Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology & Neuroscience

First Advisor

Jerry Stitzel

Second Advisor

Kenneth Wright

Third Advisor

Ryan Bachtell

Fourth Advisor

Christopher Lowry

Fifth Advisor

Kent Hutchison

Abstract

Cigarette smoking is the most common cause of preventable death in the United States. Approximately 440,000 deaths occur annually in the U.S. due to tobacco related illnesses, including cancer, stroke, and heart disease. Despite the known health-risks associated with smoking and strong motivation to quit, the lifetime cessation rate is only 4-7%, even with the most effective treatments available. Understanding the biological processes that underlie smoking and how other physiological changes modify this addiction is critical for development of more effective treatments. Broadly, there were three aims of this thesis. The first was to determine if mice would be a good model for diurnal differences in smoking behavior in humans. We show that mice do exhibit changes in sensitivity to an acute dose of nicotine (the primary neuroactive ingredient in cigarettes) over the course of the day. Once this was established, the second goal was to determine if melatonin was responsible for the diurnal differences observed in nicotine behaviors. Our results show that melatonin signaling is required for changes across the day in acute nicotine sensitivity, and also is responsible for reductions in nicotine intake in a 2-bottle nicotine preference paradigm (a model of drug seeking behavior). Finally, the third goal of the experiments detailed in this thesis was to determine the molecular mechanism by which melatonin receptor(s) are affecting nicotinic receptor(s) and resulting in behavioral changes. We were able to determine that signaling through both MT1 and MT2 melatonin receptors are required for the melatonin to change behavior, however the specific nicotinic receptor that is modulated remains unclear. These findings have implications for development of novel therapeutic drugs for treatment of drug addiction, and suggest that clock-time should be carefully considered when designing pharmacological experiments.

Share

COinS