Reagan Wetherill - US grants

[unreadable] DESCRIPTION (provided by applicant): The current proposal will examine the differences in individuals who have and have not experienced an alcohol-induced blackout by assessing memory processes when sober and intoxicated, and more importantly, explore the differences in neural activations associated with memory processes when sober and intoxicated. Previous research indicates that certain individuals may be more vulnerable to alcohol-induced blackouts than others (Baer et al., 2003; Hartzler & Fromme, 2003), and after alcohol exposure, individuals who have experienced an alcohol-induced blackout show greater memory impairments than those who have not experienced alcohol-induced blackouts. To examine this phenomenon and to better understand alcohol's effects on the brain, the proposed research uses a variety of methods, including standardized alcohol administrations and fMRI to make between-subjects comparisons, (i.e. blackout history positive versus blackout history negative) and within-subject comparisons (e.g. sober versus intoxicated performance and neural activations). As a replication and extension of preliminary findings, Study 1 will use participants from a NIAAA-funded study to assess memory performance before and after an alcohol administration (i.e., alcohol vs. no alcohol). Based on the findings from Study 1, Study 2 will use a source memory task and a standardized alcohol administration with functional magnetic resonance imaging. Specifically, Study 2 will (a) evaluate the effect of a standardized alcohol administration on behavioral performance and neural activation during source memory tasks; (b) examine the influence of alcohol-induced blackouts on the neural activity associated with both encoding and retrieval; (c) evaluate prefrontally mediated strategic memory processes (i.e., source memory) to see whether alcohol impairments are more severe in individuals with a history of alcohol-induced blackouts. The proposed research is relevant to public health because college students use alcohol more than any other drug and appear to be particularly vulnerable to the negative consequences associated with alcohol use. Furthermore, research is limited on alcohol-induced blackouts, and the proposed research will provide a better understanding of mechanisms underlying alcohol-induced blackouts and changes in brain function as a result of acute alcohol exposure using imaging technology and a standardized alcohol administrations. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT As a clinical psychologist, my long-term career goal is to establish an independent career in patient-oriented research (POR), which focuses on integrating genetic, neuroimaging, and pharmacological approaches to 1) evaluate medications that target neurobiological and behavioral mechanisms involved in the development and maintenance of alcohol use disorder (AUD) and 2) tailor treatment to the individual based on genetic variation. My prior training taught me skills in the conduct of human laboratory and neuroimaging studies. My graduate training focused primarily on individual differences contributing to alcohol use and behavioral risk-taking, alcohol administration studies, and neuroimaging. As a postdoctoral fellow, I extended this training to include neuropsychological assessments and additional neuroimaging techniques and examined neural features contributing to the initiation of alcohol use and development of AUD. However, to achieve my long-term career goal, it is essential that I address critical gaps in my knowledge and training. I was recently appointed as a Research Assistant Professor in the Department of Psychiatry at the University of Pennsylvania (UPenn), which allows me to formally pursue an independent career in POR. The K23 mechanism will enable me to focus at least 85% of my time and effort to develop a career as an independent clinical researcher. My training objectives will progress in a logical fashion to prepare me for the transition to becoming an independent clinical researcher. These include: 1) acquiring new knowledge in genetics and pharmacology and applying this knowledge to understanding the mechanisms of medications to treat AUD, and the role of genetic factors in moderating these effects; 2) conducting a research project that integrates neuroimaging, genetic, and pharmacological approaches to examine the effects of the histamine H3 receptor antagonist, bavisant (BAV), on heavy drinking and neural responses to alcohol-related cues, and whether genetic variation in the HRH3 gene moderates these effects; and 3) developing the skills necessary to communicate my research findings, grant writing to secure subsequent research funding, and to collaborate in an interdisciplinary environment. I will accomplish these training objectives through relevant coursework, guidance from my mentors, attendance at seminars and workshops, and applied hands-on research training. This multi-modal approach will enable me to acquire new knowledge in areas essential to my career goals (i.e., genetics, pharmacology), implement the proposed research plan, and build an independent research program with the goal of obtaining an R01 award prior to the end of the K23 period. The research project is an integrative study designed to examine the effects of the histamine H3 receptor antagonist, BAV, on heavy drinking and neural responses to alcohol-related cues, and to explore whether genetic variation moderates these effects. Recent data indicate that histamine H3 receptor antagonists reduce alcohol consumption [1, 2]. Although the mechanism underlying these effects has not been fully defined,presynaptic H3 receptors help to regulate the release of dopamine, acetylcholine, and norepinephrine [3] andpostsynaptic H3 receptors may alter the enhanced dopaminergic signaling induced by alcohol [4, 5]. As such,BAV could suppress mesocorticolimbic dopamine release, thereby decreasing the reinforcing effects of alcohol and devaluing the previously rewarding properties of alcohol-related cues over time. To advance our understanding of BAV's effects and the effort to personalize the pharmacotherapy of AUD, we will conduct an 8-week, parallel-groups, placebo-controlled study of BAV in 100 heavy drinkers with DSM-5 AUD. Of these 100 participants, 44 will be recruited to complete two neuroimaging scans sessions, one prior to randomization and one following 3 weeks of study medication (BAV or placebo). Using this integrative approach, I will examine the effects of BAV on heavy drinking and neural responses to alcohol-related cues, correlate neural responses with behavior (heavy drinking), and explore whether genetic variation moderates these effects. Thus, findings from the proposed study could improve our understanding of a potentially efficacious medication for the treatment of AUD and contribute substantially to personalized care. The environment at the Center for Studies of Addiction (CSA) at UPenn is uniquely positioned to support my training needs. I will be mentored by Henry Kranzler, M.D (CSA Director, primary mentor) and co-mentored by scientists in the areas of pharmacology, genetics, neuroscience, and biostatistics. Mentorship will be complemented by focused coursework and participation in seminars and workshops at UPenn. In addition, the CSA will provide the practical resources needed to conduct my research, including use of an extensive infrastructure for participant recruitment, medical screening, data management, and biostatistical support. Additional financial support provided through the CSA will enable me to have 85% protected time to conduct the proposed training and research. This comprehensive, interdisciplinary mentored approach will enhance my clinical research skills and my ability to compete successfully for R01 funding and thereby establish an independent program of research.

Cigarette smoking is the number one cause of preventable death in the U.S. however, despite the known health consequences of smoking, 1 in 5 Americans continues to smoke. Most smokers desire to quit but success rates are low. Women have greater difficulty quitting smoking and suffer greater smoking-related health consequences than men. Greater knowledge of relapse vulnerabilities in women could help to identify treatment targets and result in interventions that improve health and save lives. The guiding hypothesis for this proposal is that fluctuations in gonadal sex hormones [estradiol (E) and progesterone (P)] over the course of the menstrual cycle (MC) may greatly impact relapse vulnerability through their actions on a powerful relapse motivator, smoking-related cue (SC) exposure. This hypothesis arises from animal studies showing that gonadal sex hormones dramatically affect reward systems and reward-related behavior. Specifically, E elevates ventral striatal dopamine and accelerates both drug-cued and drug-primed reinstatement, while P has opposite effects on drug-seeking behavior. Correspondingly, when women have high E levels, such as those occurring during the late follicular phase of the MC, they may find drugs more rewarding and drug-related cues more motivating, which could markedly undermine women's success in quitting smoking at that time. Our preliminary neuroimaging results show enhanced responses to SCs in the medial orbitofrontal cortex, a region known to be involved in the coding of reward magnitude, in women during the follicular compared to the luteal phase, but the direct effects of the hormonal milieu on neural responses to SCs remains untested, divesting us of critical, treatment-relevant information. Thus, the overarching goal of this proposal is to characterize the influence of the natural hormonal milieu on brain and behavioral responses to SCs. Specifically, in AIM 1, to link hormonal status to the brain responses to SCs, over the course of 3 monthly MCs, in a repeated measures counter- balanced design, we will compare the brain responses to highly appetitive SCs in a group of healthy, naturally- cycling females who are chronic smokers at 3 distinct time points within their natural MC. Given that the early follicular phase is associated with extremely low levels of both E and P, it offers a natural and ideal comparator condition. Sessions will be carefully timed to occur during high E, which corresponds to the late follicular phase, during high P, which corresponds to the mid-luteal phase, and during the time of the MC when both E and P are low (LEP). E/P concentrations will be used to verify conditions and as covariates to examine their associations with brain responses. In AIM 2, to link hormonal status and brain responses to the behavioral biases to SCs, in synchrony with the imaging sessions, women from Aim 1 will also participate in 3 laboratory sessions consisting of a neuro-behavioral battery that includes tasks to probe affective and attentional biases to SCs at both time points. This research addresses a critical gap in our knowledge: namely, the impact of the hormonal milieu on brain response to SCs, an important relapse trigger. The results may guide hormonally- informed treatment strategies with the potential to reduce relapse, thus improving health and saving lives.  

Worldwide, more than 3.5 million people die annually from smoking-related lung diseases. Although public awareness regarding smoking-related risks has increased and tobacco smoking has declined in the United States, the use of Electronic Nicotine Delivery Systems, or ENDS (e.g., e-cigarettes, vape pens), has dramatically increased, particularly among youth and young adults. The increased popularity of ENDS is due in part to targeted marketing efforts asserting that these products represent a ?safer alternative? to traditional cigarettes. To date, however, there is a paucity of human data on the potential toxicity of ENDS use, particularly relative to that of cigarette smoke. Inducible nitric oxide synthase (iNOS) is an enzyme that is constitutively expressed in lung epithelium and is specific for inflammation, a common pathway for many types of lung disease. We propose to measure lung inflammation using Positron Emission Tomography (PET) imaging with [18F]-6- (1/2)(2-fluoro-propyl)-4-methylpyridin-2-amine ([18F]NOS), an exciting new PET radiotracer that targets the inducible isoform of nitric oxide synthase. The goal of the proposed study is to leverage our experience with this novel imaging technique to compare, for the first time, lung inflammation in ENDS users with cigarette smokers and nonsmokers. Specifically, we will quantify, localize, and compare, for the first time, lung inflammation in ENDS users with cigarette smokers and nonsmokers using PET lung imaging with [18F]NOS (Aim 1) and examine and compare biomarkers of airway (fractional exhaled nitric oxide (FeNO)) and lung inflammation (i.e., pro- inflammatory cytokines (TNF-?, IL-1?, IL-8)) and lung function (as measured by forced expiratory volume (FEV) and forced vital capacity (FVC) using spirometry) (Aim 2). To accomplish these goals, 60 subjects [3 groups of 20: ENDS users, traditional cigarette smokers, and nonsmoking controls] will be carefully screened and smoking status will be biochemically verified. Subjects will complete self-report measures, undergo a one-hour [18F]NOS PET/CT (computed tomography) scan of the chest, provide a breath and blood sample for measurement of biomarkers of airway and lung inflammation, and complete lung function tests using spirometry. The proposed study would be the first use of [18F]NOS PET lung imaging to localize and quantify the extent of lung inflammation, examine biomarkers of airway and lung inflammation, and lung function due to ENDS use and cigarette smoking. By measuring specific inflammatory effects of ENDS use on lung tissue, our proposal directly supports the FDA's goal of developing ENDS product standards to protect public health.