Dena Davidson - US grants

This resubmitted application is a request for a Mentored Research Scientist Development Award (KO1) from NIAAA. My commitment to a research career, together with my interest in receiving specialized training to conduct high quality research in the treatment of alcohol abuse and dependence make a KO1 award the optimum funding source at this stage of my career. With funding from a KO1, I learn how to independently design, implement and analyze behavioral pharmacology studies with human subjects. I will work closely with my mentor, Dr. Robert Swift, and with other core faculty members at Brown University's Center for Alcohol and Addiction Studies (CAAS). Part of my didactic training will include participating in all CAAS academic program activities. I will also regularly present at international conferences in my field. The primary aim of the research proposed in this application is to develop methods for assessing the behavioral mechanisms underlying medication-induced decreases in alcohol intake in humans. Although new medications are being introduced to control alcohol intake in alcoholics, little is known about how these medications actually change the effects of alcohol in people. Two studies are proposed to assess alcohol effects that are often considered to be important to maintaining problem drinking and precipitating relapse drinking. The first study will develop behavioral measures of stimulation in social drinkers using a controlled, laboratory alcohol administration protocol. The second study will apply these behavioral measures of stimulation and further develop our behavioral measures of urge in social drinkers using a field a alcohol self-administration protocol. The utility of these behavioral measures of stimulation and urge will be assessed by pre-treating subjects with one of three doses of naltrexone (NTX). NTX is a pharmacotherapy that decreases alcohol-induced subjective stimulation, alcohol craving and alcohol intake. In summary, this period of funding will be used to: 1) provide me with the necessary training to begin an independent research career in alcohol abuse and dependence; 2) develop new methods for measuring alcohol's effects on stimulation and craving; and 3) assess the effects of different doses of NTX on these behaviors.

The primary aim of the research proposed to develop methods for assessing the behavioral mechanisms underlying medication-induced decreases in alcohol intake in humans. Although new medications are being introduced to control alcohol intake in alcoholics, little is known about how these medications actually change the effects of alcohol in people. The purpose of this study is to develop a behavioral assessment battery to measure urge and stimulation in social drinkers during a field alcohol self-administration protocol. The utility of these behavioral measures of stimulation and urge will be assessed in social drinkers, pretreated with one of three doses of naltrexone. Naltrexone is an FDA approved pharmacotherapy for lowering alcohol consumption.

APPLICANT'S ABSTRACT: The long-term research goal of the applicant investigators is to maximize the clinical effectiveness of treatment for alcoholism. The specific aims of this protocol are to compare 3 and 6 months of naltrexone (NTX) as an adjunct to two psychotherapies that differ in scope and intensity. The effect of these treatments will be assessed with patients who differ in their psychosocial need and psychosocial resources at their disposal, and in their level of cravings for alcohol. In this randomized clinical trial, 50 mg of NTX daily and either Motivational Enhancement Treatment (MET), or the more comprehensive Broad Spectrum Treatment (BST), will be provided over 12 weeks (Phase I). Following Phase I, half of the group receiving NTX in both psychotherapy conditions will crossover to placebo, in double-blind fashion. Daily medication will continue for an additional 3 months (Phase II). MET will terminate in Phase I, while those patients with greater psychosocial need and fewer psychosocial resources may continue in BST during Phase II. Medication and BST terminate at the end of Phase II, and patients are then followed for 12 months (Phase III). Outcome measures during all treatment phases include: 1) drinking outcomes (time to first drink; % days abstinent; % heavy drinking days); 2) negative drinking consequences; and 3) psychosocial adjustment. Overall, it is anticipated that the optimum treatment package will be one that targets the majority of the unique psychosocial needs of the patient while addressing the biological aspects of alcohol dependence via effective medication management.

DESCRIPTION (provided by applicant): Craving is arguably the most contentious construct in addiction research. On the one hand are the testimonials of alcoholics that cravings dominate their thoughts and weaken their resolve to stay sober. On the other hand, research finds that craving is neither necessary nor sufficient to explain drinking. In 1996, the NIAAA brought together addiction experts to determine why craving is not a reliable predictor of drinking. One of the gaps in the knowledge base identified by this group was that craving has not been adequately conceptualized and studied in humans. Lack of such research is an important problem because it impedes the understanding of the nature, course, behavioral sequelae, and regulatory function of craving on alcohol consumption. The long-term goal of my research is to better understand the phenomenon of craving and its relation to drinking and relapse. The objective of this application is to examine 2 influential models of craving, the Cognitive Processing Model of Craving and Drug Use, and the Two-Affect Model of Urges and Drug Motivation, which yield different predictions regarding the association between craving and drinking. The central hypothesis of the proposed research is that the circumstances under which craving is likely to predict drinking will only be elucidated through theory-driven research and the use of paradigms that can manipulate factors known to elicit drinking, and simultaneously measure craving and drinking behavior. Three studies are proposed to investigate factors known to elicit drinking in alcoholics by using an innovative modification of conventional cue-reactivity methodology-the cue-availability paradigm. Study I will examine the effects of alcohol priming and alcohol availability on craving, affect, alcohol seeking, and drinking behavior in non treatment-seeking alcoholics. Study 2 will examine the effects of negative mood induction and alcohol availability on craving, affect, alcohol seeking, and drinking behavior in non treatment-seeking alcoholics. Study 3 will replicate and add to the findings from Study 2 by providing a test of convergent validity on drinking behaviors measured by the cue-availability paradigm to similar measures assessed by a validated taste-rating task. The effects of participating in these laboratory alcohol administration studies on subsequent ad libitum drinking will be measured as a secondary aim. The proposed research is innovative because it uses a paradigm that has the flexibility to manipulate factors known to affect alcohol seeking and drinking behaviors, simultaneously measures craving and affect, and tests two models of craving. We expect that this research will provide important new information regarding factors that moderate craving, and the association between craving and drinking in the population of interest-alcoholics. The major impact of this research will be to address a gap in the knowledge base regarding the conceptualization of craving in humans, which in turn will advance the field and inform patient care.