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.

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 #
5R37AA009986-19
Application #
8515874
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
1995-08-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
19
Fiscal Year
2013
Total Cost
$326,335
Indirect Cost
$105,091
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Zamudio-Bulcock, Paula A; Homanics, Gregg E; Woodward, John J (2018) Loss of Ethanol Inhibition of N-Methyl-D-Aspartate Receptor-Mediated Currents and Plasticity of Cerebellar Synapses in Mice Expressing the GluN1(F639A) Subunit. Alcohol Clin Exp Res 42:698-705
Cannady, Reginald; Rinker, Jennifer A; Nimitvilai, Sudarat et al. (2018) Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior. Handb Exp Pharmacol 248:311
Gioia, Dominic A; Xu, Minfu; Wayman, Wesley N et al. (2018) Effects of drugs of abuse on channelrhodopsin-2 function. Neuropharmacology 135:316-327
Nimitvilai, Sudarat; Lopez, Marcelo F; Woodward, John J (2018) Effects of monoamines on the intrinsic excitability of lateral orbitofrontal cortex neurons in alcohol-dependent and non-dependent female mice. Neuropharmacology 137:1-12
den Hartog, Carolina R; Gilstrap, Meghin; Eaton, Bethany et al. (2017) Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing Ethanol Resistant NMDA Receptors. Front Neurosci 11:84
Nimitvilai, Sudarat; Uys, Joachim D; Woodward, John J et al. (2017) Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques. J Neurosci 37:3646-3660
Cannady, Reginald; McGonigal, Justin T; Newsom, Ryan J et al. (2017) Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior. J Neurosci 37:4359-4369
Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J et al. (2017) Ethanol Dependence Abolishes Monoamine and GIRK (Kir3) Channel Inhibition of Orbitofrontal Cortex Excitability. Neuropsychopharmacology 42:1800-1812
Tabakoff, Boris; Ren, Wenhua; Vanderlinden, Lauren et al. (2016) A novel substituted aminoquinoline selectively targets voltage-sensitive sodium channel isoforms and NMDA receptor subtypes and alleviates chronic inflammatory and neuropathic pain. Eur J Pharmacol 784:1-14
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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