Drug and alcohol abuse pose an enormous public health burden on society, with high rates of mortality, great human suffering and incalculable economic costs. Yet, substance abuse is preventable, especially with a deeper understanding of the etiology and sources of individual risk. People vary in their susceptibility to use and abuse drugs, for reasons that are not fully understood. Translational studies in animal models and humans offer several promising leads for identifying high-risk individuals, including those who experience greater reward from drugs. In this project we examine two predictors of drug reward in humans, the personality trait of extraversion, and the sensitivity of the brain reward circuit t monetary gains. The brain reward circuit, known as the Fronto-Limbic Accumbens REward Seeking (FLARES) circuit, has been well characterized in human imaging studies and in studies with laboratory animals. It is comprised of the ventral striatum including the nucleus accumbens, with dynamic interactions with the frontal cortex, limbic and ventral tegmental areas. Using healthy volunteers as subjects, we will extend previous findings that extraversion is related to both brain responses to monetary reward and behavioral responses to drug reward. Then, addressing an as-yet unstudied relationship, we will determine whether the activity of the FLARES circuit predicts behavioral preference and subjective reward (euphoria) with two drugs of abuse, amphetamine and alcohol. Finally, we will test the novel hypothesis that the relationship between extraversion and drug euphoria is mediated by the brain reward circuit. Our long-term goal is to identify the neurobiological and psychological processes that underlie risk for drug abuse. We hypothesize that the trait measure of risk (extraversion), the measure of brain reward and the measure of drug-induced euphoria are closely inter-related, and together represent a bio- behavioral risk factor for drug use. The project involves a unique collaboration combining the behavioral expertise of Dr. de Wit with the brain imaging expertise of Dr. Phan. Our central hypothesis is that sensitivity of the brain reward circuit mediates the relationship between personality and the rewarding effects of drugs. We will use an innovative design that links brain to behavior by coupling functional magnetic resonance imaging with psychopharmacology.

Public Health Relevance

Individuals differ in their risk for developing drug addiction, possibly because of neurobiological differences in the brain reward circuit. In this project we combine psychopharmacological and neuroimaging approaches to investigate individual differences in pleasurable effects of drugs, in relation to both the brain's response to reward, and the personality trait of extraversion. The studies will advance our understanding of the biological basis of substance abuse risk, and help to identify at-risk individuals.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wetherington, Cora Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Doss, Manoj K; Weafer, Jessica; Ruiz, Nicholas A et al. (2018) Alcohol and pharmacologically similar sedatives impair encoding and facilitate consolidation of both recollection and familiarity in episodic memory. Cogn Neurosci 9:89-99
de Wit, Harriet; Epstein, David H; Preston, Kenzie L (2018) Does human language limit translatability of clinical and preclinical addiction research? Neuropsychopharmacology 43:1985-1988
Crane, Natania A; Gorka, Stephanie M; Weafer, Jessica et al. (2018) Neural activation to monetary reward is associated with amphetamine reward sensitivity. Neuropsychopharmacology 43:1738-1744
Doss, Manoj K; Weafer, Jessica; Gallo, David A et al. (2018) MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections. Neuropsychopharmacology 43:791-800
Bershad, Anya K; Miller, Melissa A; Norman, Greg J et al. (2018) Effects of opioid- and non-opioid analgesics on responses to psychosocial stress in humans. Horm Behav 102:41-47
Vena, Ashley; King, Andrea; Lee, Royce et al. (2018) Intranasal Oxytocin Does Not Modulate Responses to Alcohol in Social Drinkers. Alcohol Clin Exp Res 42:1725-1734
de Wit, Harriet; Sayette, Michael (2018) Considering the context: social factors in responses to drugs in humans. Psychopharmacology (Berl) 235:935-945
Childs, Emma; Astur, Robert S; de Wit, Harriet (2017) Virtual reality conditioned place preference using monetary reward. Behav Brain Res 322:110-114
Bershad, Anya K; Miller, Melissa A; de Wit, Harriet (2017) MDMA does not alter responses to the Trier Social Stress Test in humans. Psychopharmacology (Berl) 234:2159-2166
Weafer, Jessica; Lyon, Nicholas; Hedeker, Donald et al. (2017) Sweet taste liking is associated with subjective response to amphetamine in women but not men. Psychopharmacology (Berl) 234:3185-3194

Showing the most recent 10 out of 210 publications