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OPTICALLY-INDUCED POPULATION DISCHARGE THRESHOLD TESTING: A NOVEL INVESTIGATION OF A MURINE MODEL OF ALCOHOL WITHDRAWAL INDUCED CNS HYPEREXCITABILITY

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abstract
Alcohol Use Disorder is a major, costly problem in society. Alcohol use is the third highest risk factor for health problems with much of that burden attributable to problems associated with alcohol withdrawal (WD). During WD the central nervous system (CNS) is described as being hyperexcitable. Hyperexcitability is a consequence of homeostatic pressure to compensate for alcohol’s potentiation of inhibitory systems. When the drug is removed from the system the compensatory changes in excitability are revealed leading to excess activity. The increase in activity is associated with the symptoms of WD including seizure. Seizure represents the most severe symptom of WD, and is responsible for a significant portion of WD associated mortality. Treatment of alcohol WD relies on potentiating the inhibitory system with benzodiazepines (BZD). This is largely effective, but some individuals still experience WD symptoms even with BZD treatment and there is a risk of respiratory depression from BZD treatment and BZDs can be abused. Here we demonstrate a platform in which CNS excitability during WD is probed called the optically-induced Population Discharge Threshold (oPDT). We demonstrate that the metric is sensitive to WD hyperexcitability and represents a novel model for experimentation. We propose that oPDT can be used for pharmacological screening for new, more effective treatment options. Furthermore, we demonstrate that oPDT is not altered with treatment with the drug ethosuximide (ETX) during WD. ETX is a Ca2+ channel blocker which has been shown to reduce WD anxiety-like behavior, certain seizure types associated with thalamic dysfunction, and mortality in an animal model of WD. Our results indicate that the hyperexcitability measured by oPDT represents a change in circuit function that is insensitive to ETX. This suggests that the symptoms of WD may be differentiable, and that while hyperexcitability is ubiquitous during WD it may be the circuit and population context in which the hyperexcitability exists rather than the hyperexcitability itself that is relevant to symptomology. In summary, we have demonstrated a novel method for investigating WD hyperexcitability and shown that circuit level investigations of excitability can differentiate pharmacologic efficacy. We suggest that while hyperexcitability is an underlying feature of WD symptoms its role and the modulation of hyperexcitability are dependent on the neurobiological context in which it exists.
subject
Alcohol Withdrawal
Hippocampus
Optogenetics
Seizure
contributor
Alberto, Gregory Erick (author)
Weiner, Jeff (committee chair)
Daunais, James (committee member)
Budygin, Evgeny (committee member)
Stapleton-Kotloski, Jennifer (committee member)
date
2017-08-22T08:35:23Z (accessioned)
2019-08-21T08:30:12Z (available)
2017 (issued)
degree
Neurobiology & Anatomy (discipline)
embargo
2019-08-21 (terms)
identifier
http://hdl.handle.net/10339/86341 (uri)
language
en (iso)
publisher
Wake Forest University
title
OPTICALLY-INDUCED POPULATION DISCHARGE THRESHOLD TESTING: A NOVEL INVESTIGATION OF A MURINE MODEL OF ALCOHOL WITHDRAWAL INDUCED CNS HYPEREXCITABILITY
type
Dissertation

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