Access Type

Open Access Dissertation

Date of Award


Degree Type


Degree Name



Psychiatry and Behavioral Neurosciences

First Advisor

Mark K. Greenwald






August 2017

Advisor: Dr. Mark K. Greenwald

Major: Neuroscience (Translational)

Degree: Doctor of Philosophy

Nicotine use, especially cigarette smoking, is a significant public health problem. Existing pharmacotherapies attenuate nicotine craving and withdrawal symptoms. However, the majority of patients relapse within the first year of treatment. Treatment studies indicate a commonly cited precipitant to smoking relapse is stress. Pharmacotherapies do not attenuate, and may exacerbate, the effects of acute stress. Experimental studies (preclinical and clinical) indicate that acute stress potentiates drug-seeking behavior across drugs of abuse. Despite a robust literature linking acute stress and substance use, neurobiological mechanisms remain poorly understood. A more complete understanding of the neurobiological effects of acute stress on brain function may facilitate development of novel interventions. Adjunctive stress-blunting medications may improve the effectiveness of existing pharmacotherapies.

The present study investigated the effects of pharmacological stress-induction among cigarette smokers. Non-treatment-seeking cigarette smokers were recruited locally and screened for psychiatric, medical, and neuroimaging contraindications. Using a double-blind, placebo-controlled within-subject random cross-over design, participants (N = 21) completed two oral-dosing experimental sessions: active (yohimbine [YOH] 54mg + hydrocortisone [HYD] 10mg) and placebo (YOH 0mg + HYD 0mg) stress. Prior research indicated that YOH+HYD is a robust pharmacological stress-induction technique that stimulates the Autonomic Nervous System (ANS) and Hypothalamic-Pituitary-Adrenal (HPA) axis systems, increases circulating levels of noradrenaline and cortisol (two primary stress hormones), and potentiates drug-seeking behavior. Throughout each experimental session, subjective and physiological effects were measured. In addition, participants completed a 60min magnetic resonance imaging (MRI) scan which consisted of three task paradigms: 1) letter 2-back, 2) smoking cued letter N-back, and 3) breath-hold challenge. Participants completed a working memory paradigm (letter 2-back) during proton functional magnetic resonance spectroscopy (1H fMRS). Left dorsolateral prefrontal cortex (dlPFC) neurochemistry was evaluated during letter 2-back task performance. Next, participants completed a cued N-back paradigm that consisted of images (cigarette smoking or neutral) centered behind capitalized letters across three levels of N-back task difficulty: 0-, 1-, and 2-back. Finally, participants were instructed (visually) to control their breathing across three phases: ‘normal’ breathing, paced breathing (3s in/3s out), and breath-hold challenge (11s). After the MRI scan, participants completed a choice progressive ratio task. Across 11 independent choice trials, participants could earn one cigarette puff (preferred brand) or money ($0.25) via behavioral responding. Each successive unit earned (puffs or money, independently) was associated with a higher response requirement (progressive ratio schedule). At the end of the 30min task, participants smoked the exact number of cigarette puffs earned and/or were provided the amount of money earned. Number of puffs earned and smoked was a direct measure of nicotine-seeking and self-administration behavior (nicotine motivation). Participants were compensated for their time.

Results indicated that oral pretreatment with YOH+HYD increased biomarkers of a physiological stress response: systolic and diastolic blood pressure, heart rate, saliva cortisol and α-amylase (indirect biomarker of noradrenaline levels), relative to placebo. YOH+HYD potentiated nicotine-seeking and self-administration behavior (controlling for nicotine dependence level), relative to placebo. Appetitive and relief-motivated cigarette craving, nicotine withdrawal symptoms, negative affect, and anxiety levels increased throughout each session, but did not differ by experimental session (active vs. placebo stress). Similarly, positive affect decreased throughout each session, but did not as a function of stress. 1H fMRS indicated that letter 2-back performance increased left dlPFC glutamate (GLU) levels relative to interleaved fixation cross rest (indicative of task engagement) during the placebo, but not active stress, session. Further, YOH+HYD impaired letter 2-back response accuracy, relative to placebo. Across N-back levels (0-, 1-, and 2-back), fMRI indicated more robust neural activation across ‘reward’-associated brain regions in response to smoking images (> neutral images) during placebo, relative to active stress.

Results demonstrated YOH+HYD induced a sustained physiological stress response (ANS and HPA axis) and potentiated nicotine-seeking and self-administration. YOH+HYD attenuated dlPFC task engagement and impaired response accuracy during a well-established working memory task. These findings provide experimental support for a plausible neurobiological mechanism through which acute stress may potentiate nicotine self-administration. Acute stress-impaired dlPFC function may potentiate nicotine self-administration and, among abstinence-motivated individuals, precipitate smoking relapse. Prior research demonstrated dlPFC function is associated with a host of cognitive processes (e.g. delayed gratification, self-control, decision making, etc.) associated with prolonged smoking abstinence. Future studies are needed to confirm this hypothesis, investigate dose-response relationships, and evaluate the efficacy of stress-blunting medications in combination with existing pharmacotherapies for smoking cessation.

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