Dissertation
Investigating acid-sensing ion channel 1A (ASIC1A) as a novel contributor to the effects of alcohol
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2021
DOI: 10.17077/etd.006328
Abstract
Acute alcohol intoxication is associated with a variety of cognitive and behavioral effects. High doses of alcohol can cause memory impairment and amnestic episodes called “blackouts.” Conversely, low-dose alcohol has been suggested to improve memory. Alcohol also has other dose-dependent effects, ranging from excitement, stimulation, and disinhibition at low doses to sedation, ataxia, and obtundation at high doses. The neurobiology underlying these complex dose-dependent effects is incompletely understood, but may be significant, as the acute effects of alcohol are thought to be related to risk for alcohol use disorders. We hypothesized that acid-sensing ion channel 1A (ASIC1A) would play a role in the effects of alcohol, as it contributes to memory and synaptic plasticity, as well as responses to other drugs of abuse. We first tested the role of ASIC1A in alcohol-induced memory changes with Pavlovian fear conditioning in mice. We found that ASIC1A disruption tended to prevent low-dose alcohol memory enhancement and worsen higher- dose memory impairment. Furthermore, when we assessed other effects of alcohol, we found that ASIC1A disruption caused alcohol to be less sedating and more stimulating, which was not due to blood alcohol differences. We recorded in vivo amygdala neural activity and found ASIC1A disruption changed neural responses to alcohol, consistent with altered effects on fear memory processes. Finally, we found that alcohol dose-dependently potentiated ASIC1A homomeric function in vitro, suggesting a possible mechanism of action. Surprisingly, when we tested ASIC1A disruption in several assays of chronic alcohol, we did not see effects in conditioned place preference, behavioral sensitization, or voluntary oral consumption of alcohol. Taken together, these results indicate that ASIC1A is a novel molecular contributor to alcohol neurobiology; however, the apparent differences in ASIC1A contribution to the acute and chronic effects of alcohol highlight the need for further work to determine underlying mechanisms and applicability to other addiction-related behaviors. Ultimately, these findings thus open up new research directions that may be relevant for understanding and treating alcohol use disorders.
Details
- Title: Subtitle
- Investigating acid-sensing ion channel 1A (ASIC1A) as a novel contributor to the effects of alcohol
- Creators
- Gail Inanna Snyder Harmata
- Contributors
- John A Wemmie (Advisor)Brian J Dlouhy (Advisor)Gordon Buchanan (Committee Member)Hanna Stevens (Committee Member)Nandakumar Narayanan (Committee Member)John H Freeman (Committee Member)Ryan T Lalumiere (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Autumn 2021
- DOI
- 10.17077/etd.006328
- Publisher
- University of Iowa
- Number of pages
- xiv, 99 pages
- Copyright
- Copyright 2021 Gail Inanna Snyder Harmata
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 80-99).
- Public Abstract (ETD)
Alcohol abuse and addiction are major problems in society, affecting millions of people and costing hundreds of billions of dollars a year in the U.S. alone. However, how alcohol works in the brain is very complex and is incompletely understood. Alcohol could mediate some of its effects due to a molecule called acid-sensing ion channel 1A (ASIC1A). Alcohol and ASIC1A both affect learning and memory, and ASIC1A is involved in responses to other substances of abuse such as cocaine and morphine. Thus, we tested whether ASIC1A was needed for a variety of effects of alcohol in mice and in cells in a dish. We found that ASIC1A was important for multiple intoxicating effects of alcohol such as stimulation, sedation, memory changes, and brain activity changes. We also found that alcohol seemed to change the function of the molecule in cells in a dish, suggesting a new way alcohol could act in the body. Surprisingly, we did not find a role for ASIC1A in chronic alcohol behaviors in mice like drinking, although additional tests should be done to rule out this out completely. Ultimately, this suggests ASIC1A contributes to intoxicating effects of alcohol, which helps us better understand how alcohol works and may help us to better treat alcohol-related problems.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984210944202771
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