Degree Name
PhD (Doctor of Philosophy)
Program
Biomedical Sciences
Date of Award
12-2025
Committee Chair or Co-Chairs
Justin Gass
Committee Members
Brooke Schmeichel, Brooks Pond, Michelle Chandley, Doug Thewke
Abstract
Cannabis and alcohol are the most widely used psychoactive substances, particularly in vulnerable populations such as veterans diagnosed with PTSD and those diagnosed with Alcohol Use Disorder (AUD). With the increasing legalization of recreational cannabis, understanding the combined neurobiological and behavioral effects of cannabis and alcohol is vital. Delta9 -tetrahydrocannabinol (THC), the psychoactive compound found in cannabis, has been shown to significantly impact both physiological and behavioral outcomes related to fear memory when used concomitantly with alcohol. Unfortunately, current treatment options for substance use disorders are limited and often have little success. Therefore, new pharmacological targets are urgently needed to improve intervention efficacy and reduce the high risk of relapse.
This study investigated the combined behavioral effects of THC and chronic alcohol exposure in a rat model of co-dependency and explored the therapeutic potential of modulating the metabotropic glutamate receptor 5 (mGlu5) with the positive allosteric modulator CDPPB. To model THC and alcohol co-use, rats were exposed to 2 daily sessions of THC vapor for 5 days, followed by a chronic intermittent ethanol exposure (CIE) for 9hr/day for 10 days. Multiple aspects of learning, memory, and drug-seeking were assessed, including fear learning, recognition memory, and alcohol self-administration. Animals exposed to THC + CIE showed significant deficits in recognition memory and fear extinction learning. Furthermore, this same group showed increased alcohol-seeking and reinstatement following abstinence. Alterations in key receptors which mediate learning and memory, CB1 and mGlu5, were assessed via RT-qPCR and immunohistochemistry. To reverse these deficits, a subset of animals received a subcutaneous dose of CDPPB (30mg/kg) during various testing phases. Modulation of mGlu5 via CDPPB treatment enhanced fear extinction learning and reduced alcohol self-administration in co-use animals. Therefore, we can conclude that behavioral deficits due to THC + CIE exposure can be prevented through modulation of mGlu5 function. These findings elucidate a crucial neurobiological mechanism associated with co-addiction and identify mGlu5 as highly efficacious pharmacological target for developing advances clinical treatments for comorbid cannabis and alcohol use disorders.
Document Type
Dissertation - embargo
Recommended Citation
Adams, Bailey, "Behavioral and Neural Alterations Induced by Concurrent THC and Alcohol Use: Preclinical Insights into Comorbid Effects and Therapeutic Implications of mGlu5 Modulation" (2025). Electronic Theses and Dissertations. Paper 4636. https://dc.etsu.edu/etd/4636
Copyright
Copyright by the authors.
