Lance O. Bauer - US grants

Cocaine abuse is a rapidly growing medical proboem presenting neuropsychologists with a challenge to develop treatments which address its neuropsychological effects. However, there are presently no objective data in the literautre which describe the neuropsychological effects of chronic cocaine abuse. There are also no objective data describing the recovery from the neuropsychological effects of cocaine abuse or when treatment for cocaine abuse should end. The proposed study is the first to provide objective data which describe the nature, severity, and time course of neuropsychological impairments in recovering cocaine abusers. In the proposed study, the neuropsychological status of a group of npatients undergoing treatment for cocaine dependence will be evaluated repetedly (e.e., at 1-3, 7-9, 16-21, and 94-100 days from their last drug-taking episode) and contrasted with the neuropsychological staus of a group of inpatient alcoholics and a group of drug-free controls evaluated at comparable intervals. Neuropsychological functioning will be assessed in six major areas: CNS and ANS arousla, CNS and ANS reactivity, sensory functiioning, motor functioning, visual and auditory attention, and languate comprehension. Measures from both the behavioral (e.g., reaction time, detection rate) and electrophysiological (e.g., EEG, ERP) domains will be used.

Two studies are proposed to examine electrophysiological and neuropsychological test performance in recovering substance abusers. Study #1 will examine 30 cocaine dependent and 30 alcohol dependent patients after 2-4 and 8-10 months of verified abstinence. Study #2 will examine 2 groups of methadone-maintained patients with recent (2-4 months) or without histories of cocaine dependence. As a secondary goal, Study #2 will also compare methadone-dependent patients in the early asymptomatic stages of HIV-1 infection of those without infection. It will also allow examination of the potential additive or interactive effects of current HIV infection and previous cocaine dependence. The test battery will include several measures from our current battery, e.g., tremor, smooth pursuit and saccadic eye movements, EEG photic driving responses. Several new measures will also be added to assess sensory function (SEP, ABR, PRVEP) and higher level cognitive abilities, such as cognitive flexibility and short term memory. The same measures will be recorded from groups of non-drug-dependent, age- and education- matched controls. The resultant data will be useful for describing the nature, severity, and persistence of neuropsychological/electrophysiological impairments in recovering cocaine dependent patients. The data will also identify subgroups of cocaine dependent patients who may be at greatest neuropsychological risk, due to opiate dependence and/or HIV infection.

Electroencephalographic techniques, especially event-related electro- encephalographic potentials (ERP), have been used to examine the CNS functioning of individuals at low and high risk for drug dependence. The proposed study will employ these techniques in an examination of 300 non- drug dependent teenagers (aged 16-18) varying in their risk. Three risk factors will be investigated: 1) gender, 2) a family history of either opiate or alcohol dependence, and 3) a personal history of antisocial personality (ASP) characteristics. The ERP battery will include three sets of tasks which putatively challenge frontal brain function. One set of tasks will require rapid changes in strategy, planning, and/or cognitive set. The second task set will manipulate the complexity, speed, or timing of the required motor response. The third will provide measures of ERP activity during the anticipation of avoidable stressors. A fourth task set will evaluate EEG activity at rest and ERPs during "nonfrontal" tasks. The proposed study will evaluate the hypothesis that subjects at high putative risk for drug dependence (i.e. those with ASP disorder, or a family history of opiate dependence or alcohol dependence) exhibit signs of impaired functioning on tests of cognitive flexibility and motor regulation. In contrast, high risk FH+ or ASP+ subjects are hypothesized to function better than their low risk counterparts on tests of stress avoidance. The validity of these hypotheses will also be evaluated using a battery of more traditional neuropsychological tests.

Component 28 has three phases. The first phase is a continuation of a study that prospectively compares the EEG activity and psychological symptoms of 30 alcohol-dependent patients, assessed after 1, 2, and 8 weeks of abstinence, to 20 matched nonalcoholic controls, assessed over a comparable period. This study is also designed to evaluate abnormalities in the EEG activity and psychological status of alcohol dependent patients as predictors of their outcome (i.e., relapse vs. continued abstinence). It is hypothesized that the severity and persistence of EEG and psychological abnormalities will be associated with a decreased latency to or increased likelihood of relapse. The second phase of this component is a new study that will examine benzodiazepine/GABA receptor sensitivity in abstinent alcoholics. For this purpose, we will intravenously administer a subhypnotic dose of the benzodiazepine, midazolam, and a placebo to 20 alcoholics who have remained abstinent for 3 weeks. For comparison purposes, these drugs will also be administered to 20 nonalcoholic controls. The general hypothesis states that abstinent alcoholics will exhibit electrophysiological and subjective signs of reduced benzodiazepine sensitivity, relative to normal controls. The third phase of the component will examine the ability of the benzodiazepine antagonist flumazenil to restore benzodiazepine sensitivity to normal levels in abstinent alcoholics. For this purpose, we will pretreat groups of abstinent alcoholics and normal controls with either 1.5 or 15 mg flumazenil or placebo. On the following day, all subjects will receive an IV dose of midazelam and complete the same test battery used in Phase 2. The general hypothesis states that normal controls will show no change in test performance as a result of flumazenil treatment. Flumazenil is expected to restore the test performance of alcoholics to control group levels. The three phases of component VI constitute a program of research designed to improve our understanding of the biological substrates of alcohol dependence and their relevance to relapse.

neurotoxicology; thiamine; cocaine; drug abuse chemotherapy; human therapy evaluation; vitamin therapy; alcoholism /alcohol abuse chemotherapy; neuropharmacology; clinical research; oral administration; human subject; nutrition related tag;

The acute withdrawal of alcohol from patients with histories of chronic dependence is known to precipitate a syndrome that is variable in its presentation. The central nervous system correlates of alcohol withdrawal have been studied previously. However, most studies have focused on >35 year old patients with limited or unspecified histories of other drug abuse. We therefore have little understanding of the CNS effects that result from combining alcohol withdrawal with other drug withdrawal, or with medical (malnutrition) or psychiatric (antisocial personality) variables that frequently accompany other drug abuse. Such knowledge is particularly relevant in the context of the movement toward outpatient detoxification and unanswered questions regarding the abilities of such patients to safely perform tasks at home or at work while simultaneously undergoing alcohol/drug withdrawal. In this study, we propose to compare the neurophysiological and neuropsychological status of 150 alcohol dependent patients with (n=75) or without (n=75) co-morbid cocaine dependence. A group of non drug-dependent subjects (n=35) will be tested as a control. The assessment battery will include measures of resting EEG activity, sensory functioning, motor functioning, visual and auditory selective attention, and short term memory. The additive and/or interactive effects of vitamin deficiency and antisocial personality disorder will also be evaluated. The principal hypothesis states that patients concurrently withdrawing from both alcohol and cocaine dependence will be characterized by impaired performance on specific measures of EEG activity, and motor and sensory function.

DESCRIPTION (Adapted From The Applicants Abstract): The neuroimaging study proposed presently differs from many of the extant studies of the neurophysiological effects of HIV/AIDS in several substantive areas. For example, the proposed study will not focus exclusively on thc subset of HIV/AIDS patients with profound dementia in the terminal stages of disease. Secondly, it will also not focus exclusively upon verifying a neurological or neuropsychological staging system which is subjective and has unknown specificity and reliability. Thirdly, the proposed study will not exclude HIV/AIDS patients who are female or possess comorbid psychiatric disorders. The focus of the proposed study will instead be directed toward the quantitative assessment of degrees of impairment in a broader sample of HIV/AIDS patients using objective and reliable neurophysiological tools. For this purpose, we will recruit 120 HIV-1 seropositive and 120 HIV-1 seronegative subjects. All of the subjects will undergo identical procedures which will include structured medical and psychological evaluations. An attempt will be made to match the groups on several neurophysiologically relevant background variables (i.e., depression level, drug use history, gender, and age). The dependent measures will include several quantitative electroencephalographic measures, sensory evoked potential latencies and amplitudes, and topographic analyses of endogenous event-related potentials. Additional dependent measures will include objective and quantitative measures of balance, tremor, and eye movements. The overall goal of the study will be to construct a multivariate model in which one can test the role of various risk factors (e.g., antisocial personality disorder), comorbid disorders (e.g., mood disorder; cocaine, alcohol, or heroin dependence), and markers of disease severity (e.g., CDC clinical stages A, B, or C; viral load, CD4+ count, TNF-alpha) in either mediating, amplifying, or adding to the degree of neurophysiological impairment. In addition, cerebrospinal measures of cytokine and beta-chemokine activity will be gathered for the purpose of examining their correlation with neurophysiological functioning in the subset of HIV/AIDS patients who consent to a lumbar puncture. A secondary study will evaluate the same measures listed above among 45 HIV/AIDS patients before and 3 months after the initiation of a standard antiviral medication regimen as compared to 45 unmedicated HIV/AIDS patients (because of medication intolerance or noncompliance) who are also tested twice. An analysis of change scores across groups will permit a formal test of the effects of antiviral treatment on neurophysiological status.

DESCRIPTION (provided by applicant): This revised, A1, application describes the current and proposed configurations of the University of Connecticut Health Center's (UCHC) Postdoctoral Training Program in Alcohol Research. The Program is designed to provide 4 trainees per year with a common knowledge base in alcohol theory, research design, data analysis strategies (e.g., SEM and HLM), ethical issues in preclinical and clinical research, and grantsmanship skills. In addition, more intensive individual training, concordant with the specialized interests of each trainee, is provided in such areas as neurobiology, neuroimaging, early childhood risk factors, genetic and family studies, women's health, treatment, comorbid disorders, longitudinal outcome studies of at-risk populations, and daily process studies. The range of experiences available to our trainees aligns closely with the range of NIAAA P60, U10, and R01 grant support awarded to our faculty. Over the past 10 yrs, our program has matured. It has not grown in size. Its Director has also not changed. Yet, over time, we have seen a real change in the outcomes of our trainees. For example, the proportion of Training Program graduates who obtained faculty or faculty-equivalent positions increased from 4 of the 13 graduates during 1995-2000, to 11 of the 12 graduates during 2000-2005, to 6 of the 6 graduates during 2005-2011. Publication productivity has also improved. The number of full length articles authored or co-authored by trainees during and after the training period now averages 3.84 articles (median=3.6) per trainee per year. We think that the 31-year history of the Postdoctoral Training Program in Alcohol Research at UCHC should be extended. The Program offers a unique opportunity for the training of a future generation of alcohol researchers focusing on a variety of clinically relevant topics. Our record to date suggests that graduates of this program have been successful in manuscript and grant submissions, and are able to function effectively in a variety of settings relevant to alcohol research.

DESCRIPTION (provided by applicant): The general goal of the proposed work is to test a theory that links the COMT and GABRA2 genes to intermediate phenotypes, and, in turn, to the important clinical problem of relapse to substance abuse. It will test whether genes that have been empirically linked to substance dependence, and to measures of frontal brain function (viz., fast beta power in the spontaneous electroencephalogram and frontal P300a amplitude), also confer an increased risk for relapse to these disorders. The specific goals of the project are: (1) to examine whether the genotypes of 100 cocaine-, heroin, or polydrug-dependent patients who return to substance use within 4 months after study enrollment are different from those of 100 patients who successfully maintain abstinence and 50 non-substance-dependent controls;(2) to replicate our previous findings of enhanced electroencephalographic fast beta activity and reduced frontal P300a amplitude in patients who return to substance use in comparison to patients who maintain abstinence and to healthy non-substance-dependent controls;(3) to determine if polymorphisms in GABRA2 and COMT genes are respectively associated with phenotypic variation in EEG fast beta power and frontal P300a amplitude;(4) to determine if genetic markers improve the prediction of relapse beyond the predictive accuracy attained with EEG fast beta power and frontal P300a amplitude, in combination with other known risk factors, including severity/chronicity of dependence, age, type of substance dependence, and Antisocial Personality Disorder.

1,2-benzenediol; 1,2-dihydroxybenzene; 2-hydroxyphenol; 4-Aminobutanoic Acid; 4-Aminobutyric Acid; 8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; AOD use; Abstinence; Age; Alcohol or Other Drugs use; Aminalon; Aminalone; Antisocial Personality; Antisocial Personality Disorder; Brain; Butanoic acid, 4-amino-; CRISP; Catechols; Clinical; Cocaine; Computer Retrieval of Information on Scientific Projects Database; Dependence; Dependence, Substance; Diacetylmorphine; Diamorphine; Disease; Disorder; EC 2; Electroencephalogram; Encephalon; Encephalons; Enrollment; Funding; GABA; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genotype; Goals; Grant; Heroin; Institution; Investigators; Link; Measures; Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl- (5alpha,6alpha)-, diacetate (ester); NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Patients; Phenotype; Polymorphism (Genetics); Polymorphism, Genetic; Pyrocatechols; Receptor Protein; Relapse; Research; Research Personnel; Research Resources; Researchers; Resources; Risk; Risk Factors; Severities; Sociopathic Personality; Source; Substance Addiction; Substance abuse problem; Testing; Transferase; Transferase Gene; United States National Institutes of Health; Variant; Variation; Work; abuse of substances; disease/disorder; enroll; gamma-Aminobutyric Acid; improved; o-Dihydroxybenzenes; ortho-Dihydroxybenzenes; polymorphism; receptor; substance abuse; substance use; theories

ATGN; Afferent Neurons; African; Amides; Animals; Antibody-Producing Cells; Antigens; Apoptosis; Apoptosis Pathway; Aspiration, Respiratory; BALB/c; Binding; Binding (Molecular Function); Blood Serum; Breathing; CRISP; Capsicum; Cell Death, Programmed; Chinese; Chinese People; Cicatrix; Clinical Research; Clinical Study; Common Rat Strains; Computer Retrieval of Information on Scientific Projects Database; Data; Dendritic Cells; Disease; Disorder; Dorsal Root of the Spinal Nerve; Dose; Drug Administration, Topical; Esthesia; Food Additives; Funding; Gasser's Ganglion; Gasserian Ganglion; Generalized Growth; Grant; Green Pepper; Growth; Human; Human, General; Hyperalgesia; Hyperalgesic Sensations; INFLM; Immune; Immune Globulins; Immune response; Immunity; Immunoglobulin-Producing Cells; Immunoglobulins; Immunoglobulins / Antibodies; Inbred BALB C Mice; Inflammation; Inhalation; Inhaling; Injection of therapeutic agent; Injections; Inspiration, Respiratory; Institution; Investigators; Laboratories; Lung; Malignant Melanoma; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Mediating; Medical; Mice; Mice, Inbred BALB C; Modeling; Molecular Interaction; Molecular Weight; Monitor; Mouse, BALB C; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Native Americans; Nerve Cells; Nerve Unit; Nervous; Nervous System Physiology; Neural Cell; Neurocyte; Neurologic function; Neurological function; Neurons; Neurons, Afferent; Neurons, Sensory; Nociception; Normal Cell; Pain; Painful; Patients; Peppers, Bell; Posterior root of spinal nerve; Rat; Rattus; Receptor Protein; Red Pepper; Research; Research Personnel; Research Resources; Researchers; Resources; Respiratory System, Lung; Roots, Dorsal; Scars; Semilunar Ganglion; Sensation; Sensory Cell Afferent Neuron; Serum; Site; Source; Staging; Structure of trigeminal ganglion; Symptoms; T-Cells; T-Lymphocyte; Thymus-Dependent Lymphocytes; Tissue Growth; Topical application; Toxic effect; Toxicities; Trigeminal Ganglias; Trigeminal Ganglion; Tumor Cell; Tumor Immunity; United States National Institutes of Health; Veiled Cells; allodynia; base; cell type; disease/disorder; drug efficacy; host response; hyperalgia; immunogen; immunoresponse; inspiration; lymphocyte proliferation; melanoma; neoplastic cell; nervous system function; neural; neuronal; nociceptive; ontogeny; pulmonary; receptor; receptor, vanilloid 1; relating to nervous system; response; spinal nerve posterior root; thymus derived lymphocyte; topical administration; topical drug application; topically applied; tumor; vanilloid receptor subtype 1

Component II - Predicting Treatment Outcome in Adolescent ADD Although an abundance of studies have associated comorbid psychiatric disorders, as well as some psychological constructs, with a poor response to Alcohol Use Disorder (ADD) treatment, the neurobiological processes underlying these associations have received scant attention. The proposed study will attempt to elucidate some of these processes. For example, we will examine whether AUD-positive youths exhibit neurophysiological and genetic signs that are more strongly correlated with outcome than Conduct Disorder. Also, we will ask whether these signs improve the prediction of outcome beyond that predicted by selfefficacy and readiness to change. Because neurophysiological status and genotype are objectively measured, they are not influenced by the variable reliabilities of the adolescent patient's report and the clinician's judgment. Accordingly, they offer an opportunity to estimate risk for treatment failure with a greater level of precision and may eventually prove valuable in clinical settings. N=235, 13-18 y.o. adolescents meeting DSM-IV criteria for AUD will complete a standardized treatment consisting of 2 weeks of individual Motivation Enhancement Therapy (MET) followed by 8-weekly sessions of group Cognitive Behavioral Therapy (CBT). The therapy will utilize an established treatment manual. All participants will be assessed for outcomes at the end of the 10 week treatment and at quarterly ntervals during a 12-month post-treatment period. Outcomes will be measured by the number of days of drinking and heavy drinking, and days of marijuana use. The primary analysis will employ structural equation modeling techniques to evaluate a causal path linking treatment outcome to GABRA2 genotype, electroencephalographic and event related potential signs of frontal brain dysfunction, and conduct disorder ymptoms. Relevance to Public Health: The proposed study will provide valuable data regarding predictors of treatment outcome in adolescents with Alcohol Use Disorders. It will examine the typical predictors, ncluding comorbidity, but it will also explore the value of objective laboratory measures, including candidate genes. The findings may have implications for devising optimal treatments based upon a systematic assessment of risk for treatment success or failure.

One goal of the proposed study is to evaluate the connections of three genes implicated in risk for externalizing disorders to: (1) impairments in specific domains of brain function that have also been implicated in risk for these disorders; and (2) an impairment in the maturation of these domains. Another goal is to evaluate the shared connections of the genes and brain dysfunction to both body mass/adiposity and alcoholism risk. The specific aims are: 1) To evaluate 150 girls, aged 14-16 yrs, and 150 girls, aged 16-18 yrs. The analysis will test for differences between the age cohorts in neurophysiological and behavioral signs of frontal and paralimbic brain function. The sample size of 300 establishes a foundation upon which we may, in a future application, build a longitudinal study and test for maturational change directly. 2) To test the association of neurophysiological and behavioral signs of frontal/paralimbic brain function, as well as their maturational change, with CHRM2, GABRA2, and ANKK1 gene polymorphisms. It is hypothesized that the genes will associate with different domains of dysfunction: (a) CHRM2 will primarily associate with impairments, and less change with age, in selective attention, working memory, and boredom susceptibility, (b) GABRA2 will primarily associate with motor impulsivity and response disinhibition, and less change in these domains with age. (c) The TaqlA and nearby polymorphisms in ANKK1 will primarily associate with reward seeking and response disinhibition, and less change in these domains with age. 3) To test the associations of the candidate genes, and neurophysiological and behavioral measures, with adiposity. An additional aim is to assess their association with various indicators of alcoholism risk, such as a smaller subjective response to alcohol and earlier ages at first use and first intoxication. It is hypothesized that all of the genetic and impulsivity measures will correlate with body mass/adiposity and alcoholism risk outcomes because all are indicators of an externalizing construct that promotes them.

The objective of this Alcohol Research Training grant is to provide specialized training for post-doctoral fellows in alcohol research. The program is designed to focus on the etiology, neurobiology, and mechanisms of alcohol use and misuse, and novel treatments for alcohol use disorders. It utilizes an interdisciplinary approach, representing psychology, psychiatry, medicine, social work, public policy, epidemiology, genetics, and neuroscience, and it draws on experienced faculty from inter-related institutions: University of Connecticut School of Medicine (UConn Health) and University of Connecticut (UConn-Storrs). The program will benefit from a variety of resources, including our P60 Alcohol Research Center, library services, a computer center, courses in advanced statistical techniques and a newly funded Certificate Program in Addictions Studies, human laboratories, an outpatient clinical research center, and the UConn Health Disparities Institute and Health Career Opportunities Programs. Trainees will select from four Core areas in clinical and translational research: 1) etiology and risk factors of alcohol use disorders; 2) neurobiology of alcohol use and disorders; 3) treatment of alcohol use disorders; and 4) mechanisms of alcohol treatment or its use. Our Training Faculty also has strong interests in multicultural and racial/ethnic minority aspects of alcohol use, HIV and other medical and psychiatric co-morbidities, electronic health technologies, and translational research. The training experience will emphasize these Elective research areas as well. Fellows will be assigned a primary and secondary mentor, based on similar research interests across these core and elective areas. The primary mentor will provide instruction in methods, design, analysis and ethics of alcohol research within the trainee's core research area(s), and the secondary mentor will ensure the trainee is meeting program and personal professional milestones, and when appropriate, collaborate with the trainee on writing papers for publication in elective areas. Additionally, each fellow will establish relationships with at least one external advisor, a prominent alcohol scholar outside the training institutions. The purposes of this connection are to extend the fellow?s training experiences beyond the local research community and stimulate networking and career development opportunities within the larger alcohol research field. The training program will include a curriculum involving seminars on foundations of alcohol research, ethics, professional development and grant writing. In conjunction with other T32s in the New England, we will hold an Alcohol Research Retreat in which trainees will present and can meet others in their own and other career stages. Expectations will be to 1) produce at least two first authored publications per year of training, 2) initiate and complete an independent or collaborative research project, 3) present research at RSA and other scientific conferences, and 4) prepare a grant application by the end of the training period. Given our successes in objectively measured standards with recent trainees, this program is well-poised to train the next generation of alcohol researchers.

ABSTRACT The Pilot Project Core will be managed by Lance Bauer, in consultation with the UCONN ARC Executive Committee and the Program Advisory Committee. Both proposed and all new applications in the out years will be reviewed to: (1) determine scientific merit; (2) improve the quality of the research through feedback, revision, and mentorship (if needed); (3) create a system whereby resources are allocated fairly and equitably; and (4) ensure that the research meets ethical standards. The proposed Pilot Project Core has a heavy emphasis on supporting new investigators in alcohol research, including new faculty members to our Medical School. Four pilot projects are proposed. The first project will examine the ivergent effects of alcohol on metabolism of oxidative epithealial vs glycolytic mesenchymal breast cancer cells, an important study given alcohol's putative role in increasing breast cancer risk. A second project focuses on the use of cognitive remediation, a behavioral therapy, to reduce depression and drinking among older adults. The third project is a one year follow-forward study of alcohol use and internet gaming among young adults, an area of growing interest in the US. The fourth project is a study of parental alcoholism and psychological adjustment in young adults. An open call will be issued in YR2 for pilot additional studies, funds permitting. The Pilot Project Core will allow investigators to pursue and develop innovative projects related to the etiology and treatment of alcohol dependence and related behaviors, the theme of the Center. This component provides an incubator for new ideas, provides for a critical and collegial review of proposals, and provides resources to pilot test potentially important ideas. It is an especially important resource for new and junior investigators.

This P50 application from the University of Connecticut Alcohol Research Center (UCONN RC) requests five years of funding for the Center's research programs on vulnerability to alcohol dependence and promising biological and psychosocial treatment interventions. The Administrative Core describes the UConn ARC's organizational framework, quality control mechanisms related to research and publications, and supporting research facilities. The visiting scholars program, consulting and mentoring activities, and journal editorship activities strengthen the UConn ARC's role as a regional and national resource. Research Project #1 will focus on several possible drinking to cope (DTC), stress-related pathways (including genetic) that may increase the susceptibility for developing heavy drinking and alcohol-related problems among former college students six plus years after graduation. This study will examine changes across 3 assessment waves in day-level associations among DTC motivation and its antecedents and outcomes and whether changes in these daily processes are related to individual differences across personality factors and other variables. Continuing our Center's emphasis on novel treatments, we propose two additional studies. Dual reinforcement contingency management (CM) for alcohol use disorders, Research Project #2, will evaluate the effects of reinforcing negative phosphatidylethanol (PEth) results alongside CM for attendance on several outcomes among patients in community treatment centers. It is hypothesized that this combination will result in greater attendance, more PEth negative samples, higher proportions of self-reported non-drinking days, and lower proportions of heavy drinking days. Research study #3 is a placebo controlled trial to evaluate the safety and efficacy of dutasteride among male and females with AUD. Reductions in drinking and the persistence of treatment effects will be examined. If replicated, the moderation of dutasteride treatment effects by a variant in FKBP5 would expand the growing list of potential genetic predictors, facilitating the development of personalized medication treatment recommendations for AUD. Finally, the proposed pilot studies core will support up to six studies that relate directly to the Center's themes of vulnerability and novel treatments for alcohol dependence and help support junior investigators and faculty new to alcohol research.