Harriet de Wit - US grants

The research is designed to assess the relationship between the reinforcing properties of psychoactive drugs and personality, mood states and subjective reactions to the drugs in humans. These relationships will be assesed in a situation where subjects are given an opportunity to choose to ingest one of two available drugs with concurrent measurements of subjective effects. In one group of studies these relationships will be investigated in specific populations of subjects (anxious, depressed, overweight and heavy drinkers) using stimulants and anxiolytics. If reinforcing effects are greater in certain populations of subjects this may indicate that they are at a greater risk for dependence. In other studies, a similar preference procedure will be used with subjects remaining in the laboratory in order to test a broad spectrum of drugs including anxiolytics, stimulants, barbiturates, alcohol and opiates. The purpose of these studies is to further refine our methods for determining the dependence potential of drugs and as well, to use these methods to determine whether there are certain individuals who possess psychological characteristics which put them at greater risk for excessive drug use.

These studies will investigate the effects of food deprivation on self- administration of commonly-used and abused drugs, and the subjective and physiological effects of these drugs in normal volunteers. The three drugs to be studied are marijuana, alcohol, and tobacco. The subjective and physiological effects of these drugs will be assessed concurrently with changes in drug intake, under conditions in which subjects have and have not restricted their food intake. In two of the studies, subjects in a fed or fasting (24 hour) state will sample marijuana and alcohol (and placebo) and then later choose whether they want to self-administer more of the substance. Subjective and physiological effect will be measured during the sampling period. In the third study, the effects of acute (24 hours) food deprivation on smoking behavior, smoke exposure, and mood states will be examined. In the fourth study, smoking behavior will be examined in overweight smokers enrolled in a 10 week weight-loss program. All four studies will explore whether food deprivation increases drug intake in humans, as it does in laboratory animals. Further, underlying mechanisms for increased drug intake may be examined via the measurement of other drug actions, i.e., their subjective and physiological effects.

Preliminary studies have demonstrated individual differences in metabolic and subjective responses to psychoactive drugs in humans. A strong relationship was found between mood changes induced by ethanol and changes in cerebral metabolism in the temporal and parietal cortices of the brain. The studies proposed here would extend these findings to other abused drugs and to other subject populations. The relationship between the subjective and cognitive effects of drugs and their effects on regional cerebral metabolism of glucose (rCMglu) will be studied in normal volunteers using positron emission tomography (PET) with 18fluoro-2-deoxy-d-glucose (2FDG) as the tracer. Three studies will be conducted. The first and second studies will examine the effects of diazepam and amphetamine on rCMglu and mood. The third study will extend previous findings with ethanol to additional groups: males who are light social drinkers, males who are moderate social drinkers, and females who are light social drinkers. In all studies, subjects will first participate in a behavioral preference procedure, in which individual responses to the mood-altering effects and reinforcing effects of each drug will be measured in a naturalistic situation. Subjects will then participate in the PET sessions, one with placebo and two with different doses of the drug. Mood effects of the drugs will also be monitored during PET sessions. A PET-MRI image correlation and subtraction procedure will be utilized to identify regions of interest on the PET images. Knowledge gained about the correspondence between brain activity and subjective responses to abused drugs may improve our understanding of why certain drugs are abused and why certain individuals are at risk for abusing them.

Marijuana continues to be the most commonly used illicit drug in this country, with an estimated 12 million current users. This project is designed to study the behavioral effects of smoked marijuana and oral delta-9-tetrahydrocannabinol (THC) that are relevant to the abuse of this class of drugs. The subject population will be male and female human volunteers who are experienced cannabis users. The proposed studies utilize within-subject repeated-measures designs and methods which are extensions of those originally developed to study the behavioral effects of drugs of abuse in laboratory animals. Dependent measures common to most of the studies include subjective effects, heart rate and body sway. The aim of one study is to determine the effect of one parameter of smoking topography (depth of inhalation) on the behavioral and physiological response to marijuana. This issue is of clinical relevance because marijuana smoking is associated with pulmonary toxicity, and depth of inhalation could affect the location and extent of deposition of toxic smoke constituents in the respiratory tract. This study will also provide data on the relationship between expired air carbon monoxide, an easily obtained, noninvasive index of smoke absorption, and plasma THC level after marijuana smoking. Another study is designed to assess the duration of behavioral impairment that occurs after marijuana smoking, an issue of clear importance in terms of public safety. Two studies examine the role that classical conditioning plays in determining the subjective and physiological responses that occur when subjects smoke placebo marijuana. The remaining studies, which comprise the bulk of the application, deal with the discriminative stimulus and reinforcing effects of the cannabinoids. There has been considerable public concern about the availability of high-potency marijuana. Two studies examine the role of marijuana THC content (potency) on marijuana self- administration. One assesses subjects' preference for high- versus low-potency marijuana. The other addresses the issue of whether users make compensatory changes in their smoking behavior (titration) when smoking marijuana of different potencies. Two studies investigate the effect of alcohol on marijuana self-administration. These studies should provide valuable insights into the reinforcing effects of this common drug combination. Incorporated into the design of several of the studies are two additional factors which are believed to be important determinants of the behavioral effects of drugs of abuse: extent of previous use of the drug (drug history) and information provided to experimental subjects about the study (instructional set). Overall, the project should provide significant new information on the behavioral and pharmacological determinants of marijuana use.

Acute responses to drugs are known to vary across individuals and across settings, in ways that may be related to their potential for abuse. The proposed studies will investigate several organismic and environmental variables which influence subjective and behavioral responses to acute drug administration in humans. The subjective, physiological and behavioral effects of low, acute doses of drugs will be assessed in normal volunteers under double-blind, placebo-controlled conditions. The first series of studies examines organismic, or subject-related variables and the second series of studies examines environmental variables. The first series of studies will extend our previous findings of individual differences in responses to ethanol and benzodiazepines: One study will examine individual differences in sensitivity to ethanol and triazolam, and a second study will examine the stability of responses to the drugs over a two-month period. Another study will examine the effects of prior exposure to therapeutically-administered benzodiazepines on subsequent acute response these drugs. Another study will examine responses to stimulant and sedative/hypnotic drugs in women at three phases of the menstrual cycle: Despite the practical and theoretical implications of this issue, little is known about variations in drug effects related to levels of circulating ovarian hormones or other cycle-related events. The studies examining environmental determinants of drug responses will focus on the influence of psychosocial context on responses to amphetamine and to ethanol. Specifically, these studies will investigate how the presence or absence of other individuals during the period of acute drug effects alters subjective response to the drugs. The studies proposed in this application will extend previous findings from this laboratory, investigating variables that affect the abuse potential of drugs. In addition, the results may have implications for our understanding of the basic mechanisms underlying the effects of psychoactive drugs.

This descriptive study is designed to characterize the pharmacokinetics of an acute 12-hour administration of 17-beta-estradiol.

The purpose of the proposed study is to determine whether the administration of a dopamine antagonist (pimozide) blocks the subjective, psychomotor, or memory effects of moderate doses of ethanol.

We will investigate interactions between circulating ovarian hormones (progesterone and estrogen) and subjective and behavioral responses to d- amphetamine in normal healthy women. We will administer amphetamine and placebo in the luteal and follicular phases of teh menstrual cycle, and assess measures of mood, physiological responses and psychomotor performance.

This study is designed to investigate the acute subjective and behavioral effects of glucocorticoid administration (25-200 mg, iv.). Ten subjects will participate in 5 laboratory sessions spaced at least 72 hours apart. Subjects will be normal healthy volunteers.

This study is designed to test the hypothesis that centrally-mediated actions of neurosteroids may be greater in post-menopausal women than in women with normal menstrual cycles. We propose to use standardized self- report measures to assess the mood-altering effects of several doses of progesterone in these two groups of women.

This study is designed to investigate interactions between 17-beta- estradiol and subjective, behavioral, and physiological responses to d- amphetamine in normal healthy women.

The purpose of the proposed study is to test the sensitivity of a newly- modified version of a questionnaire to changes in hunger in food-deprived subjects. Subjects will arrive at the CRC after an overnight fast and will then be given a standardized breakfast. For the following 12 hours, at hourly intervals, subjects will complete the questionnaire.

This study is designed to investigate the pharmacological effects of all the combined chemical constituents of the marijuana plant to the effects of the principle psychoactive ingredient, delta-9-THC, alone. The subjective, physiological and behavioral effects of marijuana and delta-9-THC will be compared after administration by the oral route.

We will examine the effects on appetite of a moderate dose of dronabinol (oral delta^9 THC). At the start of each session, subjects will eat a special lunch in the CRC and then will return to our laboratory. One and 1/2 hr after consuming the lunch, subjects will ingest either a dronabinol (7.5 mg) or placebo capsule. Appetite and subjective effects questionnaires will be administered at baseline (immediately prior to drug administration) and at 0.5-hr intervals over the course of a five hour session. At the end of the session, subjects will go to the CRC and be given a sampling tray of foods. Nutrient analysis of foods eaten will be performed.

This study is designed to assess ethanol preference and choice across three hormonally distinct phases of the menstrual cycle in women and between women and men. We expect that women will choose more alcohol during the premenstrual phase than during the midluteal or follicular phases. Men are expected to choose more ethanol than women, and ethanol choice is not expected to vary across any sessions in men.

[unreadable] DESCRIPTION (provided by applicant): Momentary increases in impulsive behavior, including increases in disinhibition or lapses in self-control or attention, may increase drug use and especially relapse to drug use. This project will investigate variables that increase or decrease impulsive behavior, with the goal of eventually relating these to susceptibility to relapse to cigarette smoking. Impulsive behavior will be measured using standardized tasks assessing decision-making (i.e., delay discounting), behavioral inhibition (i.e., Stop Task performance) and attention. In the first series of studies we will investigate variables that acutely increase impulsive behavior, including acute stress, sleep deprivation, administration of alcohol, and, in cigarette smokers, nicotine deprivation. In the second series of studies we will investigate factors that decrease impulsive behavior, including acute administration of the stimulant drugs amphetamine and bupropion. In the third series of studies we will determine whether stimulant drugs prevent the acute increases in impulsive behavior induced by environmental events. Finally, we propose to develop a laboratory model of smoking relapse to study the role of impulsivity in relapse. In this model, we plan to test whether, and to what extent, variables that affect impulsive behavior affect susceptibility to relapse. Throughout all of these studies, we will continue our investigation of the subtypes of impulsive behavior and other cognitive processes. We will investigate the relationships between impairments in decision-making, inhibition and attention, and begin to investigate their role in relapse. Understanding the underlying factor structure of impulsive behavior is important from both basic science and clinical perspectives. In combination with parallel studies being conducted with non-humans, these projects will improve our knowledge of the neurobiology of impulsive behavior. Clinically, the projects may lead to novel strategies for preventing and treating substance abuse. [unreadable] [unreadable]

DESCRIPTION: (Applicant's Abstract) The long-term objective of the proposed research is to provide information about the neurobiological basis of the euphoric effects of abused drugs in humans. It is generally believed that the discriminative stimulus and subjective effects associated with abuse liability of stimulants in humans correspond to the discriminative stimulus and reinforcing effects of these drugs in laboratory animals. Nevertheless, there are several inconsistencies in the effects of stimulants that suggest that the neuropharmacology underlying subjective and behavioral effects is not the same in laboratory animals and humans. For example, despite the well-documented effects of selective dopamine (DA) antagonists on the discriminative stimulus and reinforcing effects of stimulants in laboratory animals, no studies have shown convincingly that these antagonists alter the subjective effects of stimulants in humans. This suggests that the effects of stimulants on other transmitter systems, such as the serotonin (5-HT) system, may, in part, modulate the subjective effects of stimulants in humans. Indeed, there is preliminary evidence that 5-HT antagonists can attenuate some of the subjective effects of stimulants. The aim of the proposed project is to examine the contribution of the DA and 5-HT systems to the acute subjective effects of methamphetamine, a psychostimulant that is increasingly popular among drug abusers. Like cocaine and d-amphetamine, methamphetamine has effects on both DA and 5-HT systems. As an initial step towards examining the role of 5-HT in the effects of psychostimulants, the proposed studies will compare the acute effects of three antagonists, with a range of relative selectivity for DA and 5-HT receptors, on the subjective effects of methamphetamine in healthy human volunteers. The three antagonists will be haloperidol, risperidone, and mirtazapine. The primary dependent measures will be self-reported ratings of mood and subjective state (e.g. ratings of drug liking and euphoria). Objective measures of drug effects (physiological, motor, and psychomotor) will also be obtained. It is hypothesized that the combined effects of these antagonists on DA and 5-HT systems will result in an attenuation of the subjective effects of methamphetamine.

DESCRIPTION (provided by applicant): We propose to investigate the involvement of nicotinic acetylcholine receptors (NAChR) in i) the consumption of alcohol, and ii) the subjective responses to alcohol in human social drinkers. Prior research has indicated an unequivocal relationship between nicotine and alcohol consumption with the use of one increasing the likelihood that the other will be consumed as well. Experimental studies in animals have repeatedly shown that alcohol consumption increases when a nicotine pretreatment is administered and recently a corresponding effect has been found in human social drinkers. It has been hypothesized that nicotine may alter the subjective responses to alcohol and that the stimulant-like effects and euphorigenic properties of alcohol may be mediated through action at NAChRs. The proposed studies will examine this relationship between the stimulant-like effects and consumption of alcohol and nicotinic acetylcholine function through two different approaches: nicotine administration and receptor blockade. Mecamylamine, a non-competitive, nicotinic receptor antagonist that readily passes the blood-brain barrier, will be administered in two studies to assess the effect of NAChR blockade on the subjective effects of alcohol and its consumption. We will investigate the efficacy of mecamylamine in attenuating the stimulant-like and euphorigenic properties of alcohol as well as its voluntary consumption. The third study proposed will administer nicotine through transdermal patches and assess its impact on the effects and consumption of alcohol. The proposed studies can be a significant and important first step in elucidating the interaction between two of the most commonly used drugs in this country. In addition to providing informative data on possible mechanisms mediating the reinforcing effects of alcohol, these studies can also serve as a first step to determining the efficacy of nicotinic antagonists as a treatment for alcohol abuse or dependence.

genetics

smoking; pharmacokinetics; cannabinoids; Cannabis; substance abuse related disorder; carbon dioxide; heart rate; clinical research; breath tests; blood tests; human subject;

[unreadable] DESCRIPTION (provided by applicant): Relapse remains the most persistent and significant problem in drug abuse treatment. As many as 90% of smokers who attempt to quit eventually relapse, and smokers remain at high risk for relapse well after their acute withdrawal symptoms have subsided. Although relapse most commonly occurs soon after abstinence, recent studies with animals indicate that drug-seeking responses to conditioned stimuli gradually increase in magnitude for as long as 6 months of abstinence, a phenomenon known as "incubation". While cue reactivity is closely linked to operant drug-seeking responses in the animal laboratory, the relationship between cue reactivity and drug-taking in humans has not been firmly established. We propose to investigate whether this incubation phenomenon occurs in human cigarette smokers by studying their reactivity to smoking cues and time to relapse to smoking after varying periods of abstinence and whether changes is cue reactivity are associated with changes in time to relapse. The project will be conducted at the University of Chicago, in parallel with a similar project at the National Institute on Drug Abuse Intramural Research Program in Baltimore. The goals of the study are: 1. To assess "incubation" of smoking-cue reactivity after increasing durations of abstinence in cigarette smokers. We will investigate the reactivity to smoking cues among abstinent cigarette smokers, as a function of duration of abstinence after 7, 14, and 35 days of abstinence. Based on the studies with laboratory animals, it is hypothesized that cue reactivity will be greater after longer periods of abstinence. 2. To assess "incubation" of the tendency to resume smoking after increasing durations of abstinence. After 7, 14 or 35 days of abstinence maintained with monetary incentives, subjects will be allowed to return to smoking, with gradually decreasing monetary incentives for maintaining abstinence. We tentatively hypothesize that the latency to smoking will decrease, and the likelihood of returning to smoking will increase, after longer periods of abstinence. This is a translational project that applies novel findings in laboratory animals to a clinical setting. The study uses an innovative procedure to investigate a phenomenon that has not yet been characterized in humans, but which may have clinical relevance for drug users attempting to abstain. The project is the result of a unique collaboration among basic and clinical scientists at the University of Chicago and the NIDA Intramural Research Program. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Ecstasy is a widely used drug that reportedly has unique effects, distinct from other stimulants;most notably it is said to increase feelings of empathy and closeness to others. These so-called 'empathogenic'effects on social and emotional processing appear to contribute to the widespread recreational use of the drug, as well as its purported utility as an aid in psychotherapy. The main psychoactive constituent of ecstasy is 13,4- methylenedioxymethamphetamine (MDMA), which acts on serotonin and dopamine, two neurotransmitter systems integrally involved in modulation of affect and reward. In this project, we propose to investigate dimensions of social and emotional processing that may contribute to the putative 'empathogenic'effects of MDMA. We will study the effects of MDMA (0, 1.0 and 1.5mg/kg) on emotional recognition and emotional responsivity, both central aspects of social and emotional processing, and on sociability. On measures of emotional recognition, we hypothesize that MDMA will reduce recognition of negative or threatening emotions, such as fear, anger and sadness. Conversely, we expect MDMA to enhance emotional responsivity to positive material. On aspects of sociability, we hypothesize that the drug will enhance perception of social targets as friendly and attractive, and increase the motivation to engage in a social activity. We will also conduct exploratory investigations to identify sources of individual differences in subjective and physiological response to MDMA, including differences associated with gender and selected genotypes. In a single, double-blind, placebo controlled study, healthy volunteers (N=100) with a history of ecstasy use will be tested with MDMA and two active control drugs, methamphetamine (MA;20mg) and oxytocin (OT, 20 IU). MA shares many psychostimulant properties with MDMA but does not appear to exert 'empathogenic'effects, whereas OT appears to produce certain pro-social effects that resemble those attributed to MDMA. The proposed study is highly innovative because it applies state-of-art techniques from social neuroscience to investigating processes involved in the rewarding effects of drugs (see McGregor et al., 2008;Schnur and Shurtleff, 2008). This project will potentially broaden our perspective on how drugs interact with the social and emotional context in which they are used, and how these interactions influence vulnerability to repeated or compulsive use of these drugs. PUBLIC HEALTH RELEVANCE: Ecstasy is a widely abused drug that appears to have unique psychological effects including feelings of empathy and closeness to others. This study will assess the effects of MDMA, the active drug in ecstasy, on both behavioral and subjective measures of emotional processing and sociability in humans. The study has implications for basic science to identify the brain circuits involved in social and emotional processing. It has public health implications by helping researchers understand why people use ecstasy, and some clinicians have suggested that MDMA might facilitate emotional processing during psychotherapy.

DESCRIPTION (provided by applicant): This project will examine the underlying factor structure of impulsive behaviors, and investigate the genetic basis of impulsive behaviors in healthy human volunteers. Impulsive behaviors are strongly implicated in risk for drug abuse, and are thought to be determined in part by genetic factors. Here, the investigators will examine the two main components of impulsive behavior: Impulsive Choice (maladaptive decision-making) and Impulsive Action (i.e., behavioral inhibition) using standardized behavioral tasks. They will empirically derive constructs based on subjects' performance on the tasks, and then examine polymorphisms in genes thought to contribute to variations in the constructs. The investigators will focus on genes that affect function of the dopamine system. The project addresses an urgent need to define behaviorally the underlying components of impulsivity, and to identify genetic factors that influence variability. The findings will help us understand impulsive behaviors, which are key risk factors, or intermediate phenotypes, for drug use. First, we will phenotype healthy unrelated young adults (N=1,000) on carefully selected behavioral measures of Impulsive Choice and Impulsive Action, and identify the factors comprising these heterogeneous behaviors. Participants will be tested twice for maximum reliability, and we will use factor analysis to identify the underlying latent factors. Second, we will examine associations between the derived factors and genetic variation in dopamine and other selected genotypes, in three levels of analysis. Using a candidate gene approach, we will focus on polymorphisms in selected genes related specifically to dopamine function. We hypothesize that genotypes resulting in low dopamine function will be associated with higher impulsive behaviors. Using a pathway-based approach, we will investigate polymorphisms in a larger set of genes of interest based on the published literature. Finally, using a hypothesis-free approach, we will examine ~1 million polymorphisms that will survey all the genes in the genome. Thus, we will include both hypothesis testing and exploratory approaches to comprehensively examine the genetic basis of impulsivity. The project is significant because it will advance understanding of impulsive behavior and its genetic underpinnings, which has direct relevance to risk for substance abuse. The study is innovative because it combines rigorous behavioral analysis with multi-level genetic analysis.

DESCRIPTION (provided by applicant): Recent theories of drug abuse suggest that addiction involves aberrant memory processing. In nonhumans, stimulant drugs facilitate both encoding and retrieval processes, either of which could influence future drug-seeking behavior. In humans, subjective states of arousal or mood are known to bias emotional memory, raising the possibility that drugs producing these states may also bias memory and thereby influence drug-taking. The effects of drugs of abuse on memory have not been carefully studied in humans. In this exploratory study we propose to examine the effects of d-amphetamine (AMP) on encoding and retrieval processes, with a focus on emotional memory. We will address three main questions: 1) does AMP administered at the time of encoding facilitate subsequent retrieval assessed in a drug free state? 2) does AMP administered at the time of retrieval improve memory for stimuli previously encoded in a drug-free state? 3) is retrieval enhanced if the individual is in the same state (AMP or placebo) during both encoding and retrieval, compared to receiving AMP during either encoding or retrieval? The study will use a four-session within-subject design in healthy young adults (N=60). Each session consists of two phases, an encoding phase, followed 48 hours later by a retrieval phase. Subjects will receive capsules containing AMP (20 mg) or placebo before encoding or retrieval in all four combinations. During the encoding phases subjects will view or study standardized stimuli with emotionally positive, negative and neutral content, and their memory for the stimuli will be assessed 48 hours later during the retrieval phase. Based on findings with laboratory animals, we hypothesize that AMP administered during either encoding or retrieval will facilitate memory for stimuli with emotional content. Based on human studies of arousal and mood-congruence, we further hypothesize that memory facilitation may be related either to the drug's potential to increase either arousal or positive mood states. Finally, based on evidence for state-dependent learning, we hypothesize that memory will be maximized when encoding and retrieval take place in the same (drug or no-drug) state. The memory processes studied here have important consequence for drug-seeking. Drug-seeking behavior is strongly influenced by memory of previous events, and drug- induced biases during either encoding or retrieval could profoundly influence future drug use. This project will form the basis for future investigations of the effects of memory biases on drug-seeking behavior.

DESCRIPTION (provided by applicant): This project is designed to investigate the effects of drugs of abuse on affective responses to stimuli with positive or negative emotional valence. The studies explore the hypothesis that drugs modulate responses to affective stimuli, and that these effects, in turn, influence the drugs' subjective or reinforcing effects. We will study bidirectional interactions between acute effects of stimulants, alcohol and cannabinoids on affective responses. The studies focus in particular on affective responses to stimuli with social content, to investigate the idea that drugs influence the perception and valence of social stimuli. We will assess the effects of drugs on responses to positive or negative visual images, including images with social or nonsocial content. In addition, we will investigate drug the effects of drugs in real-life positive or negative social situations. In all studies we will compare these emotional responses in men and women. This innovative approach bridges the area of neuropsychopharmacology with affective neuroscience, and if successful, will extend our understanding of the processes that lead to compulsive drug-seeking behavior.

DESCRIPTION (provided by applicant): This project will examine the acquisition of conditioned drug-related responses in healthy adults. Conditioned drug cues are believe to play an important role in drug use, especially in relapse when they illicit drug-seeking behavior. Although numerous studies have demonstrated acquisition of conditioned drug cues in animal models, few studies have examined acquisition and expression of these responses in humans. To understand how conditioned stimuli acquire their powerful motivational force, we need to understand how they are acquired, how the conditioned responses are manifested (e.g., behavioral, physiological, neural), and how they persist. The knowledge gained will provide a translational link between the rich animal literature and the human clinical situation, and eventually allow us to target the learned responses as targets for addiction treatment. We have developed a novel procedure to study acquisition of Pavlovian conditioned responses in humans, showing that visual and auditory stimuli paired with a moderate dose of methamphetamine acquire positive incentive properties. Here, we propose to refine the procedure. We will measure the responses using sensitive measures of behavior, physiology, and brain activity using fMRI. We will determine the optimal parameters of conditioning, test the persistence and extinction of the conditioned response, and test the effects of the stimulus on emotional responses and neural activity using fMRI. Together, these studies will improve our understanding of how conditioning contributes to drug use, and provide a strong method and empirical basis to study conditioning with other drugs, the effects of potential treatment medications, and individual differences in cue reactivity.

DESCRIPTION (provided by applicant): Poor inhibitory control is a known risk factor for drug abuse. Individuals with poor inhibitory control may be at risk because they have difficulty refraining from actions (e.g., drug use) despite known adverse consequences. However, recent evidence suggests that these individuals may also be at risk for another reason: that they experience more positive subjective, or euphorigenic, effects from drugs. The long-term goal is to identify the mechanisms underlying risk for drug abuse in individuals with poor inhibitory control, and ultimately to develop therapeutic agents to reduce this risk. The objective here is to investigate associations between impulsive action (i.e., poor inhibitory control) and subjective and behavioral measures of the rewarding effects of methamphetamine and alcohol in healthy young adults. The central hypothesis is that individuals high in impulsive action will be more sensitive to the rewarding effects of both of these drugs. The rationale for this proposal is that behavioral evidence linking poor inhibitory control and drug reward sensitivity will lay the foundation for investigations of common neurobiological mechanisms underlying both risk factors. Such neurobiological mechanisms would serve as potential targets for therapeutic agents aimed at reducing risk for drug abuse in individuals with poor inhibitory control. The central hypothesis will be tested by addressing two specific aims: 1) examine the degree to which impulsive action in humans predicts stimulant drug reward and 2) examine the degree to which impulsive action predicts alcohol reward. For both aims, participants will be pre-selected as exhibiting low or high impulsive action, and then we will compare these groups' responses to the rewarding effects of the two drugs. Impulsive action, defined as difficulty controlling or inhibiting behavior, will be measured using the stop signal task, a well-validated measure of behavioral control. Under the first aim, the rewarding effects of methamphetamine (20 mg) will be compared in high and low impulsive individuals, using both subjective self-report measures of euphoria and arousal, and behavioral measures of drug choice. Under the second aim, a similar approach will be taken in separate groups of subjects, to examine the rewarding effects of alcohol (0.8 g/kg) in relation to baseline impulsive action. Based on preliminary findings with the prototypic stimulant d-amphetamine, it is hypothesized that individuals high in impulsive action will report significantly greater euphoria and arousal than those low in impulsive action following both methamphetamine and alcohol. Based on findings from animal studies, it is hypothesized that high impulsive individuals will also exhibit greater choice for both methamphetamine and alcohol over placebo. This approach is innovative because it examines a novel association between two risk factors for drug abuse, that have until now been studied separately. This contribution is significant because it is the first step to developing targeted therapy, both pharmacological and behavioral, to prevent and treat drug abuse in individuals with poor inhibitory control.

PROJECT SUMMARY/ABSTRACT The Integrative Training in the Neurobiology of Addictive Behaviors Program at The University of Chicago offers training for both pre- and postdoctoral trainees in drug abuse-related research. We have an outstanding panel of core faculty trainers, who are productive researchers, with successful training credentials of both pre- and postdoctoral trainees. Their expertise and therefore their training areas, range from molecular biology, electrophysiology, pharmacology and animal models of drug addiction, to the social, behavioral and psychopharmacological aspects of human drug use, including etiology, treatment and drug policy. Our goal is to prepare the next generation of scientists to investigate the etiology, prevention and treatment of drug abuse with integrative approaches. We propose a program for 3 predoctoral and 4 postdoctoral trainees. Trainees will be supported by the Training Program for 1-3 years. Trainees obtain specialized intensive training in their `home' laboratories, but they are also exposed to the full breadth of addictions research outside their own area, from molecular to policy. In addition to their doctoral program requirements, predoctoral trainees will participate in a bi-weekly training grant seminar and a didactic course providing a broad overview of addiction (history, epidemiology, pharmacology, treatment and policy). Trainees will also participate in 20-hour rotation experiences in laboratories conducting addictions research distinct from their own expertise. The organizational structure will include an Executive Committee making overall training decisions, a Selection Subcommittee to ensure a good flow and balance of trainees, a Program and Review Subcommittee to monitor trainees' progress through the program, and an External Advisory Committee to provide expert outside consultation. The University of Chicago provides a unique environment with both a long history of interdisciplinary collaboration and recently a significant commitment to neuroscience research. This provides a rich intellectual context for trainees in drug abuse related research. To ensure that there is substantial interaction among the trainees, and between trainees and trainers, we will schedule bi-weekly meetings consisting of journal club presentations, seminars by invited speakers, and didactic classes. We will devote resources to recruiting underrepresented minorities and we will provide comprehensive training in ethical conduct of research.

DESCRIPTION (provided by applicant): 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.