Using a multi-modal imaging approach, we intend to investigate the impact of progesterone (PROG) and its neurosteroid metabolite, allopregnanolone (ALLO) on brain neurochemistry (gamma aminobutryic acid; GABA and glutamate; Glut concentrations), neuronal activation during working memory (dorsal lateral prefrontal cortex; DLPFC) and resting state connectivity (dorsal anterior cingulate; dACC and ventral striatum; VS). Nicotine dependence remains a critical public health issue in the United States, costing approximately 200 billion dollars each year in medical expenditures and lost productivity. Subgroups of Americans are unevenly affected by nicotine dependence as females compared to males are particularly at risk for the adverse health effects of nicotine dependence and individuals of lower versus higher socioeconomic status are more likely to smoke. Interestingly, the predominantly female sex hormone PROG exerts a positive effect on cognition and nicotine craving during abstinence and drug liking during re-exposure in both males and females, suggesting a possible therapeutic role for the hormone. Preclinical studies indicate that the effect of PROG in nicotine dependence would be mediated primarily through ALLO modulation of GABAergic function. To translate this line of investigation to the human laboratory, 50 men and 50 women with nicotine dependence will participate in a double blind, placebo-controlled crossover study of PROG that requires two abstinence trials (4 days each), smoking topography sessions and brain imaging (proton magnetic resonance spectroscopy; 1H-MRS and functional magnetic resonance imaging (fMRI; resting state and during cognitive task performance) pre and post each trial. PROG conversion to ALLO, which is modified by subject-level characteristics such as history of major depression, will be measured using standard GC-MS methods. Hypothesis-driven analyses examining dACC and connectivity with the striatum and prefrontal cortex will be examined using standard seed-based correlation analyses while DLPFC neurochemistry at rest and neural activation during working memory task performance are other primary outcomes. Brain imaging is conducted at the ultra-high magnetic field of 7 Tesla in order to maximize the signal to noise for 1H-MRS measurement of GABA and Glut, while allowing co-localization of regions of interest for the fMRI experiments. These brain imaging outcomes along with degree of conversion of PROG to ALLO, sex and smoking topography outcomes, will be provide critical new information regarding the potential for PROG/neurosteroids, as well as other GABA agonists, to be developed as treatments for nicotine dependence.

Public Health Relevance

Nicotine dependence remains a critical public health issue in the United States, costing approximately 200 billion dollars each year in medical expenditures and lost productivity. Females are particularly at risk for the adverse effects of nicotine dependence for as compared to males, females move from nicotine use to dependence more quickly and experience the onset of adverse medical sequelae sooner. In addition, women demonstrate a less robust response to nicotine replacement products, the mainstay of treatment for nicotine dependence, and are more likely to relapse after a period of smoking cessation. Interestingly, the predominantly female sex hormone progesterone exerts a positive effect on nicotine craving during abstinence and drug liking during re-exposure in both males and females, suggesting a possible therapeutic role for the hormone as well as other gamma-aminobutyric acid (GABA) agonists. This project utilizes the novel multi-modal imaging paradigm of combined functional magnetic resonance imaging and proton magnetic resonance spectroscopy to interrogate two different brain regions thought to play a role in nicotine dependence: the dorsal anterior cingulate cortex (dACC) and the dorsal lateral prefrontal cortex (DLPFC). We will utilize a progesterone versus placebo challenge to examine the impact of this hormone and its GABAA receptor agonist metabolite, allopregnanolone, on brain neurochemistry and neuronal activity at rest and during performance of a memory task. Our overarching goal is to determine whether brain changes with smoking abstinence and progesterone administration can be used as biomarkers of nicotine dependence and treatment response in order to enhance future drug/hormone interventions for nicotine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA037289-05
Application #
9601664
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Wetherington, Cora Lee
Project Start
2015-02-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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