Understanding the effects of alcohol on brain function is critical for developing better treatments for alcohol-related problems. In this renewal of 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 the previous funding period established that alcohol's inhibition of the NMDA receptor could be modulated by discrete domains on the receptor and identified key residues within transmembrane domains of the protein that may define an alcohol site of action. In this application, we propose a series of specific aims designed to establish how these domains control the receptor's sensitivity to alcohol and how expression of ethanol-insensitive receptors in vivo affects alcohol-induced behaviors.
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 alters the effects of alcohol on channel function.
Aim 2 will test the hypothesis that alcohol inhibition of NMDA receptors is also modified by expression of the novel NR3 subunit and through phosphorylation of key residues on the intracellular domain of the NR1 and NR2 subunits. Experiments in this aim will utilize expression and recording techniques coupled with the use of genetically modified animals.
Aim 3 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 novel NMDA knock-in mouse that is currently under development and viral over-expression techniques to alter NMDA subunit expression in discrete brain areas. 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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Medicine
United States
Zip Code
McGuier, Natalie S; Padula, Audrey E; Lopez, Marcelo F et al. (2015) Withdrawal from chronic intermittent alcohol exposure increases dendritic spine density in the lateral orbitofrontal cortex of mice. Alcohol 49:21-7
Hughes, Benjamin A; Smothers, C Thetford; Woodward, John J (2013) Dephosphorylation of GluN2B C-terminal tyrosine residues does not contribute to acute ethanol inhibition of recombinant NMDA receptors. Alcohol 47:181-6
Smothers, Corigan T; Jin, Chun; Woodward, John J (2013) Deletion of the N-terminal domain alters the ethanol inhibition of N-methyl-D-aspartate receptors in a subunit-dependent manner. Alcohol Clin Exp Res 37:1882-90
den Hartog, Carolina R; Beckley, Jacob T; Smothers, Thetford C et al. (2013) Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors. PLoS One 8:e80541
Badanich, Kimberly A; Mulholland, Patrick J; Beckley, Jacob T et al. (2013) Ethanol reduces neuronal excitability of lateral orbitofrontal cortex neurons via a glycine receptor dependent mechanism. Neuropsychopharmacology 38:1176-88
Xu, Minfu; Smothers, C Thetford; Trudell, James et al. (2012) Ethanol inhibition of constitutively open N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 340:218-26
Xu, Minfu; Smothers, Corigan Thetford; Woodward, John J (2011) Effects of ethanol on phosphorylation site mutants of recombinant N-methyl-D-aspartate receptors. Alcohol 45:373-80
Mulholland, Patrick J; Carpenter-Hyland, Ezekiel P; Woodward, John J et al. (2009) Ethanol disrupts NMDA receptor and astroglial EAAT2 modulation of Kv2.1 potassium channels in hippocampus. Alcohol 43:45-50
Asatryan, Liana; Popova, Maya; Woodward, John J et al. (2008) Roles of ectodomain and transmembrane regions in ethanol and agonist action in purinergic P2X2 and P2X3 receptors. Neuropharmacology 55:835-43