Understanding the effects of alcohol on brain function is critical for developing better treatments for alcohol- related problems. In this application to extend an ongoing research project, we focus on understanding how alcohol affects the function of a key ion channel expressed by neurons. This channel, the N-methyl-D- aspartate (NMDA) receptor, plays a major role in excitatory glutamatergic transmission and is critically involved in complex processes that underlie learning, memory and other higher cognitive processes. Previous studies carried out during this project established that alcohol's inhibition of the NMDA receptor could be modulated by discrete domains on the receptor and we identified key residues within transmembrane domains of the protein that may define an alcohol site of action. We used this knowledge to generate a novel knock-in mouse that shows reduced sensitivity to the acute actions of ethanol. In this application, we propose a series of specific aims designed to further understand how transmembrane domains control the receptor's sensitivity to alcohol and how expression of ethanol-insensitive receptors in vivo affects alcohol-induced behaviors and drinking.
Aim 1 will test the hypothesis that specific amino acids within sub-domains of the NMDA receptor determine the ability of ethanol to inhibit receptor function. Experiments in this aim will use recombinant expression and recording techniques to test how site-directed mutagenesis of residues in key transmembrane domains including TMl and pre-TM4 alters the effects of alcohol on channel function.
Aim 2 continues studies investigating how phosphorylation affects the ethanol sensitivity of NMDARs and examines how different co-agonists alter ethanol inhibition.
Aim 3 studies will test the hypothesis that the behavioral responses to alcohol can be modified by expression of mutant NMDA receptors that show altered ethanol sensitivity. Experiments in this aim will use a newly created GluN2A knock-in gene construct to generate knock-in mice with reduced sensitivity to ethanol. Overall, results from these studies are expected to lead to a more complete understanding of the role of NMDA receptors in mediating alcohol's action of the brain.

Public Health Relevance

Processes that affect an individual's sensitivity to the intoxicating effects of alcohol are an important predictor of future alcohol problems. Research to be carried out in this proposal will determine the factors that influence the alcohol sensitivity of a brain ion channel that is critically involved in regulating brain activity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AA009986-20
Application #
8653689
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Cui, Changhai
Project Start
1995-08-01
Project End
2019-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29403
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Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J et al. (2016) Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol. Neuropsychopharmacology 41:1112-27
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Xu, Minfu; Smothers, C Thetford; Woodward, John J (2015) Cysteine substitution of transmembrane domain amino acids alters the ethanol inhibition of GluN1/GluN2A N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 353:91-101
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