Date of Award

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

L. Judson Chandler

Second Advisor

Justin T. Gass

Third Advisor

John J. Woodward

Fourth Advisor

Peter W. Kalivas

Fifth Advisor

Sudie Back

Abstract

Post-traumatic stress disorder (PTSD) and substance use disorder (SUD) are two highly prevalent and highly debilitating psychological conditions that often occur comorbidly. In accordance with the self-medication hypothesis, drugs like alcohol and cannabis are used following exposure to a traumatic event to acutely reduce anxiety, but, in the long term, these substances cause impairments in learning and memory processes in the prefrontal cortex and reduce the effectiveness of therapeutic treatments for these disorders. As such, the overarching hypothesis of this dissertation is that exposure to stress, alcohol, and cannabis lead to alterations in learning and memory due to modifications in prefrontal cortex signaling, and it is further hypothesized that these impairments can be reversed by normalizing glutamatergic function in this region. These experiments were divided into three main branches of study using behavioral pharmacology as well as optogenetics and fiber photometry to investigate the deleterious effects of stress, cannabis, and alcohol exposure on cognitive functioning and glutamate signaling in the prefrontal cortex. In the first set of studies, restraint stress was followed by set-shifting and alcohol self-administration behavioral tasks to examine stress-induced changes in cognitive flexibility and drug seeking behavior respectively. These experiments established stress induced increases in ethanol seeking and relapse like behavior as well as impairments in cognitive flexibility. The second set of studies established the detrimental effects of alcohol exposure on fear learning during extinction training. Further, this effect was shown to be dependent on glutamatergic activity in the prefrontal cortex using microinjection and optogenetic studies. In the third set of studies, THC vapor and chronic ethanol administration led to deficits in prefrontal cortex reliant behaviors including cognitive flexibility, ethanol seeking, and responses to fear stimuli, and fiber photometry was used to measure effects of these drugs on prefrontal cortex glutamate signaling. Additionally, the pharmaceutical compounds CDPPB and N-acetylcysteine (NAC) were used to pharmacologically reverse the behavioral and signaling impairments that occur as a result of alcohol and cannabis exposure respectively. Taken together, the data presented within this dissertation highlight the effects of alcohol and cannabis on prefrontal cortex-reliant signaling and behavior and use clinically available therapeutics to treat these deficits in a model of PTSD/SUD comorbidity.

Rights

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