Electronic Theses and Dissertations

Date of Award

1-1-2020

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Nicole M Ashpole

Second Advisor

Kristine L Willett

Third Advisor

Jason Paris

School

University of Mississippi

Relational Format

dissertation/thesis

Abstract

The overarching goal of this research is to explore the biological mechanisms of aging and formulate novel therapeutic approaches to mitigate age-related impairments. The presence and pervasiveness of ~24 hour (circadian) rhythms in molecular and behavioral dynamics suggests that the mechanisms regulating these rhythms are integral to biological aging and possibly amenable to therapeutic interventions. Based on evidence presented in this dissertation, we conclude that the endocannabinoid system is a mediator of both central and peripheral circadian physiology. Additionally, the hormetic pharmacological properties of the synthetic cannabinoid CP55940 suggest that bidirectional modulation of circadian rhythms via cannabinoids is possible. Chapter 1 summarizes seminal work and recent advances in the fields of biological aging, circadian rhythms, cannabinoid pharmacology, and the concept of hormesis. The culmination of this chapter poses the central question: are exogenous cannabinoids capable of bidirectionally restoring age-related changes in circadian rhythms? Chapter 2 describes behavioral pharmacology studies wherein young and aged mice were administered varying doses of CP55940 to determine how exogenous cannabinoids affect locomotion, body temperature, and nociception. Data acquired from these high-powered experiments demonstrate that CP55940 is significantly more potent and efficacious in old mice, and that extremely low doses of this exogenous cannabinoid elicit paradoxical locomotor stimulation in young mice. In Chapter 3 we quantified the age- and sex-specific characteristics of voluntary wheel running (VWR) in mice housed under constant darkness - a model for age-related circadian rhythm disruption. We then assessed the ability of CP55940 to alter the timing of activity onset, offset, and total locomotion. Our results indicate that higher doses of CP55940 given immediately after waking acutely suppress wheel running behavior but lead to a rebound in activity later in the day. The final chapter summarizes these results and discusses future studies which can expound upon this novel research. Collectively, this work establishes experimental and analytical methods useful for investigating cannabinoid pharmacology and evaluating circadian rhythm-restoring therapeutics in aged rodents. Given the recent surge in cannabinoid use and the lack of preclinical evidence of these compounds in elderly subjects, these results provide a critically needed foundation for future experimental work.

Available for download on Tuesday, August 31, 2021

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