Warren K. Bickel - US grants

methadone; alcoholism /alcohol abuse therapy; human subject;

Many drugs of abuse are known to disrupt learning and performance. Little is known, however, about the behavioral mechanisms that are affected when learning is disrupted. The focus of the present application is study the effects of drugs on human learning and performance by employing the repeated acquisition of behavioral chains procedure. This procedure has been productively employed in the animal laboratory but has been infrequently examined in humans. The procedure provides a method by which learning can be repeatedly studied in the same subject. Not only will this project obtain a profile of a variety of drugs on this procedure in humans but also later studies will try to identify the behavioral mechanisms (either stimulus control or reinforcement) which are affected by drugs. By identifying the behavioral mechanisms which are affected by drugs we increase our ability to generalize to other behavior similarly controlled. This project will also collect traditional clinical pharmacology measures of self-report as well as the effects of drug on physiology. By collecting these various types of measures, comparisons across them can be made. The studies will employ cumulative dosing procedure which will increase the efficiency of the study but also obtain dosing patterns that more closely approximates typical drug self-administration. The subjects will be tested again the day after cumulative dosing which will permit the assessment of residual drug effects ('hangover').

This is a revision of a competing renewal application which was approved but not funded. In this revision we have made every effort to respond to the critiques of the prior review. Behavioral economics, the application of microeconomic principles to the study of behavior, has value for the field of drug dependence. The value stems from (1) its ability to integrate the effects of independent variables into a singular term, referred to as unit price, and (2) its ability to specify conditions under which choice of a drug vs. a non-drug reinforcer varies from being probable to improbable. The former suggests the parsimony of this approach; the latter suggests its utility in accounting for the selection of drug vs. other reinforcers. The purpose of this proposal is two-fold. The first purpose is to continue our basic research on unit price. We will examine whether several important operations that have yet to be incorporated into unit price (e.g., punishment, reinforcer delay, & probability of reinforcement) can be parsimoniously integrated. These experiments will demonstrate the generality and define the limitations of unit-price. The second purpose is to examine the utility of behavioral economics in the evaluation of medications for the treatment of drug dependence. We will examine the effect of agonist and antagonist treatment on the economic measure of elasticity (the responsiveness of drug consumption to unit price). This new measure, elasticity, may provide an index of whether a medication renders drug use more sensitive to cost factors in the environment. Further, we will examine whether the behavioral- economic determinants of drug choice can assist in assessing the effectiveness of medications under different environmental conditions and whether those determinants can be used to develop a laboratory analog of conditions that promote patient entry into treatment. These experiments will put what we have learned about behavioral economics into the service of assessing medications for the treatment of drug dependence. Moreover, the behavioral-economic determinants of drug choice will allow us to assess and characterize medications under conditions that may more closely approximate clinical conditions than do current assessment models. Finally, developing an assay to assess factors that determine entry into treatment may be useful for any form of treatment. Overall, the continued assessment of the basic factors related to the behavioral economics of drug self-administration and the application of those factors to address medication development provide an important opportunity to explore and utilize this new approach.

The application of drug discrimination (DD) procedures to human subjects has been successful with stimulant and opioid drugs. These discriminations are orderly, pharmacologically specific, and are consistent with findings from non-human studies. Additionally, these studies typically show concordance between DD measures and self-reports of drug effect. Despite their widespread use and abuse, benzodiazepines (BZD) and other sedative hypnotics have yet to be investigated in the human DD paradigm. This project will develop a behavioral DD paradigm for laboratory use with humans and will use this paradigm to comparatively evaluate the discriminative stimulus characteristics of BZD and other sedative hypnotics. Ultimately, the usefulness of this paradigm will be determined by its pharmacologic specificity; that is, a highly specific discrimination will permit careful characterizations of the similarities and differences between BZD and other sedative-hypnotic compounds, while a drug-specific or a non-specific discrimination would have limited usefulness in this regard. In this project, the specificity of the discrimination will be determined by employing progressively more stringent tests across six studies. Study 1 will first develop the procedure and, if necessary, manipulate dose, drug, instructions and the number of training sessions to establish a discrimination between triazolam and placebo. This study will then test whether d-amphetamine is labeled as triazolam or placebo and, thus, establish whether the trained discrimination is more specific than a drug vs. no-drug discrimination. Studies 2-4 will test whether amitriptyline, buspirone, hydromorphone, pentazocine, phenobarbital and secobarbital will be labeled as triazolam or placebo and, thus, establish whether the discrimination is more specific than a sedative vs. nonsedative discrimination. Studies 5-6 will test whether chlordiazepoxide, clonazepam, diazepam, and lorazepam will be labeled as triazolam and, thus, establish whether the discrimination is drug specific. Overall, this project will thoroughly characterize the specificity of the trained discrimination and determine its utility for the study of BZD pharmacology. Additionally, the concordance between, DD and self-reports measures will be examined and, thus, test the widely held assumption that these measures are comparable. The development of a human DD procedure for studying BZD will provide an empirical tool to 1) examine the interoceptive stimulus effects of BZD and how these effects vary across different drugs, doses, populations and situations, 2) understand the neuropharmacology of BZD effects in humans, and 3) screen new anxiolytic, hypnotic, and anticonvulsant drugs for abuse liability.

Opioid dependence is an enduring public health problem and the severity of that problem has escalated dramatically because of its association with IV drug use and AIDS. Although opioid dependence is frequently acknowledged as a problem of urban areas, what has been less frequently acknowledged is that opiold dependence occurs in, and is a public health problem for, rural areas. Such a lack of recognition has often led to a paucity of treatment alternatives for the opiold dependent individual in these rural areas. In this application, we propose to establish the first outpatient detoxification clinic to provide pharmacotherapies for opioid dependence in the State of Vermont. Approximately 20 patients per year will participate in clinical pharmacology studies to examine a promising new opiold treatment agent - buprenorphine. Although buprenorphine has several advantages over existing pharmacotherapies, considerably more needs to be known about its clinical pharmacology so that it can be used with the greatest efficacy and efficiency. The focus of our investigations will be to answer questions about buprenorphine's clinical pharmacology that will directly impact the manner in which buprenorphine will be used in treatment settings. Specifically, in a series of 10 clinical pharmacology studies, we will answer the following three questions: (1) what are the range of conditions under which methadone-maintained patients can be transferred to buprenorphine without precipitating withdrawal? (2) What is the duration of buprenorphine's blockade of the effects of morphine-like opioids? (3) What is the feasibility of a buprenorphine/naltrexone combination product? These studies will occur in the first few months of a six month detoxification program. Moreover, given that opiold-dependent individuals must be detoxified from buprenorphine treatment, we will maximize the resources of this proposed project by randomly assigning subjects to different double-blind buprenorphine detoxification schedules. This study will provide information about the most efficacious way to detoxify individuals on from buprenorphine. If NIDA were to Identify some other promising new agent, we would integrate and examine the clinical pharmacology of that new compound as well. The adjunct psycho-social therapy will be one that we have developed from an existing NIDA grant and that our data suggests will have positive clinical impact. This project will provide information about the clinical pharmacology of buprenorphine which should enhance the treatment of opioid dependence and will establish the first outpatient pharmacotherapy for opiold dependence in the State of Vermont.

Opioid dependence is an enduring public health problem and the severity of that problem has escalated dramatically because of its association with IV drug use and AIDS. Although opioid dependence is frequently acknowledged as a problem of urban areas, what has been less frequently acknowledged is that opiold dependence occurs in, and is a public health problem for, rural areas. Such a lack of recognition has often led to a paucity of treatment alternatives for the opiold dependent individual in these rural areas. In this application, we propose to establish the first outpatient detoxification clinic to provide pharmacotherapies for opioid dependence in the State of Vermont. Approximately 20 patients per year will participate in clinical pharmacology studies to examine a promising new opiold treatment agent - buprenorphine. Although buprenorphine has several advantages over existing pharmacotherapies, considerably more needs to be known about its clinical pharmacology so that it can be used with the greatest efficacy and efficiency. The focus of our investigations will be to answer questions about buprenorphine's clinical pharmacology that will directly impact the manner in which buprenorphine will be used in treatment settings. Specifically, in a series of 10 clinical pharmacology studies, we will answer the following three questions: (1) what are the range of conditions under which methadone-maintained patients can be transferred to buprenorphine without precipitating withdrawal? (2) What is the duration of buprenorphine's blockade of the effects of morphine-like opioids? (3) What is the feasibility of a buprenorphine/naltrexone combination product? These studies will occur in the first few months of a six month detoxification program. Moreover, given that opiold-dependent individuals must be detoxified from buprenorphine treatment, we will maximize the resources of this proposed project by randomly assigning subjects to different double-blind buprenorphine detoxification schedules. This study will provide information about the most efficacious way to detoxify individuals on from buprenorphine. If NIDA were to Identify some other promising new agent, we would integrate and examine the clinical pharmacology of that new compound as well. The adjunct psycho-social therapy will be one that we have developed from an existing NIDA grant and that our data suggests will have positive clinical impact. This project will provide information about the clinical pharmacology of buprenorphine which should enhance the treatment of opioid dependence and will establish the first outpatient pharmacotherapy for opiold dependence in the State of Vermont.

APPLICANT'S ABSTRACT: Opioid dependence is an enduring public health problem and the extent of that problem has escalated because of its association with IV drug use and AIDS. Although widely accepted as a problem of urban areas, opioid dependence in rural areas has been less frequently recognized. This is unfortunate because opioid dependence occurs in, and is a public health problem for, rural areas. Moreover, this lack of recognition has often led to limited treatment alternatives for the rural opioid addict. In this application, we propose to continue the first and only outpatient detoxification clinic to provide pharmacotherapies for opioid dependence in the State of Vermont. Approximately 84 patients per year will participate in clinical pharmacology studies and/or a detoxification study examining buprenorphine, a promising new pharmacotherapy for opioid dependence. These studies will address aspects of buprenorphine's unique clinical pharmacology that will directly impact the manner in which buprenorphine is provided to patients. Specifically, we propose to answer six questions across three series of studies. In the first series, we will continue our research on alternative dosing schedules which has demonstrated that subjects can safely receive buprenorphine every other day or every three days by doubling or tripling the buprenorphine dose, respectively. These dosing schedules will eliminate the need for take- home medication for patients requiring days off from the clinic. In continuing this research, we will answer three questions. First, can buprenorphine be administered safely and effectively every four days? Second, what is the duration of buprenorphine's blockade of the effects of morphine-like opioids during 2-day, 3-day and 4-day dosing schedules? And third, do every 3-day and every 4-day dosing schedules function as reinforcers for opioid-dependent outpatients? In the second series, we will characterize the interaction between buprenorphine and opioid antagonists, to determine whether buprenorphine can facilitate the transition to, and be combined with, opioid antagonists. Specifically we will answer two questions. First, what are the range of conditions under which buprenorphine can be co-administered with naloxone or naltrexone without compromising agonist activity or precipitating withdrawal? And second, can buprenorphine and naltrexone be chronically co- administered without adverse effects? In the third series, we will conduct a detoxification study using daily and 3-day dosing schedules to address the extent to which the buprenorphine dosing schedule influences opioid abstinence and treatment retention during detoxification with buprenorphine. We plan to conduct a minimum of 9 clinical pharmacology studies and 1 detoxification study (for a total of 10 studies) in the five-year period. Overall, this research will provide critical knowledge about buprenorphine's clinical pharmacology that will permit buprenorphine to be used with the greatest efficacy and efficiency in clinical settings. Moreover, this project will positively contribute to the public health status of this region by providing the only outpatient pharmacotherapy services for opioid dependence in the State of Vermont.

Buprenorphine (BUP) dose-dependently blocks the behavioral effects of hydromorphone (HYD) for periods up to 24 hours. The present double-blind study examined the duration of this blockade for up to 96 hours across a 24, 48, and 72 hour BUP dosing schedule (BDS). 8 male, opiod dependent outpatients abstinent from illicit opiods and maintained on either 4 or 8 mg/70kg, s.1. BUP (n=4 group) were exposed to each dosing schedule in a mixed sequence and participated in 10 laboratory sessions. During the 24 , 48, and 72 hour BDS subjects received their maintenance dose, 2x their maintenance dose, 3x their maintenance dose every 24, 48, 72 hours respectively. Under the 24, 48, and 72 hour BDS, subjects received placebo on the interposed days. In laboratory sessions, subjects received sequential s.c. injections of saline, 6 and 12/70Kg HYD at 90 minute intervals using a cumulative dosing procedure. As a positive control for HYD effects without BUP blockade, one of these sessions occurred following a three day exposure to 2mg/79Kg of BUP; placebo BUP was not used for ethical reasons. A blood sample was drawn before and physiology and behavior assessed throughout each session. As expected, HYD produced the greatest effects under the 2 mg BUP condition. In the 8 mg group, BUP blocked HYDs effects on observer and subject rated measures of opioid agonist effects in a dose related manner for up to 48 hours under the 24, 48, 72 hour BDS. BUP blockade of the cumulative 18 mg HYD challenge dissipated by 72 hours. These effects were not replicated in the 4 mg subject group and may reflect differences in BUP metabolism as suggested by plasma BUP levels. BUP did not block physiological responses to HYD in either the 4 or 8 mg group. Overall the data suggest that the 24, 48 hour BDS maintain effective blockade of exogeneous opioids for up to 48 hours in patients maintained on an 8 mg sublingual BUP dose. However since blockade may be compromised during the 72 hour BDS, the 72 hour schedule may not be restricted to patients with appreciable periods of abstinence from street opioids. During 12/1/95-11/30/96 follow up blood samples were drawn from 6 subjects and the study is now complete.

human therapy evaluation; opioid receptor; drug abuse chemotherapy; pharmacology; buprenorphine; naltrexone; naloxone; psychopharmacology; drug withdrawal; drug administration rate /duration; combination chemotherapy; pharmacokinetics; clinical research; injection /infusion; placebos; human subject;

This is a revision of a competing renewal application which was approved but not funded. In this revision we have made every effort to respond to the critiques of the prior review. Behavioral economics, the application of microeconomic principles to the study of behavior, has value for the field of drug dependence. The value stems from (1) its ability to integrate the effects of independent variables into a singular term, referred to as unit price, and (2) its ability to specify conditions under which choice of a drug vs. a non-drug reinforcer varies from being probable to improbable. The former suggests the parsimony of this approach; the latter suggests its utility in accounting for the selection of drug vs. other reinforcers. The purpose of this proposal is two-fold. The first purpose is to continue our basic research on unit price. We will examine whether several important operations that have yet to be incorporated into unit price (e.g., punishment, reinforcer delay, & probability of reinforcement) can be parsimoniously integrated. These experiments will demonstrate the generality and define the limitations of unit-price. The second purpose is to examine the utility of behavioral economics in the evaluation of medications for the treatment of drug dependence. We will examine the effect of agonist and antagonist treatment on the economic measure of elasticity (the responsiveness of drug consumption to unit price). This new measure, elasticity, may provide an index of whether a medication renders drug use more sensitive to cost factors in the environment. Further, we will examine whether the behavioral- economic determinants of drug choice can assist in assessing the effectiveness of medications under different environmental conditions and whether those determinants can be used to develop a laboratory analog of conditions that promote patient entry into treatment. These experiments will put what we have learned about behavioral economics into the service of assessing medications for the treatment of drug dependence. Moreover, the behavioral-economic determinants of drug choice will allow us to assess and characterize medications under conditions that may more closely approximate clinical conditions than do current assessment models. Finally, developing an assay to assess factors that determine entry into treatment may be useful for any form of treatment. Overall, the continued assessment of the basic factors related to the behavioral economics of drug self-administration and the application of those factors to address medication development provide an important opportunity to explore and utilize this new approach.

This study is a continuation of our assessment of the discriminative stimulus effects of flumazenil, a benzodiazepine receptor antagonist. That study demonstrated that flumazenil (0.56 mg/70 kg) is readily discriminated from saline. In addition, substitution tests with various doses of flumazenil (0, 0.10, 0.32 and 1.0 mg/70 kg) demonstrated dose- dependent increases on several self-report measures sensitive to sedative- like effects (e.g., PCAG subscale of the ARCI, sedative rating on the adjective rating scale) in the 6 subjects who completed the study. This study is being conducted in order to determine whether the observed agonist effects of flumazenil are benzodiazepine-like by training a flumazenil (0.56 mg/70 kg) versus saline discrimination and then conducting substitution tests with three test doses of midazolam (1.0, 1.8, and 3.2 mg/70 kg). The substitution tests are being conducted under a novel-response drug discrimination procedure, which offers subjects a response alternative appropriate for effects unlike flumazenil or saline. Self-reported effects of flumazenil and midazolam are also being compared. In addition, we are testing one dose of caffeine (75 mg/70 kg) as a negative control. Three subjects have completed this study. Thus far, results indicate that flumazenil and midazolam have similar, but not identical, discriminative stimulus effects in humans.

Understanding drug dependence may require the scientific investigation of the impulsive and loss of control behavior typically exhibited by the drug-dependent. Impulsivity has been defined as the selection of a smaller more immediate reward over a larger more delayed reward. Loss of control refers to a preference for the self-controlled decision or choice, that at a later time reverses in favor of the impulsive choice. One approach to understanding both impulsivity and loss of control is by examining how delayed rewards are discounted. The discounting of delayed rewards, however, has only been rarely studied in drug-dependent individuals. In this new application, we will systematically explore the delay discounting of a variety of potential outcomes in the drug dependent and the factors that may modulate the discounting process including the discounting of health outcomes that result from AIDS-risk behavior. Two series of studies are proposed. Series One will consist of five experiments. In these experiments, we will assess delay discounting in opioid-dependent (Experiment 1), cocaine-dependent (Experiment 2), marijuana dependent (Experiment 3), alcohol-dependent (Experiment 4), and nicotine-dependent (Experiment 5) participants vs normal controls matched on age, sex, IQ, education, smoking status (for Exp 1-4), martial status, and SES. In each of these studies, we will examine the delay discounting (including sign effect and preference reversals) of (1) money, (2) primary drug of dependence, and (3) health outcomes that result from risky sexual behavior. Series Two, which is composed of four experiments, employs conditions that may modulate delay discounting. Experiment 6 and 7 will examine the effects of drug withdrawal on the delay discounting behavior of opioid- and nicotine-dependent individuals. Experiment 8 will examine the effects of alcohol administration on delay discounting in nicotine-dependent individuals. Moreover, we will use other measures of impulsivity in each study and examine the correlation of these measures with delay discounting. Collectively, these proposed measures will provide a comprehensive assessment of impulsivity in the drug- dependent. Also, we will assess AIDS-risk behavior and craving to determine whether those that engage in risky behavior, or report the drug cravings also drastically discount the future. These studies will provide systematic information about the paradoxical behavior (loss of control and impulsivity) evident in the drug-dependent, permit comparisons of these behaviors across types of drug dependence, and provide insight into the processes that may lead to engaging in AIDS-risk behavior.

chemosensitizing agent; buprenorphine; morphinans; analgesics; clinical research; human subject;

Recent evidence indicates that drug use is increasing among adolescents, which may lead to a plethora of negative outcomes during these formative years. The aim of this proposal is to develop and evaluate an interactive, computer-based Drug Abuse Prevention Multimedia program for adolescents that incorporates the effective components of both drug abuse prevention science and informational technology. The program's curriculum incorporates the components of primary prevention efforts shown to be efficacious in preventing initiation to drug use and is presented in the context of both Computer Assisted Instruction and video- based simulation technologies. This program may promote the increased adoption of effective prevention science, as it is designed to be efficacious, cost-effective, easily exportable and able to applied with fidelity. In Phase I, we demonstrated the program's scientific, technical and commercial merit and feasibility by developing several sections of the program asking youth to systematically evaluate these sections and revising the sections based on student feedback. In Phase II, we will complete development of the program and conduct a controlled trial evaluating the efficacy of the program in increasing knowledge about drug abuse prevention, retarding initiation of drug-taking, and in affecting a range of variables associated with adolescent drug use. PROPOSED COMMERCIAL APPLICATION: An effective multimedia drug abuse prevention program would be a valuable resource to the public school system, - as it would enable them to markedly reduce the expense of their drug abuse prevention programs while permitting the adoption of effective methods of preventing the initiation of drug use among middle school-aged adolescents.

The Community Reinforcement Approach (CRA) with contingency management is an efficacious drug abuse treatment. Unfortunately, efficacy alone is not sufficient for a treatment to be adopted by treatment programs. Adoption of CRA with contingency management may be facilitated if it could be delivered in ways that are less costly. The aim of this proposal is to examine the efficacy of two modifications to CRA with contingency management that make it less costly to provide. The first method will consist of delivering CRA via computer-based interactive technology. Such technology may render the treatment less costly by decreasing counselor contact time. The second method will reduce costs by using an incentive system that employs buprenorphine privileges contingent on drug abstinence as opposed to monetary-based incentives. We propose to examine the efficacy of these cost-reducing methods in the context of buprenorphine maintenance treatment of opioid dependence. While opioid dependence is frequently acknowledged as a public health problem of urban areas, it is less frequently acknowledged as an issue for rural areas. Opioid dependence, however, can be a serious problem in rural areas, especially with the current threat of AIDS due to high-risk behavior by substance abusers. The aims of this project are to address this serious public health concern by continuing the first and only outpatient clinic to provide pharmacotherapies for opioid dependence in the State of Vermont. While in treatment, patients will participate in two randomized clinical trials. In the first trial, patients will be randomly assigned to receive one of three treatments: (1) computer- delivery CRA with the voucher incentive system (e.g., provision of monetary vouchers contingent on drug abstinence), (2) therapist-delivered CRA with the voucher incentive systems, or (3) standard counseling. In the second treatment, patients will be randomly assigned to receive one of three treatments: (1) CRA with buprenorphine-related contingency management (alternative dose regimens and dose adjustment), (2) CRA with the voucher incentive program, or (3) standard counseling. Contingency management procedures in both trials will target both opioid and cocaine abstinence in this population. Primary outcome measures will include abstinence, retention and cost-effectiveness. Measures will also be taken of HIV-risk behavior. Overall, this research will contribute new empirical information by identifying the efficacy of two methods of reducing costs of CRA with contingency management treatment. Such information may contribute to the adoption of this efficacious treatment. This research will also examine the utility of computerizing substance abuse treatment. The computerization of some substance abuse treatment services is a novel approach that may positively impact the future of drug abuse treatment services. Finally, by providing the only outpatient pharmacotherapy services for opioid dependence in the State of Vermont, this project will contribute positively to this region's public health.

DESCRIPTION (provided by applicant): The discounting of delayed reinforcers among the drug dependent has been increasingly studied. The results of that research are consistent and reflect an important dimension of drug dependence. Specifically, these studies have shown that drug-dependent individuals discount money more than matched controls. Moreover, drug-dependent participants discount their drug of dependence more than they discount money. Ex-dependent or recently abstinent drug users discount money either at a rate intermediate between current drug-dependent individuals and matched controls, or at a rate that approximates discounting of the matched controls. Furthermore, reinforcing abstinence has been shown to decrease the discounting of money and cigarettes in the drug dependent. Overall, these studies suggest that drug-dependent individuals discount more than controls and the excessive discounting among the drug dependent may be a reversible effect of drug use. In this competing continuation, we propose to continue this productive research by addressing three specific aims. The first specific aim is to examine whether drug-dependent individuals with co-morbidity discount delayed reinforcers more than individuals without that co-morbidity. Exp. 1 will examine co-morbid substance dependence disorder by comparing the discounting of opioid-dependent cigarette smokers, opioid-dependent non-smokers, non-opioid-dependent smokers, and non-opioid- dependent, non-smoking matched controls. Exp.2 will examine a non-substance dependence co-morbid psychiatric disorder among cigarette smokers, namely, depression. Specifically, we will compare the discounting of depressed smokers, non-depressed smokers, depressed non-smokers, and non-depressed, non-smoking matched controls. The second specific aim is to extensively compare delay and probability discounting in smokers and non-smokers. A prior study reported that smokers did not differ from non-smokers on probability discounting. That prior report examined the discounting of money at only one magnitude. Exp.3 will systematically replicate and extend that prior study by examining and comparing delay and probability discounting. Specifically, we will compare those two types of discounting with several commodities, each at several magnitudes, in both smokers and matched controls. The third specific aim is to examine the relationship between discounting and abstinence. Previously we have shown that ex-smokers do not discount differently than non-smokers. Two hypotheses to explain that observation are (a) smokers who are successfully abstinent discounted less prior to the initiation of abstinence (less discounting leads to abstinence) and (b) abstinence leads to less discounting. These hypotheses may not be mutually exclusive. In Exp.4, we will examine whether individuals with proximate plans to quit cigarette smoking discount differently than both current smokers with no proximate plans to quit and ex-smokers. In Exp.5, we will follow up our initial observation regarding the effects of reinforced abstinence on discounting. Specifically, we propose to replicate and extend that observation with cigarette smokers by imposing and removing a contingency management procedure. If our prior work is replicated, then discounting should decrease when smoking abstinence is reinforced. We will extend that work by determining whether the decrease in discounting reverses when cigarette smokers relapse.

DESCRIPTION (provided by applicant): Relapse poses significant challenges to the treatment of a broad array of behavioral disorders, especially for addictions like cigarette smoking. Relapse can be considered a reversal in preference. Unfortunately, the behavioral phenomena that contribute to or underlie relapse are generally not well understood. One such process is delay discounting (DD), which refers to the reduced value or worth of a delayed reinforcer compared to the value of an immediate reinforcer. Importantly, DD predicts the preference reversals (PR) inherent in relapse by providing a mechanistic account for a change in preference. Preferences reverse from the larger, more temporally distant reinforcer to a smaller, more immediate reinforcer as the immediate one becomes closer temporally. DD also predicts circumstances where the likelihood of PR are low;that is, Individuals with very low discount rates will tend to prefer larger, delayed reinforcers and those with very high discount rates will prefer smaller, sooner reinforcers. The understanding of PR are important because these reversals 1) provide a mechanism to understand relapse (a reversal from preferring abstinence to preferring a return to the addictive activity) and 2) may explain the three distinct subgroups that collectively produce the typical relapse curve: that is, (a) the small number of individuals who do not respond to treatment or relapse immediately post-treatment, (b) the small portion individuals who do not relapse during the post-treatment measurement period and (c) the vast majority of individuals who respond to treatment, but later relapse at one of the post-treatment measurement periods. We propose to determine if discounting can predict relapse when viewed as a continuum and whether it predicts relapse when viewed categorically. Additionally, we will compare whether the continuum or categorical approach accounts for more of the variance associated with the data. We will also compare theoretically derived logistic models composed of DD, dependence, impulsivity, and negative affect measures as predictors of relapse and/or success following treatment. To complete these aims will collect pre-treatment measures of discounting and other measures and examine their relationship to relapse among tobacco smokers. This population is ideal because tobacco smoking is a major public health problem, tobacco smokers demonstrate considerable relapse and exhibit extreme discounting. Identifying these phenotypes and achieving these aims will have important theoretical and practical implications, including 1) clarifying our understanding of neurobehavioral mechanisms and processes that underlie relapse and its inverse-successful abstinence-and 2) suggest novel ways to tailor treatments for enhanced outcomes among phenotypic subgroups.

Project Summary/Abstract Cognitive behavioral treatments (CBT) available for addiction produce efficacious and replicable results. However, those results provide considerable opportunity for increases in efficacy. CBT assumes that changes in cognition and improvement in relevant skills (such as drug refusal) will produce changes in target behaviors. Unfortunately, considerable evidence suggests that addicted individuals exhibit a variety of deficits in what is called executive function (associated with a hypoactive prefrontal cortex). From this perspective, executive function refers to a self-directed action to alter behavior and change future outcomes. Executive dysfunction could impede learning and implementation of CBT skills, and executive function therapy (EFT) used in combination with CBT could increase efficacy of behavior change in addicted persons. We plan to develop and test EFT in a multi-step process in Aim 1. Task 1 will computerize, when possible, selected assessments, which are not computerized; control treatments; and a program allowing us to control automatically the type and sequence of modules for each therapy and control treatment. Measures and therapies were selected in a systematic review of research on measurement and rehabilitation of executive function. Task 2 will collect data on executive function assessment instruments from controls to develop an operational definition of dysfunction in the target population. Tasks 3 and 4 will develop each computational model of executive function, then evaluate if each produces improvement in the targeted executive function component in stimulant abusers. Task 5 will analyze and review pre- and post-evaluation data, and assess the model's robustness in accounting for data from Task 4. Models will be revised and re-tested as necessary. In Aim 2, we plan to develop an innovative computational neuroscience model of executive function and dysfunction to aid in therapy development. Computational neuroscience employs computer and mathematical models constrained by empirical knowledge of the neural system to understand brain function, explain existing data, codify how variables influence cognitive function, and identify hypotheses for empirical testing. In this project, computational neuroscience will provide novel understanding of executive functioning, inform therapy development, contribute to a computational model of therapy, and aid in diagnostic assessments regarding particular treatments. Successfully achieving the aims could allow us to develop and target a treatment for empirically determined deficits in the addicted. This will be important for CBT and other therapies (motivational interviewing and 12- step approaches). This proposal will contribute to personalized medicine approaches in addictions, where treatment is defined by documented executive dysfunction in individual addicts. Our new treatment could spawn a variety of important areas of inquiry, such as neuroimaging studies to document changes in the prefrontal cortex, research on how the treatment could enhance treatment efficacy, studies exploring EFT for drug abuse prevention, and use of means like neurofeedback to enhance executive function. Project Narrative Stimulant addicts have been shown to exhibit executive dysfunction. Overall, this proposal will test treatments to improve executive function among stimulant addicts. This may enhance the efficacy of CBT treatment. Moreover, this proposal will contribute to personalized medicine approaches in the addictions, where the treatment delivered is defined by the documented executive dysfunction in individual addicts. Importantly, our work targets cocaine- and amphetamine- (including methamphetamine) addicted individuals. These addictions, particularly methamphetamine, represent a significant public health crisis that this study could positively impact.

DESCRIPTION (provided by applicant): This proposal will establish a unique training program in an emerging area-translational research in addiction. This field has a diverse set of disciplinary perspectives, procedures, paradigms, and technologies to measure or alter processes affecting development, maintenance, and cessation of drug dependence in humans. Scientists trained in translational research will be at the crossroads of basic and clinical research, where they can provide a crucial pathway between these two domains. Trainee research opportunities will include, among many others, laboratory studies of antibody-based therapy for methamphetamine abuse, studies of the behavioral economics of addiction, novel medications to treat cocaine and opiate dependence, behavioral treatments of marijuana dependence, behavioral and neural mechanisms of change, treatment service dissemination, and cost- effectiveness of reducing drug treatment barriers. The project will train addiction scientists to participate in translational science that directly assesses the clinical relevance of basic research;conducts scientific analyses of basic processes underlying drug abuse;helps develop and assess behavioral and pharmacological treatments of addiction;determines approaches to integrate these findings into clinical practice;and identifies policies that support integration. This program will be greatly enhanced by the prior training success of the program's 12 core faculty, who are MDs or PhDs with appointments in Pharmacology and Toxicology, Psychiatry, and Health Behavior and Health Promotion departments and have 22 NIDA, 3 N1AA, 1 N1CHD, 1 SAMSHA, 1 NIMH, and 16 VA research grants. Among the 28 predoctoral and 37 postdoctoral students trained by these core faculty, 86% of the predoctoral and 89% of postdoctoral students are still involved in research/academics and 49% of postdoctoral trainees have faculty positions. Collectively, trainees authored more than 500 publications were first author on 40% of them, and obtained 43 research grants. The new program proposed here will train, through stepped increases in enrollment, a total of 5 predoctorals, 7 postdoctorals, and 19 medical students by the end of the grant cycle. Trainee selection will be based on scholastic excellence and commitment to addiction research careers. Training will take place at the Center for Addiction Research. PUBLIC HEALTH RELEVANCE: This proposed training program is relevant to the public health because it will train new scientists at the pre and post doctoral level to conduct translational research into addictions and its treatment.

DESCRIPTION (provided by applicant): Cocaine use and its associated risky sexual behaviors (e.g., sex with multiple partners, inconsistent condom use, trading sex for drugs or money) represent a significant contributor to the ongoing spread of HIV. However, little is known about how sex, drugs, and money are valued in this population, nor about the perturbed neural processes mediating these tradeoffs. In this application, we directly address the objective of PAS-07-324 to increase understanding of processes of cocaine addiction that influence decisions about high-risk sexual behavior. We propose to explore this via the convergence of behavioral and neural underpinnings of the pathological decisions made by Chronic Cocaine Users (CCUs) not in treatment using a model-based approach, behavioral decision tasks, and functional magnetic resonance imaging (fMRI). Our overall hypothesis is that the processes of addiction result in a dysfunctional decision system that underlies the risky sexual behavior engaged in by CCUs;in other words, CCUs engage in risky sexual behavior because they discount future outcomes as a result of a hypoactive executive system (in prefrontal cortex) and a hyperactive impulsive system (in limbic brain circuits). To improve our understanding of cocaine addiction processes that influence decisions about risky sexual behavior, we will obtain critically needed information about the CCU's valuation of relevant commodities (sex, drugs, money), recognizing that these commodities serve multiple functions and may interact with one another in novel ways. We will study valuation and inter-temporal choice within and across different commodities to gain new insights into the decisions made by CCUs, including decisions closely tied to the high-risk behavior of trading sex for drugs or money, and how they differ from Recreational Cocaine Users (RCUs) and Community Control Participants (CCPs). We hypothesize that different commodities will show different profiles of effect depending on availability of other commodities (same or different commodities), their temporal location (immediate or later), and the subject group (CCUs, RCUs, CCPs). Additionally, given the existing data, we anticipate systematically replicating that the discounting of money (money now vs. later) will be predictive of HIV risk behavior in a new population (CCUs). The inclusion of neural correlates will permit us to identify for the first time the role of different neurobehavioral decision systems in decision making predictive of HIV risk behavior. By comparing money discounting to discounting of drug and sexual activity within and across commodities, we will determine whether novel discounting procedures and associated neural processes are more predictive of risky behavior than money discounting. Completion of this project will provide substantial new information about neural valuation systems that are altered by addiction and lead to risky sexual behavior. Understanding how the commodities of interest interact with one another and the neural systems that participate in that valuation may suggest new approaches to alter the pathologic valuation and impact risky behavior associated with the spread of HIV. PUBLIC HEALTH RELEVANCE: Completion of this project will provide new information about stimulant addiction and associated risky sexual behaviors that have been shown to contribute to the spread of HIV. By examining the regions of the brain that underlie an addict's perturbed decision making, we expect our data to result in treatment applications. We believe that greater understanding of the mechanisms that alter an addict's valuation of commodities like sex, drugs, and money could lead to new approaches to altering the pathologic decision making, thus reducing the correlated risky behaviors associated with the spread of HIV.

PROJECT SUMMARY (See instructions): Tobacco use is the second leading risk factor for death, estimated to be responsible for 9% of all deaths worldwide. The degree of harm (i.e., rates of death and disease) to the population due to use of tobacco products is dependent on both magnitude of use (prevalence and intensity of product use) and toxicity of the products used. To determine how the introduction of new tobacco products would affect population harm, we need more sensitive and comprehensive procedures for abuse liability assessment, including the likelihood that a new tobacco product will be used in place of, or together with, conventional tobacco products such as cigarettes. Current methods of abuse liability assessment of drugs developed over several decades have been shown to have excellent external and predictive validity. However, accurate assessment of the abuse liability of tobacco products will require greater sensitivity to (1) detect differences between the increasing number of similar products, (2) acknowledge and incorporate environmental and situational factors that can affect the likelihood or magnitude of use, and (3) provide the ability to distinguish between products that might be used together compared to those that might substitute for each other. In Project 2, we aim to apply a behavioral economic approach to the development of more sensitive and comprehensive abuse liability assessment methods for tobacco products. Specifically, we will use these behavioral economic methods of abuse liability assessment across three platforms or approaches that vary in cost, and effort (e.g., human laboratory, ecological assessment, and questionnaire). Modified abuse liability methodology that incorporates behavioral economic analyses is expected to lead to more accurate assessments of potential population harm from the possible introduction of new products and the avoidance of past mistakes. Specifically, in Specific Aim 1, we will compare the demand function for a potential modified-risk tobacco product, Camel snus (oral, spit-less tobacco pouches), to demand functions for conventional cigarettes (positive control for an abused substance) and for medicinal nicotine (negative control for a low abuse liability safer product) across a range of prices in the laboratory setting, on an outpatient basis, and using questionnaire-based methods. In Aim 2, we will investigate product choice across a range of prices in each of these platforms. In Aim 3, we will examine how changing the price of cigarettes might affect the consumption of alternative products in each of the same settings. In Aim 4, across all the studies we will compare the three assessment procedures and three platforms in terms of (1) rendering the same assessment, cost of assessment and prediction of the clinical trial proposed in Project 4. In light of recent legislation giving FDA broad regulatory authority over tobacco products, these studies will provide timely and much needed information regarding the methods to use to assess the likelihood of initiation and continued use of these products, which have the potential to impact public health. Moreover, the development of more sensitive abuse liability methodology as proposed in this application has the potential to define the standards by which abuse liability assessment of modified-risk tobacco products is conducted.

DESCRIPTION (provided by applicant): Self-Control Improvement Intervention (SCII): Improving Abstinence in Smokers. More than 15 years of our translational research has shown that discounting (i.e., devaluing) future rewards in favor of immediate rewards (which we will refer to as self-control failure) is endemic among individuals addicted to cigarettes and other drugs. Indeed, we propose that individuals who excessively discount future rewards may be stimulus bound and more susceptible to drug-related cues and negative consequences. Consistent with this view, treatment success among smokers is inversely correlated with their rates of discounting. Unfortunately, no research translating basic findings on excessive discounting among smokers into clinical treatments has been conducted. This proposed project is a systematic effort to translate basic research on self-control failure into effective interventons to normalize or improve self-control among smokers. In the first phase, a laboratory study will determine if smokers with less self-control are more stimulus bound. Within this phase, we will delineate the target for subsequent intervention, self-control failure (i.e., excessive discounting, and its functional relation to measures that could determine whether smokers are stimulus bound under cigarette available and deprivation conditions. Concurrently, we will examine the quantitative relation between smokers' discounting rates and responsiveness to those measures. In the second phase, we will conduct a proof-of-concept field study testing a novel Self-Control Improvement Intervention (SCII). This intervention is based on our prior work demonstrating that working memory training (hereafter, SCII) improves self-control in stimulant-dependent individuals. We will examine (1) whether SCII decreases the extent to which smokers are stimulus bound, and (2) if this decrease in being stimulus bound is dependent on baseline self- control level. In the third phase, we will seek to improve current smoking cessation treatments (i.e., combination cognitive behavioral therapy and nicotine replacement therapy) that have been shown to be efficacious, but still fail to produce abstinence in the vast majority o participants. This will be accomplished by incorporating SCII into the multi-modal smoking treatment program among those individuals who we demonstrated to be sensitive to the SCII in Phase 2.

DESCRIPTION (provided by applicant): Alcohol-dependent individuals frequently have deficits in self-control, as measured by their excessive discounting of delayed rewards. The dual neurobehavioral decision systems model suggests that these deficits may result from a disruption in the regulatory balance between two interacting neurobiological systems. These systems are the executive system (prefrontal cortex and parietal cortex) which is responsible for valuing delayed rewards (i.e., long-term goals), and the impulsive system (limbic and paralimbic areas) which is associated with immediate rewards (i.e., instant gratification). Our recent research has demonstrated that working memory (WM) training repairs self-control, putatively by restoring regulatory balance between these systems. There is, however, still much to learn about repairing self-control. In Aim 1, we will further explore the effects WM training on a range of WM, self-control, and clinically relevant (e.g., craving) measures. Additionally, the neural mechanisms of WM training will be explored though functional neuroimaging techniques. We will examine the dose-effect function of WM training by systematically varying the number of WM training sessions across several groups of alcohol-dependent individuals. The duration of these improvements in self-control will be tested by conducting follow-up assessments one month, three months, and six months after training. In Aim 2 we plan to capitalize on the neurobiological knowledge gained in Aim 1 to test the effects of two variants of real time fMRI neuro-feedback on our suite of WM, self-control, and clinically significant measures. This novel exploration of neuro-feedback effects on neurocognitive and clinically significant measures will include a direct comparison of feedback techniques based on a specific brain region and across a distributed neural network. Long-term changes in neural function and/or our neurocognitive measures will be explored during a one-month follow-up visit. Successfully achieving our aims could allow us to both refine our current techniques (i.e., WM training), and possibly begin the process of developing novel techniques (i.e., neuro-feedback) for the repair of self-control in alcohol-dependent individuals. This application will contribute to personalized medicine approaches in alcohol dependence, where treatment is defined by documented self-control deficits. Furthermore, the functional neuroimaging data collected across both aims should provide unique insights into both patterns of neural disruption seen in alcohol dependence and any treatment associated changes in neural function.

DESCRIPTION (provided by applicant): Although recognized as a chronic relapsing disorder, addiction is still largely treated as an acute disorder. To better treat addiction as a chronic disorder, self-management and social support should be provided. Social media provides a unique and cost-effective opportunity to arrange and develop the social support system necessary for sustained recovery. Unfortunately, little is known about the specific methods to develop an efficacious social media outlet that facilitates user self-management, the adoption of health behavior, engagement in efficacious treatment, and the flow of ideas among those in recovery. Advances in social network science have demonstrated that social interactions are complex dynamical systems with emergent properties (e.g., engagement), not reducible to the individuals in those social networks. This proposed project is a systematic effort to translate basic research on the emergent properties of online social networks to support continued addiction recovery. Here we propose to recruit 1536 poly-substance dependent individuals in recovery from the International Quit & Recovery Registry to participate in two intent-to-treat randomized controlled trials. In these trials, we will examine whether topology of the social network (Experiment 1) and the similarity of individuals to one another (Experiment 2) strongly influence social network engagement, exploration, social learning, and involvement in an efficacious treatment. We will also learn whether such engagement supports continued recovery from addiction. Our hypotheses are that topologies with greater redundancy in connections and networks with increased similarity across individuals will increase involvement and engagement among network members, and this increased involvement will translate into decreases in the relapse rate of group members. As drug-related behaviors are strongly influenced by group pressure and social learning, the potential effects of these two variables on engagement with efficacious treatment and others supportive of recovery could have a dramatic impact on the societal cost incurred by individuals who attempt and fail to reach full recovery status.

PROJECT SUMMARY/ABSTRACT Persons with obesity, prediabetes and type 2 diabetes excessively discount the future in cross sectional studies, and increases in delay discounting (DD) are associated with worsening glycemic control. By implication this worsening glycemic control could be related to the transition from prediabetes to type 2 diabetes. People who are more impulsive and discount the future may demonstrate greater responsivity to food cues, and variability in patterns of eating, which will result in variability in blood glucose. A large body of research shows that variability in blood glucose, as assessed by continuous glucose monitors (CGM), may contribute to risk for diabetes complications. Logically substantial discounting may result in a more variable pattern of eating, which in turn results in variability of blood glucose levels in those with deteriorating beta cell function and insulin resistance. Pilot data from our SOBC grant support a relationship between DD and variability in eating behavior, as well as variability in eating being related to HbA1c values. These results suggest from an experimental medicine approach that reducing DD should reduce variability in behavior by making people less responsive to individual and environmental cues that signal immediate gratification. Episodic future thinking (EFT) has been shown to reduce DD. We propose to study individuals with HbA1c values ranging from normal through prediabetes to type 2 diabetes over a two-week period to establish associations between DD, variability in eating and activity, and glycemia using continuous glucose monitors. We will then randomize these persons to EFT or control conditions for another two weeks. Most importantly for understanding factors related to whether glucose variability exacerbates disease progression in diabetes is that the data from CGM can give information about fasting glucose, variability in glucose and average glucose levels. Based on these methods we plan to two specific aims. Specific Aim 1 will assess the relationship between DD and variability in eating, activity, and blood glucose levels over a baseline two-week period. Specific Aim 2 will assess the effects of decreasing DD using EFT on variability in eating, variability in activity, and variability in blood glucose levels over a two-week intervention period. We would follow effects of these short term relationships with a longer term clinical trial to assess effects of EFT on changes in blood glucose variability as well as HbA1c levels.

PROJECT SUMMARY/ABSTRACT In 2009, the Food and Drug Administration (FDA) was granted authority, to reduce, but not eliminate, nicotine in tobacco products if it benefited the public health. With this authority, the FDA could test the speculation that the dose of nicotine could be reduced to a level that would not result in the addictive process usually observed with conventional cigarettes. In the proposed project, we will use behavioral economic methods to examine consumption of reduced-nicotine cigarettes within the context of the larger tobacco marketplace. These experiments will assess the abuse liability of reduced-nicotine compared to conventional cigarettes and the impact of introducing reduced-nicotine cigarettes into the larger marketplace either in addition to or instead of conventional cigarettes and address two specific aims. Specific Aim 1 is to examine the effect of nicotine concentration in tobacco and resulting plasma nicotine on laboratory behavioral economic measures of demand intensity and elasticity with a within-subject design. Specific Aim 2 is to assess behavioral economic measures of demand intensity and elasticity of cigarettes and substitution by dose in the Experimental Tobacco Marketplace under 4 conditions that mimic 2 different potential regulatory environments and 2 control conditions. The Experimental Tobacco Marketplace is a method we recently developed in our laboratory that allows experimental price manipulation while simulating real-world markets featuring a wide range of available tobacco products. This novel model will permit us to prospectively identify the possible consequences of introducing low nicotine containing cigarettes into the complex tobacco market. These studies address at least three important gaps in knowledge concerning abuse liability of reduced-nicotine cigarettes: (1) How valued are reduced-nicotine cigarettes (abuse liability), (2) Would these reduced-nicotine cigarettes be preferred and substitute for conventional cigarettes in an ever more complex tobacco marketplace, and (3) Would the introduction of reduced-nicotine cigarettes into the marketplace influence the consumption of other non-combustible nicotine products.

PROJECT SUMMARY/ABSTRACT The goal of tobacco regulations is to improve public health. Tobacco regulations, however, are often implemented before they have been tested in a research setting, thereby increasing the likelihood of untoward effects caused by such regulations. The goal of this project is to use the Experimental Tobacco Marketplace to empirically assess the effects of regulatory changes on tobacco consumption among smokers. The specific aims will address how factors such as dose, price, environmental constraints (smoke-free work environments), and flavors affect consumption and substitutability of cigarettes and vaporized nicotine products. In these within-subject studies, the research team will examine choices in the Experimental Tobacco Marketplace with some purchases actualized. This novel method will increase the external validity of modern regulatory science. Moreover, the obtained results will help direct policymakers' decisions about the availability and pricing of alternative, potentially less harmful, tobacco products.

ABSTRACT Cigarette filter ventilation is a major design feature of the majority of cigarettes sold in the United States and abroad. Although filter ventilation was initially intended to produce a lighter tasting and potentially safer cigarette by diluting mainstream cigarette smoke, data have since suggested that ventilation instead increases total harm from smoking by inducing compensatory smoking (e.g., increased puff volume and/or more cigarettes smoked per day due to reduced nicotine yields) and may increase cigarette abuse liability (addictive potential). The goal of this project is to use the recently developed Experimental Tobacco Marketplace to assess the effects of removing filter ventilation, thereby modeling a regulatory environment in which filter ventilation was banned, on behavioral economic measures of abuse liability. In a series of studies featuring both between- and within-subject design components, the research team will compare purchasing and consumption of unventilated and ventilated cigarettes across a broad range of prices, as well as examine how filter ventilation impacts the degree to which an array of alternative nicotine delivery systems (e.g., electronic cigarettes, smokeless tobacco) serve as economic substitutes for cigarettes. Moreover, we will model electronic cigarette regulatory restrictions on flavor and available nicotine concentrations to examine how such restrictions interact with cigarette filter ventilation to affect tobacco consumption. Together, the findings from this project could be used to inform and maximize the efficacy of regulatory action regarding cigarette filter ventilation and alternative nicotine delivery systems.

PROJECT SUMMARY/ABSTRACT Smoking is the leading preventable cause of mortality and morbidity in the United States, each year contributing to approximately 443,000 deaths. Smoking and high relapse rates are likely due to factors that affect both limbic and executive circuits in the brain, including vulnerability to salient smoking-related cues and loss of cognitive control. Accumulating evidence indicates that in addiction, the frontal-striatal circuits involved in limbic reward and impulsive action are relatively hyperactive, while the executive control circuits are relatively hypoactive. Thus, intervention efforts should be directed at either decreasing the relative activity of the impulsive reward circuit or increasing the relative activity of the executive control circuits. Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-approved treatment for depression which is also being investigated for as a possible treatment for smoking cessation. The goal of this project is to use the novel theta burst stimulation (TBS) protocol to induce sustainable decreases and increases in the impulsive and executive control circuits, respectively. To do so, we will apply an attenuating form of TBS to the ventromedial prefrontal cortex to target the impulsive reward circuit and a potentiating form of TBS to the dorsolateral prefrontal cortex to target the executive control circuit. We will then investigate the efficacy of these protocols for reducing a range of smoking measures, including cigarette valuation, delay discounting, cigarette self-administration, and brain reactivity to smoking cues. The results from these investigations will pave a clear pathway for the systematic development of neural-circuit based strategies as treatments for tobacco use and dependence.

PROJECT SUMMARY Developing a new generation of interventions for alcohol use disorder (AUD) constitutes an important scientific gap and, if addressed, will open innovation opportunities. To address this gap, we propose to examine an emerging novel framework for addiction, reinforcer pathology. Reinforcer pathology specifies that reinforcers are integrated over a temporal window, and the length of that window determines the relative value of different reinforcers. When the temporal window is short, reinforcers such as alcohol, which are brief, intense, and reliable, will have greater value. Conversely, as the temporal window lengthens, other more temporally extended reinforcers begin to have greater influence and alcohol valuation will decrease. The concept of reinforcer pathology identifies the temporal window, measured with delay discounting (i.e., the decline in the value of a reinforcer as a function of its delay), as a therapeutic target for AUD, and it permits target engagement via innovative interventions (e.g., episodic future thinking; EFT) to provide novel insights into alcohol valuation. This project uses multiple analytical levels (e.g., the behavioral laboratory, an outpatient field study, neuroimaging, and computational modeling) to quantify, predict, and modulate alcohol valuation among individuals with AUD. In Aim 1, we will examine manipulations that increase and decrease the temporal window to mechanistically test the reinforcer pathology framework. In Aim 1a, we will examine the effects of an intervention that increases the temporal window (EFT) on concomitant changes in alcohol valuation (self-administration, craving, and behavioral economic alcohol demand). In addition, participants in Aim 1a will participate in a proof-of-concept field study, where remote implementation of EFT will be used to impact alcohol drinking (measured by remote monitoring of breath alcohol) in the natural environment. In Aim1b, we will examine the effects of a manipulation that decreases the temporal window (simulation of economic scarcity) on concomitant changes in alcohol valuation. Throughout Aim 1, neural activity associated with changes in the temporal window will also be examined. In Aim 2, we will use multi-voxel analyses of fMRI data to explore two independent sub-aims related to reinforcer pathology in AUD. First, in Aim 2a, we will build multivariate group regression models of fMRI delay discounting data in a subset of participants with AUD to predict discounting in an independent subset of participants. Second, in Aim 2b, we will use real-time fMRI neurofeedback to enhance participants' ability to control their temporal window, and hence their ability to modulate delay discounting and alcohol valuation. In Aim 3, we will model the temporal window to extend the existing literature by computationally quantifying results from Aims 1 and 2 (Aim 3a), and connecting subjective value to brain regions of interest using computational neuroscience (Aim 3b). Together, the findings from this rigorous and innovative research project will improve our understanding of AUD and highlight potential novel and efficacious intervention strategies.