Degree Name
PhD (Doctor of Philosophy)
Program
Biomedical Sciences
Date of Award
5-2025
Committee Chair or Co-Chairs
Brooke Schmeichel
Committee Members
Russell Brown, Justin Gass, Matthew Palmatier, Brooks Pond
Abstract
Substance use disorders (SUD) in the United States are steadily increasing. Potent and dangerous substances such as methamphetamine (MA) and fentanyl (FEN) are often co-used as a polysubstance (POLY), either intentionally or unknowingly as FEN is a common adulterant. SUD is characterized by physiological and psychological dependence involving the negative reinforcement of anhedonia and withdrawal which drive hypermotivated drug-taking behaviors. Current theory suggests that recruitment of hypocretin/orexin (HCRT) neuropeptide in reward and stress associated brain regions contributes to drug dependence. Despite strong evidence for HCRT’s role in mono-drug dependence, a relevant model for POLY dependence has yet to be developed, leaving gaps in our understanding of HCRT with POLY use. While the relationship between drugs and HCRT, as well as drugs and neuroinflammation, are well-established, the dynamic between these three factors remains understudied.
Our laboratory developed a preclinical model of POLY (MA + FEN) dependence to further investigate HCRT modulation of POLY-taking behavior and POLY-induced neuroinflammation. We first validated the POLY self-administration model, demonstrating faster acquisition and accelerated escalation in POLY-taking compared to mono-drug models. We also observed consistent upregulation of HCRT peptide and receptors in the central amygdala (CeA), a stress-sensitive node contributing to drug dependence, in each model. We investigated the role of HCRT during POLY dependence via systemic HCRT-receptor antagonism, which attenuated POLY-taking and stress-induced reinstatement, evidencing HCRT signaling as an important component of POLY-dependence. A site of action for HCRT modulation of POLY dependence was further investigated by chemogenetic inhibition of HCRT signaling to the CeA. Silencing of HCRT-CeA signaling reduced POLY-taking and stress-induced reinstatement behavior, supporting our hypothesis that HCRT signaling in the CeA drives dependent behaviors. Finally, we examined the relationship between POLY, HCRT, and neuroinflammation by administering HCRT-1, POLY, and/or a HCRT-receptor antagonist and measured markers of neuroinflammation (TNF-a and IL1-b). We observed a modest trend for HCRT as a neuroprotective element in a model of passive POLY exposure. Together, these studies validate our model of POLY dependence, enhance our understanding of the HCRT system and the CeA during POLY dependence, and elucidate dynamic relationships between dependence, HCRT, and neuroinflammation.
Document Type
Dissertation - embargo
Recommended Citation
Zarin, Tyler, "Investigating the Role of the Hypocretin/Orexin System in a Novel Model of Polysubstance Dependence" (2025). Electronic Theses and Dissertations. Paper 4538. https://dc.etsu.edu/etd/4538
Copyright
Copyright by the authors.
Included in
Animal Experimentation and Research Commons, Behavioral Neurobiology Commons, Pharmacology Commons, Substance Abuse and Addiction Commons