e.g., associated with learning, anxiogenesis, or ethanol reinforcement) may contribute to the observed increase in ethanol consumption in this model. Using both biochemical and immunohoistochemical techniques, in Aims 1 and 2 we will investigate adaptations in glutamate receptor levels, synaptic localization and cell surface expression in brains from P and HAD rats that have been taken through repeated cycles of alcohol drinking and deprivation, provided by the Indiana Animal Core. As the models are refined, we will also investigate glutamate receptor adaptations in brains of rats provided by The Scripps Clinic, in which a more prolonged alcohol deprivation effect has been reported. These studies will allow a more detailed investigation in Aim 3 of molecular mechanisms leading to changes in NMDA and/or AMPA receptor properties associated with the alcohol deprivation effect.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA014101-02
Application #
6700309
Study Section
Special Emphasis Panel (ZAA1-CC (26))
Program Officer
Sorensen, Roger
Project Start
2003-02-01
Project End
2007-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$280,233
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Clapp, Peter; Gibson, Emily S; Dell'acqua, Mark L et al. (2010) Phosphorylation regulates removal of synaptic N-methyl-D-aspartate receptors after withdrawal from chronic ethanol exposure. J Pharmacol Exp Ther 332:720-9
Clapp, Peter; Bhave, Sanjiv V; Hoffman, Paula L (2008) How Adaptation of the Brain to Alcohol Leads to Dependence: A Pharmacological Perspective. Alcohol Res Health 31:310-339