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.

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.

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

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

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.

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

[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): 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): 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): 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.

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.