Degree Name
PhD (Doctor of Philosophy)
Program
Biomedical Sciences
Date of Award
12-2025
Committee Chair or Co-Chairs
Justin T. Gass
Committee Members
Patrick Bradshaw, Michelle Chandley, Jennifer Hall, Brooks Pond
Abstract
Posttraumatic stress disorder (PTSD) is a devastating disorder that is commonly associated with alcohol use disorder (AUD) with a comorbidity rate of up to 79%. This comorbidity presents a significant treatment challenge due to limited effective treatments. The current study investigated the potential of the mGlu5 positive allosteric modulator, CDPPB, to improve recovery of behavioral deficits in a rat model of PTSD/AUD with a critical focus on sex-dependent effects. Previous research has shown that biological sex differentially impacts several behaviors in comorbid PTSD/AUD. Therefore, a primary goal of this set of experiments was to determine how stress and chronic alcohol exposure alter fear-related behaviors in a sex-dependent manner. Fear responses are often measured through active (platform-mediated/darting) and passive (freezing) avoidance behaviors, which can exhibit sex differences. Furthermore, while a strong association exists between PTSD and AUD with neuroinflammation and cardiac dysfunction, the precise effects of stress and chronic alcohol on pro- and anti-inflammatory cytokine expression, heart rate (HR), and blood pressure (BP) remain unclear. We employed a comorbid PTSD/AUD model in male and female Wistar rats using restraint stress (RS) and chronic intermittent ethanol exposure (CIE). This was followed by several behavioral paradigms including: fear conditioning, platform-mediated avoidance, memory- linking, and threat imminence to assess sex-dependent changes in fear avoidance behaviors. To 4 assess treatment potential, a subset of rats received CDPPB (s.c. 30 mg/kg) prior to specific behavioral trials. To assess cardiovascular effects of RS+CIE, a subset of animals was implanted with radiotelemeters to analyze physiological measures (HR and BP). Neuroinflammation was assessed via enzyme-linked immunosorbent assays (ELISAs) to measure cytokine levels in various brain regions. Exposure to RS+CIE resulted in inhibited extinction learning in both sexes; however, CDPPB treatment prevented these behavioral deficits in some behaviors, but not all, and displayed marked sex-dependent effects. Physiologically, the comorbid model was found to decrease HR and BP in rodents. ELISA analysis revealed significant sex- and fear-conditioning dependent changes in cytokine levels across brain regions. This research furthers the understanding of sex-dependent fear behaviors and inflammation in PTSD/AUD, which is critical for developing sex-specific pharmacological treatments for this comorbidity.
Document Type
Dissertation - embargo
Recommended Citation
Schwartz, Britta, "Modulation of mGlu5 Receptors in a Model of Comorbid PTSD/AUD: Implications for Fear Learning and Neuroinflammation" (2025). Electronic Theses and Dissertations. Paper 4616. https://dc.etsu.edu/etd/4616
Copyright
Copyright by the authors.
