Imaging Cholinergic and Dopaminergic Systems in Cigarette Smoking and Withdrawal
Date of Award
Doctor of Philosophy (PhD)
Interdepartmental Neuroscience Program
Tobacco smoking continues to be a leading cause of preventable disease and death. Individuals face challenges in quitting smoking due to negative experiences in early abstinence such as changes in mood and cognition, as well as the onset of cigarette craving, irritability, and other adverse withdrawal symptoms. Elucidation of neural systems involved in tobacco use and withdrawal may help predict cessation outcomes. The cholinergic and dopaminergic systems of the brain are involved in the reinforcing properties of cigarette smoking. Animal studies demonstrate that chronic nicotine exposure induces changes in beta2-subunit containing nicotinic acetylcholine receptor (beta2*-nAChR) expression and dopamine responsivity to stimuli. Less is known about nicotinic effects on these systems in the human brain. Furthermore, the cholinergic and dopaminergic systems have demonstrated roles in cognition and mood independent of nicotine exposure, and may thus mediate smoking-related adaptations in these properties. The goal of this dissertation research was threefold. First, a positron emission tomography (PET) imaging study with the beta2*-nAChR partial agonist radioligand [18F]Flubatine was conducted to assess beta2*-nAChR availability as a function of tobacco use and as a potential neural correlate of cognition, mood, and withdrawal symptoms. A second PET imaging study with the dopamine D2/3 receptor (D2/3R) agonist radioligand [11C]-(+)-PHNO was conducted to assess dopamine D2/3R availability and dopamine responsivity as a function of tobacco use and as a potential neural correlate of mood, withdrawal, and smoking cessation outcomes. Finally, dual-radioligand analytical approaches were developed and applied to investigate joint cholinergic-dopaminergic mechanisms in early tobacco withdrawal. In this study, beta2*-nAChR availability was higher in recently abstinent smokers compared to nonsmokers. The extent of upregulation in beta2*-nAChR availability was associated with greater cigarette use pre-abstinence as well as worse cognitive performance, mood, and withdrawal in early abstinence. Additionally, recently abstinent smokers exhibited dopamine dysfunction in the ventral striatum compared to nonsmokers that was linked with worse mood. Finally, exploratory dual-radioligand analyses revealed potential motor- and cigarette craving-related circuits in nonsmokers and recently abstinent smokers, respectively, mediated jointly by the cholinergic and dopaminergic systems. Overall, the research presented in this dissertation uniquely incorporated sophisticated PET data analyses and clinically relevant measures to enhance understanding of neural systems involved in tobacco use and withdrawal. Future work is needed to build upon these findings to develop neuroscience-informed, targeted treatment strategies for long-term tobacco smoking cessation.
Calakos, Katina Constantina, "Imaging Cholinergic and Dopaminergic Systems in Cigarette Smoking and Withdrawal" (2022). Yale Graduate School of Arts and Sciences Dissertations. 459.