Acute ethanol intoxication is associated with behavioral and cognitive symptoms that include problems with memory processing. In some cases, ethanol intoxication can result in a complete inability to process new information, a condition known as a "blackout". Understanding how ethanol alters cognition and memory is important for determining ways to protect the nervous system from the short- and long-term adverse effects of the drug. Although the mechanisms underlying memory processing in the mammalian nervous system are not completely understood, present evidence suggests that use-dependent forms of synaptic plasticity at glutamate synapses in the hippocampus, including long-term potentiation (LTP) and long-term depression (LTD), are relevant. For the past several years our laboratory has examined the acute effects of ethanol on synaptic transmission and synaptic plasticity in the CA1 region of rat hippocampal slices. We have found that ethanol acutely inhibits a specific subtype of synaptic N-methyl-D-aspartate receptor (NMDAR) that is also inhibited by the NR1/NR2B antagonist, ifenprodil. Block of LTD by ethanol correlates with the block of these synaptic NMDARs. Effects on LTP are more complex and persistent, and involve effects on gamma-aminobutyric acid (GABA)-mediated inhibitory transmission. In recent studies, we found that GABA-enhancing neurosteroids contribute to the ability of ethanol to block LTpreliminary Additionally, the ability of ethanol to block LTP depends upon how ethanol is administered, with acute applications of high concentrations blocking LTP and slower step-wise increases in ethanol concentration to high levels resulting in a form of acute tolerance. In this project, we will extend these initial observations and pursue three sets of studies that will examine: 1. How GABAergic neurosteroids contribute to acute effects of ethanol on LTP;2. Factors contributing to the longer-lived (several hour) effects of ethanol on LTP;and 3. Factors contributing to the acute tolerance to ethanol-mediated LTP inhibition following slower increases in ethanol concentration. These studies will be done in rat hippocampal studies and will focus on the effects of ethanol and related modulators on glutamatergic and GABAergic transmission. The long-term goal of these studies is to identify ways to protect the nervous system from the adverse effects of ethanol on synaptic function and cognition.

Public Health Relevance

Alcohol is one of the most commonly abused drugs in the United States and is associated with both acute and long-term problems with memory processing. The goal of this project is to determine how alcohol alters communication between nerve cells to impair memory formation with the hope of developing better treatments for alcohol-induced memory problems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017413-05
Application #
8497547
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2009-09-20
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$339,682
Indirect Cost
$116,207
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mennerick, Steven; Taylor, Amanda A; Zorumski, Charles F (2014) Phosphatidylinositol 4,5-bisphosphate depletion fails to affect neurosteroid modulation of GABAA receptor function. Psychopharmacology (Berl) 231:3493-501
Linsenbardt, Andrew J; Taylor, Amanda; Emnett, Christine M et al. (2014) Different oxysterols have opposing actions at N-methyl-D-aspartate receptors. Neuropharmacology 85:232-42
Zorumski, Charles F; Mennerick, Steven; Izumi, Yukitoshi (2014) Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol 48:1-17
Purgert, Carolyn A; Izumi, Yukitoshi; Jong, Yuh-Jiin I et al. (2014) Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus. J Neurosci 34:4589-98
Izumi, Yukitoshi; Zorumski, Charles F (2014) Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function. Neuropharmacology 86:273-81
Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F (2013) Locally-generated acetaldehyde is involved in ethanol-mediated LTP inhibition in the hippocampus. Neurosci Lett 537:40-3
Zorumski, Charles F; Paul, Steven M; Izumi, Yukitoshi et al. (2013) Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev 37:109-22
Paul, Steven M; Doherty, James J; Robichaud, Albert J et al. (2013) The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. J Neurosci 33:17290-300
Izumi, Y; Svrakic, N; O'Dell, K et al. (2013) Ammonia inhibits long-term potentiation via neurosteroid synthesis in hippocampal pyramidal neurons. Neuroscience 233:166-73
Linsenbardt, Andrew J; Chisari, Mariangela; Yu, Andrew et al. (2013) Noncompetitive, voltage-dependent NMDA receptor antagonism by hydrophobic anions. Mol Pharmacol 83:354-66

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