Thursday, June 10, 2010

CONTENTS

A. Legislation, Budget, and Policy

B. Director’s Activities

C. NIAAA Staff and Organization

D. Multi-Media Products from NIAAA

E. Outreach

F. News Media Interactions

G. What’s Ahead

H. NIAAA Program Announcement and Request for Applications Information

I. NIAAA Research Programs

A. Legislation, Budget, and Policy

Budget Update

FY 2010 Enacted

After a series of two Continuing Resolutions, Congress passed and the President signed the FY 2010 Omnibus Appropriations (HR 3288) on December 16, 2009 which provides FY 2010 appropriations for the NIH. NIH received a total of $31 billion, an increase of $692 million or 2.2% over FY 2009.

The FY 2010 appropriation for NIAAA provides $462.3 million. This represents a $12.1 million or a 2.7% increase over FY 2009 and a $7.2 million or 1.6% increase over the President’s budget request.

In addition to our FY 2010 appropriated funds, NIAAA plans to obligate its remaining $52.4 million from the American Recovery and Reinvestment Act (ARRA) apportionment.

FY 2011 President’s Budget Request

The FY 2011 President’s budget request was released on February 1, 2010. For the NIH, the total request is $32 billion, an increase of +$1.0 billion or 3.2% over FY 2010.

NIAAA President’s Budget request for is $474.6 million. This represents a $12.4 million or a 2.7% increase over the FY 2010 comparable level of $462.2 million.

The following highlights some of the major components of the FY 2011 President’s budget request:

Research Project Grants – Under the 2011 President’s budget request, NIAAA will support a total of 728 Research Project Grant (RPG) awards for $284 million. This includes support for 163 new and competing RPGs for $58.9 million. The NIH FY 2011 budget policy for RPGs is to provide for two percent inflationary increases in noncompeting awards and a two percent increase in the average cost for competing awards.

Alcohol Research Centers – The Centers program budget will support 20 research centers at $29.2 million.

Other Research - A total of $30.7 million is included for Other Research grants. Approximately $15.3 million is provided to support 98 research career awards. Cooperative Agreements will be funded at $9.4 million and Other Research Related grants will be funded at $5.9 million.

Research Training – The budget request provides $12.5 million to support 306 pre- and post- doctoral trainees. A 6% increase in trainee stipends levels is also included.

Research and Development Contracts – A total of $38.8 million is provided for R&D contracts. Funds are included in this mechanism to support several trans-NIH initiatives, such as the Therapies for Rare and Neglected Disease program (TRND), the Basic Behavioral and Social Science Opportunity Network (OppNet), and support for other HHS agencies through the program evaluation set-aside.

Intramural Research Program – Within the Intramural Research Program, $50.8 million has been allocated to maintain this program’s overall level of effort in FY 2011.

Research Management and Support – Funding for Research Management and Support activities is increased by 5.0% for a total of $28.6 million.

The House and Senate Appropriations Committee Hearings on the FY 2011 budget were held on April 28^th and May 5^th, respectively.  At the House hearing, Dr. Collins was accompanied by Drs. Fauci, Insel, and Rodgers. At the Senate Hearing, Dr. Collins testified alone.  Testimony focused on the top 5 NIH priorities: taking greater advantage of high-throughput technologies; accelerating translational science; helping to reinvent health care; focusing more on global health; and reinvigorating the biomedical research community.  Dr. Collins addressed how far we’ve come in biomedical research and how far we have to go and highlighted research in cancer, diabetes, obesity, genes and the environment, autism and depression. At both the House and Senate hearings, the FY 2011 impact of the drop-off in funding after the investment provided by the American Recovery and Reinvestment Act was discussed.

FY 2012

Preliminary work on the budget for FY 2012 has begun using the FY 2011 President’s budget request as the base.  After intermediate stages of review, the President’s budget request for FY 2012 will be presented to Congress in February 2011, at which time it will become available to the public.

A budget mechanism distribution of NIAAA’s FY 2009 actual obligations, the FY 2010 appropriation, and the FY 2011 President’s budget request is provided on the next page. The FY 2009 and 2010 columns of this table reflect some adjustments for comparability to the FY 2011 request.

B. Director’s Activities

NIAAA Acting Director Kenneth R. Warren, Ph.D. spoke or otherwise participated at the following recent meetings:

• The Leadership Foundation 10th Anniversary February 9, 2010

• CADCA Town Hall “Substance abuse and Addiction February 9, 2010

in Health Care Reform”

• ASAM 41st Annual Medical Scientific Conference April 15-19, 2010

• FY 2010 ICCFASD Meeting April 21-22, 2010

• NIAAA Mendelson Award Lecture April 29, 2010

• NIH IC Director's Retreat April 29, 2010

• SAMHSA FASD Expert Panel May 4, 2010

• Georgetown Medical School May 14, 2010

• SMRB Full Board Meeting May 18-19, 2010

SUAA Work Group of the SMRB Reports on Optimizing Addictions Research

The Substance Use, Abuse, and Addiction (SUAA) Work Group of the Scientific Management Review Board (SMRB) continues to develop recommendations for optimizing substance abuse and addiction research at NIH. Two significant meetings took place recently.

On March 10, 2010 the SUAA Work Group provided its initial findings on the potential for organizational change to foster greater collaboration between NAAA and the National Institute on Drug Abuse to the full SMRB during a meeting held at the National Institutes of Health. At this meeting, William Roper, M.D., M.P.H., chair of the SUAA Work Group, noted that the Work Group’s majority view is that the best way to proceed is a functional reorganization of research programs with a relevant scientific focus. A minority of SUAA Work Group members support a full structural merger.

At the May 18, 2010 meeting of the SMRB, panels of experts were convened to further discuss the SUAA Work Group’s proposed organizational options considering the public health aspects of addiction, as well as how best to capitalize on research opportunities across NIH while maintaining the individual strengths of NIAAA’s and NIDA’s research portfolios. NIAAA Acting Director Kenneth Warren, Ph.D. and NIDA Director Nora Volkow, M.D. were then asked to comment on the SUAA’s proposed levels of organizational change for the two Institutes. A public comment period followed.

The Work Group was charged with “fleshing out” the functional option and is expected to present formal recommendations to the SMRB during a public teleconference later this summer. The SMRB will hold its next full Board meeting September 14–15, 2010 in Bethesda, MD.

C. NIAAA Staff and Organization

NIAAA Mourns the Loss of Brenda G. Hewitt

On May 7, NIAAA staff learned of the death earlier that day of Ms. Brenda G. Hewitt, a long-time colleague at the Institute. Ms. Hewitt, special assistant to the Director, had been a staff member at NIAAA almost continually since 1972. NIAAA staff gathered on May 11 for an in-house memorial. The Institute will organize a larger, more formal memorial at a later date to celebrate the life and career of Ms. Hewitt, who considered NIAAA to be her “second family.” We will provide more information as details become available.

Honors

Dr. George Kunos, NIAAA Scientific Director, was recently awarded the Gabor Gyorgy Medal by the Hungarian Cardiology Society. Dr. Kunos also has been named to the Advisory Board of the Hungarian Academy of Science.

Dr. Abe Bautista, Director of the Office of Extramural Activities, received the Outstanding Service and Support Award from the Society on Neuroimmune Pharmacology for extraordinary service to the society and to the accomplishment of its mission during its annual meeting in Manhattan Beach, California on April 13-17, 2010.

Dr. Vibhuti Srivastava, a Fogarty Fellow in the Laboratory of Neurogenetics, won a Travel Award to the annual meeting of the Society of Biological Psychiatry in New Orleans from May 20-22, 2010. The award covered covered Dr. Srivastava’s airfare and meeting registration.

Dr. Mary-Anne Enoch of the Laboratory of Neurogenetics was recently elected President of the International Behavioral and Neurogenetics Society. The IBANGS was founded in 1996 to promote the field of neurobehavioural genetics.

Dr. David Goldman, chief of the Laboratory of Neurogenetics, was elected a Fellow of the American College of Neuropsychopharmacology. Dr. Goldman also recently gave the Sansone honorary lecture at Washington University in St. Louis, and he was a Plenary Speaker at the annual meeting of the Society of Biological Psychiatry in New Orleans from May 20-22, 2010.

Dr. Hua Wang, a Visiting Fellow in the Laboratory of Physiologic Studies, received the best poster award at the 2010 joint meeting of the American Society for Clinical Investigation and the Association of American Physicians, which took place April 23-25, 2010 in Chicago.

Peggy Murray, NIAAA’s Senior Advisor for International Research, received her Ph.D. in Social Policy from Catholic University of America on May 15, 2010. Dr. Murray’s dissertation was on brief intervention for alcohol problems in emergency department settings.

New Appointments

Dr. Lawrence Baizer joined the NIAAA Division of Neuroscience and Behavior as a Program Director in March, 2010. Dr. Baizer earned his Ph.D. in Pharmacology from the University of Colorado Health Sciences Center, where his dissertation research focused on the role of cyclic nucleotides in the regulation of neurotransmitter release. After postdoctoral work in molecular neurobiology at Massachusetts General Hospital/Harvard Medical School, Dr. Baizer moved to the Neurological Sciences Institute of the Oregon Health Sciences University, where he was a Principal Investigator from 1988 to 2000. His laboratory investigated the molecular mechanisms of action of Growth-Associated Protein (GAP)-43, a protein involved in axonal growth during neuronal development and regeneration. From 2000-2003 Dr. Baizer was a Senior Scientist at Bioject, Incorporated, where he explored new applications for the company's technology and was involved in several clinical vaccine and pharmacokinetic trials. From 2003-2010 he served as the Scientific Review Administrator of the Neurogenesis and Cell Fate study section at the Center for Scientific Review, NIH. At NIAAA Dr. Baizer will administer grants concerned with the effects of ethanol on neurogenesis, neuronal migration and differentiation in the developing nervous system.

Dr. Soundar Regunathan joined the NIAAA Division of Neuroscience and Behavior as a Program Director in March, 2010. Dr. Regunathan obtained his Ph.D. in Biochemistry/ Neurochemistry from the University of Madras, India, working on the effects of lead on amino acid neurotransmitter systems in young rat brain. After a two year postdoctoral fellowship in the Dept of Psychiatry at McGill University, Montreal, Dr. Regunathan moved to the Division of Neurobiology at the Dept of Neurology & Neuroscience at Cornell University Medical College, New York in 1989 where he spent next 12 years, raising from the level of Research Associate to Associate Professor. In 2002, Dr. Regunathan joined the Dept. of Psychiatry at the University of Mississippi Medical Center as Professor and stayed there until joining NIAAA. His major research interest was to understand the functions of novel receptors and neuromodulators in brain with particular focus on autonomic control, neuroendocrine functions, neuroimmune regulation and neuron-glial interactions. He was originally funded by an R01 grant from NINDS in 2001 and was recently awarded an R21 grant from NHLBI in Dec 2009. At NIAAA, Dr. Regunathan will administer grants related to the effects of ethanol on glial cell functions, immune response, neurotoxicity, stress and neuropeptide signaling in the developing and adult nervous system.

Dr. Christina Barr was selected as a Tenure Track Scientist to head the Section on Comparative Behavioral Genomics within the Laboratory of Neurogenetics.

Dr. Vijay A. Ramchandani is now a Tenure Track investigator and Acting Chief of the Section on Human Psychopharmacology within the Laboratory of Clinical and Translational Studies.

Dr. Marc Rigas joined the Science Policy Branch of the Office of Science Policy and Communication on June 7th as a Health Scientist Administrator. Before joining NIAAA, Dr. Rigas worked at the U.S. Environmental Protection Agency and prior to that served as a Scientific Review Officer at the Center for Scientific Review, NIH. Dr. Rigas received his Ph.D. in bioengineering from Pennsylvania State University in 1997. He holds a bachelor's degree from the University of Pennsylvania.

Extramural Staff Activities

Fourth Meeting of Expert Panel: NIAAA Underage Screening Project Organized by Dr. Vivian Faden, the meeting took place April 20-21, 2010 at NIAAA. The goal of the meeting was to further develop the content for the Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide. Maureen Gardner created a draft template for this guide, based on the recommendations of the Third Meeting of the Expert Panel, which took place in August 2009. General reaction to the draft was very positive. The Panel agreed that often doctors are reluctant to perform these kinds of assessments because they don’t have the words. This tool will give them the words in a familiar format that doctors can relate to. Doctors need to recognize this is a problem that starts early – just like obesity – it’s a real issue that needs to be addressed. Alcohol is the number one cause of death for adolescents – (involved in traffic accidents, suicides, homicides). Once doctors have this data, along with data on how brief interventions can have a behavioral impact, it can be very powerful. Next steps will be to create a new draft, include a dentist on the Expert Panel, and meet again for further discussion and review.

NIAAA Clinical Investigations Group (NCIG)

NCIG is an Institute-directed Phase II clinical trials program created to test promising medications for the treatment of alcohol use disorders. The purpose of the program is to design and conduct rapid Phase 2 proof of concept trials (within 12 to 18 months) of promising drugs that are supported by theory, pilot data in humans and animal models, and acceptable tolerability, safety, and interaction data. If an efficacy signal is detected, an effort will be made to further advance the compound. Sources of candidate compounds include novel compounds developed by pharmaceutical companies and those already marketed for different indications.

A Data Coordinating Center provides scientific and logistical support, clinical forms and documentation development, monitoring services, and data processing. NIAAA program staff is actively involved in design and protocol development, overseeing of the conduct, and analysis of the data. A Data Safety and Monitoring Board, composed of independent outside experts, meets at trial initiation and at least every six months during the course of the study. A Medical Monitor from NIAAA Intramural reviews all Serious Adverse Events according to FDA requirements and is available for questions that may arise concerning potential drug interactions, medical or psychiatric conditions of potential participants. Informed Consent documents are reviewed by NIAAA, the Coordinating Center, the DSMB, and must be approved by the participating sites’ IRBs before trial initiation. An IND (or an exemption) is obtained from the FDA for each study. Lastly, a Certificate of Confidentiality is issued for each clinical site.

The treatment phase of first trial, evaluating the atypical antipsychotic quetiapine (Seroquel) (N = 240), is complete and data analysis is underway. Recruitment for the second study, evaluating levetiracetam (Keppra) (N = 130), was completed well ahead of schedule and is now in the treatment phase. Planning for the third study is underway with startup projected for fall of 2010. Meetings with NCIG’s medications development consultants have been scheduled in June to discuss medication candidates for future trials.

The NCIG program is housed within the Division of Treatment and Recovery Research. Team members consist of Drs. Litten, Falk, Fertig, Mattson and Ms. Ryan.

Long-term Follow-up of NCIG Participants

Under a separate contract with RTI International, participants in all NCIG trials will be followed for several years after treatment. Dr. Page Chiapella oversees and participates in the follow-up phase, including design of questionnaires, subsample selection for special evaluations, and data analyses. In addition to quantitative interviews of all consenting patients, studies are conducted to evaluate topics of special interest, such as correlates with strong placebo responses, past-year sobriety or past year relapse. For this purpose, subsamples of patients selected for their responses to the quantitative questionnaires participate in a qualitative interview designed to probe further into the questions of interest. The overall purpose of the project is to evaluate factors involved in relapse and long-term recovery.

Drs. Chiapella and Dr Mattson developed an assessment of pre-randomization characteristics that affect patients’ participation in a clinical trial, including motivation to change, pre-trial changes in drinking, beliefs about placebo, opinions on effects of medication, and satisfaction with participation. This data collection is currently in the field and is a part of the larger Long-term Follow-up of NCIG Participants.

American College of Neuropsychology (ACNP) Medications Development Group

Drs. Daniel Falk and Raye Litten are serving on the ACNP Medications Development Group. The group also consists of representatives from the pharmaceutical industry, the FDA, and academia. The purpose is to validate new outcome measures for alcohol clinical trials and resolve methodological issues related to optimal duration of conducting a clinical trial and handling of missing data. Products will include a white paper and several publications based on analyses from multiple data sets. In addition, Drs Litten, Falk, Fertig and Mattson are collaborating on the analysis of several data sets from multisite clinical trials in order to develop guidelines for the design and methodology of clinical trials.

Mechanism of Behavior Change Interdisciplinary Research Consortium (MIRC)

Mechanism of Behavior Change Interdisciplinary Research Consortium (MIRC) has been formed as a result of the 2009 MOBCI research solicitation.  The interdisciplinary consortium seeks to build high-risk, high-payoff interdisciplinary approaches to alcohol-related problems via mechanism-based strategies--in particular, the long-term MOBCI goals driving the consortium are the initiation and sustainment of change from maladaptive drinking behaviors towards more healthful drinking behaviors. 

The MIRC is currently composed of teams led by the Research Foundation for Mental Hygiene, Inc. (Jon Morgenstern, Ph.D, Principal Investigator (PI));  Yale University (Steven W. Zucker, Ph.D, P.I.); and Rutgers, The State University of New Jersey (Marsha Bates, Ph.D, P.I.).  Consortium researchers have broad disciplinary expertise, including, but not limited to, mathematics, biostatistics, neuro-imaging, social/educational psychology, and cognitive/motivational neuroscience. The focus of the three teams is as follows:

The Research Foundation for Mental Hygiene is focusing on the mechanism of behavior change initiation for drinking behavior and the transition for problem drinking to moderate/social drinking. This team is studying the mechanisms that explain why some people successfully transition from problem drinking to non-hazardous drinking and other do not. Their aims are to:

• Develop dynamic systems model for 2 existing data sets.

• Adapt existing cognitive science paradigms related to self-regulation and neuroscience paradigms related to cognitive control to develop mechanisms based multi-level model of self-regulation of problem drinking. 

• Conduct studies to reveal the cognitive mechanisms triggered by Mental Contrasting and Implementation Intention (MCII) that are responsible for behavior change.

• Develop a working model of MCII for problem drinkers and gather preliminary data within-treatment data on processes.

• Develop a working model of MCII for problem drinkers and gather preliminary data within-treatment data on processes.

The Rutgers University team is working to quantitatively model adaptive neurobiological subsystems that regulate physiological arousal and its expression to the environment and to relate subsystem control to drinking behaviors and alcohol risk.

This team will focus on:

• Heart rate variability which provides a direct window into the baroreflex system modulation of emotional arousal and is a changeable point of intervention using biofeedback.

• Facial expressions, which conveys the nature and level of emotional arousal to the environment.

• Explore genetic links of these systems and attempt to relate their controlling variables to alcohol use, problems, and genetic and psychosocial vulnerability.

• Link drinking behavior and emotions with ANS variability and baroreflex control variable to predict, explain and in future studies to intervene in unhealthy drinking behavior and risk for such behavior.

• They posit that emotional processes have variability that is related to variability of physiologic function (HRV).

The Yale University team is working to discover implicit relationship using non-linear dimensional reduction and geometric harmonic analysis. This approach seeks to discover implicit variables. The resulting new tools can be used to compress and analyze large and complex data sets, such as those derived from sensor networks or neuronal activity datasets, obtained in the laboratory or through computer modeling.

The key concepts for this work are dimensionality reduction, higher order Implicit structure of maladaptive drinking and geometric harmonics analysis. The databases that are being use for this investigation include the following:

• NESARC

• ADD Heath

• MATCH

• COMBINE

• National Comorbidity Survey

• Viet man Twin Register

• Monitoring the Future

Dr. Robert Huebner, director of the Division of Treatment and Recovery Research (DTRR), represented NIAAA at the annual meeting of the American Psychiatric Association August 12-15, in San Diego. Dr. Huebner provided an update on NIAAA programs to the Expert Advisory Panel on Addiction Psychiatry.

Drs. Daniel Falk and Raye Litten presented results of data analyses of endpoint measures, grace periods, and optimal duration of clinical trials from five alcohol clinical trials data sets at the ACNP Medications Development Group in February 2010 in Rockville, Maryland.

Dr. Raye Litten presented an update on medications development at NIAAA to Eli Lilly and Company in March 2010 in Indianapolis, Indiana.

NIAAA medications development group met with Abbott Pharmaceutical to discuss possible collaborations in April 2010 in Rockville, Maryland.

Dr. Daniel Falk is a NIAAA contributor to the PROMIS Substance Abuse Working Group. The purpose of the group is to compile a set of standardized and validated survey questions that measure alcohol consumption and consequences for use in the clinical and research community.

Dr. John Matochik of the Division of Neuroscience and Behavior (DNB), represented NIAAA at the 2^nd annual Domenici Neuroscience Symposium at the Liaison Capitol Hill Hotel in Washington, DC. The all-day symposium is sponsored by the MIND Research Network and honors the contributions of former Senator Pete Domenici (R-NM) to neuroscience research and mental health services. This year’s theme was on “Neuroscience for National Security.” Dr. Robert Thoma, an NIAAA grantee from the University of New Mexico, was one of the presenters.

Dr. John Matochik, was also chosen to participate in the evaluation of the NIH Roadmap program on Interdisciplinary Research Teams of the Future. The program is currently supporting nine interdisciplinary research consortiums across the country with the goal of promoting a team science approach to discovery. NIAAA has program responsibilities for the Interdisciplinary Research Consortium on Stress, Self-Control and Addiction at Yale University. Abt Associates Inc. of Cambridge, MA is conducting the questionnaire and interview portion of the evaluation process for NIH.

Dr. Marcia Scott of the Division of Epidemiology and Prevention Research, organized and presented at a workshop entitled “Utilization of Innovative Interdisciplinary Tools for Integrated Objective Measurement of Exposure to Physical and Psychosocial Stressors and Drug Use” and a symposium entitled “Interdisciplinary Approaches and Tools for Objective Measurement of Psychosocial Stress and Substance Use” at the Society for Prevention Research (SPR) 18th Annual Meeting in Denver, CO, on June 1-4, 2010. The workshop and symposium highlighted the progress of projects involved in the Network on Exposures to Psychosocial Stress and Addictive Substances (NEPSAS), a program supported by the NIH Genes, Environment and Health Initiative (GEI) Exposure Biology (EB) program. The EB component of GEI supports projects utilizing new methods (e.g., alcohol biosensor, ecological momentary assessment/EMA, geospatial positioning/GPS, and light sensor) to assess personal exposure to environmental stressors and responses to those stressors via key biological pathways involved in the pathogenesis of common diseases. Dr. Scott also co-organized and presented at a symposium at the SPR conference on June 4, 2010, entitled “The Intersection between Substance Use Prevention and Work Settings: Research to Inform Work-focused Prevention for Adolescents and Emerging Adults.”

Dr. Mariela Shirley of DEPR serves as Chair of the NIH OppNet Capacity Building Concept Team. OppNet is a trans-NIH initiative to expand the agency's funding of basic behavioral and social sciences research (b-BSSR) which will fund $120 million of research through 2014. The mission of OppNet is to pursue opportunities for strengthening basic behavioral and social science research (b-BSSR) at the NIH while innovating beyond existing investments. Basic-BSSR furthers our understanding of fundamental mechanisms and patterns of behavioral and social functioning, relevant to the Nation’s health and well-being, as they interact with each other, with biology and the environment. Research results lead to new approaches for reducing risky behaviors and improving health. For more information on the history of OppNet see http://www.psychologicalscience.org/observer/getArticle.cfm?id=2574; NIH OppNet web site may be found at URL http://oppnet.nih.gov/. Dr. Robert Freeman of DEPR serves on the NIH OppNet “Social Environment” Concept Development Team and the RFI Data Analysis Subcommittee.

Dr. Judy Arroyo of DEPR, and the NIAAA Minority Health and Health Disparities Coordinator, led efforts to develop the 2009-2013 NIAAA Health Disparities Strategic Plan. This document can be viewed, along with other Health Disparities information at http://www.niaaa.nih.gov/alcohol-health/special-populations-co-occurring-disorders/diversity-health-disparities.

Dr. Bill Dunty was a guest panelist in the “NIH Grant Process and Opportunities for Cancer Research Funding at NIH” session at the 101st Annual Meeting of the American Association of Cancer Research on April 20th, 2010 in Washington DC.

Dr. Andras Orosz co-organized a symposium for the RSA: Alcohol and the cardiovascular system: mitochondrial dynamics and oxidative stress. (Organizers/Chairs: Andras Orosz and Daria Mochly-Rosen)

Dr. Peter Gao is currently serving as an associate editor for the Journal of Discovery Medicine.

Dr. Svetlana Radaeva’s efforts were instrumental in NIAAA’s receipt of a $20,000 award from the NIH Office of Rare Diseases to support the 15th International symposium on Cells of the Hepatic Sinusoid in Pasadena, CA, from August 28 to September 1, 2010.

Dr. Sam Zakhari gave a presentation on February 20, 2010 at the 54th Annual Meeting of the Biophysical Society held in San Francisco, entitled “Alcohol Metabolism and Mitochondrial Injury.”

NIAAA Extramural Advisory Board Meeting: Alcohol and Cancer The Division of Metabolism and Health Effects convened a meeting of the NIAAA Extramural Advisory Board on June 8-9, 2010 to discuss the state of knowledge, gaps and research opportunities concerning the influence of alcohol on cancer risk. Worldwide, alcohol-attributable cancer accounts for 20% to 35% of all upper aerodigestive tract cancers, 9% of all liver cancer 4.5% of all breast cancer. Although cancer may be considered as a collection of diseases in which abnormal cells divide without control and are able to spread to other tissues throughout the body, the contribution of lifestyle factors such as heavy drinking to the genesis and spread of tumors cannot be ignored. Subject areas discussed included epidemiology, metabolism, epigenetics, signaling, retinoid homeostasis, protein homeostasis, inflammation, immune surveillance and stem cells.

Dr. Ralph Hingson presented “Policy Research on Impaired Driving: Lessons from Alcohol Research,” at the National Institute on Drug Abuse, Bethesda, MD, March 19, 2010.

Dr. Ralph Hingson moderated a Panel Discussion entitled “Prevention Options: What’s Right for your State?” at the Leadership to Keep Children Alcohol Free Foundation’s 2010 Prevention Day Seminar, National Harbor, MD, February 9, 2010.

Dr. Ralph Hingson presented “College Drinking Trends: Community Prevention and Intervention,” at the University of North Carolina, Charlotte, Charlotte, NC, April 8, 2010. He also presented “Alcohol-Impaired Driving and Other Injury Prevention: From Global to Local,” at the University of Michigan, Ann Arbor, MI, February 17, 2010.

Dr. Greg Bloss co-chaired a session and participated in a Funders’ Panel at the 2010 International Conference on Social Computing, Behavioral Modeling, & Prediction (SBP10) held March 29, 2010–April 1, 2010 at NIH.

Dr. Antonio Noronha, director of the Division of Neuroscience and Behavior, co-organized and chaired a Colloquium with Dr. Fulton Crews from the University of North Carolina, Chapel Hill at the 41st Annual Meeting of The American Society for Neurochemistry in Santa Fe, New Mexico, March 6-10, 2010. The Colloquium was entitled “Signaling in Innate Immunity: How do cytokines, proteases, lipases, oxidases, and other innate immune genes change the brain? Dr. Noronha gave an Overview of CNS Innate Immunity as an Introduction to the colloquium.

D. Multi-Media Products from NIAAA

Research Gallery

As part of our ongoing effort to increase the public visibility of NIAAA research, the Office of Science Policy and Communications recently launched an online Research Gallery on the NIAAA Web site. This new resource contains brief news capsules of selected research conducted or supported by NIAAA. We anticipate that the Research Gallery will serve a variety of audiences both within and outside NIAAA. Please visit the Research Gallery at: http://www.niaaa.nih.gov/news-events/research-highlights

New Publications

• NIAAA Newsletter -- The Communications and Public Liaison Branch (CPLB) published issue 20 of the NIAAA Newsletter in May. The newsletter features:

• Information on the Institute's 40th-anniversary commemorative events including a special symposium to be held October 4.

• The redesign of the Alcohol Policy Information System (APIS) to provide easier access to high-quality state-by-state alcohol policies data.

• An update on the activities of the Scientific Management Review Board (SMRB), which is continuing to develop its recommendations for optimizing substance abuse and addiction research at NIH.

• NIAAA Spectrum -- Issue 3 of the Institute's online webzine features lead stories on NIAAA's honorary Jack Mendelson and Mark Keller lecture series, as well as on the utility of medications for treating alcoholism with co-occurring depression. "From the Field" stories include those on dietary choices among individuals with alcohol use disorders, alcohol's influence on cardiovascular disease, and at-risk drinking among older adults. NIAAA's Robert Huebner, Ph.D. discusses the latest research in the understanding and treatment of alcohol use disorders. A charticle on unmet treatment need and a photo essay on 3-dimensional models for drug development round out the issue.

• Alcohol Research & Health -- The Institute will debut a special 40th-anniversary issue of its scientific journal, Alcohol Research & Health at the annual Research Society on Alcoholism (RSA) meeting on June 26. This anniversary issue describes the Institutes' multidisciplinary contributions to alcohol research and its public health impact since its founding on December 31, 1970.

New 40^th Anniversary Exhibit in Bldg 31

In May, NIAAA installed an updated exhibit structure in the Building 31 breezeway on the NIH campus. Traditionally, most NIH Institutes and Centers maintain a standing exhibit in this corridor that serves as a main thoroughfare among the administrative offices located in Building 31. NIAAA's new exhibit has a more streamlined structure than its predecessor and a simplified message: "40 Years of Alcohol Research." The structure is designed to be easily updated to promote awareness of the Institute and its messages to the NIH community.

E. Outreach

Seasonal Outreach Series Continues with High School Graduation Fact Sheet

The Office of Science Policy and Communications released its high school graduation fact sheet, Parents: Help Your Teens Party Right at Graduation, in May. Seasonal fact sheets contain relevant statistics presented in an easy-to-understand "infograph" style, practical science-based commentary, and NIAAA website information. They are disseminated widely through electronic media and in print upon request. The 2010 graduation fact sheet focuses on the physiological effects of excessive drinking and corrects some popular myths about intoxication and alcohol poisoning. It also featured statistics on heavy drinking, drunk driving, and alcohol abuse and dependence among college students and youth.

While pickup is continuing, preliminary results indicate that the fact sheet has been featured on more than 50 websites, including CNBC, Forbes, Science Daily, AOL, and Earth Times, as well as business journals and corporate publications. Thus far, it has reached a total audience of more than 6 million. As the graduation season continues, NIAAA will be distributing the fact sheet to education journalists, and in hard copy to selected high schools and PTA groups in conjunction with commencement ceremonies.

Brain Awareness Week: NIH and the National Museum of Health and Medicine at Walter Reed Army Medical Center hosted the Museum’s 11^th annual Brain Awareness Week on March 17 and 18, 2010. Brain Awareness Week, organized by the Dana Alliance for Brain Initiative, is an international partnership of government agencies, scientific organizations, university and volunteer groups dedicated to advancing education about the brain. NIAAA and other NIH institutes with neuroscience–related programs presented a series of hands-on demonstrations and exhibits, which included Dr. Ivana Grakalic’s “Alcohol and Brain Nonsense” interactive presentation about alcohol’s effects on the body and the brain, along with the “Fatal Vision” goggles obstacle course.

Take Your Child to Work Day: NIH celebrated its 16^th annual Take Your Child to Work Day on April 22, 2010. Through educational and fun activities, children ages 5-15 experienced the world of biomedical research at NIH as well as critical services and resources needed to support it. NIAAA activities included “Alcohol and Brain Nonsense” interactive presentation hosted by Dr. Ivana Grakalic, followed by “Fatal Vision” obstacle course with Fred Donodeo and Diana Urbanas.

Dr. Philippe Marmillot, Health Scientist Administrator in the Office of Extramural Activities, participated as the Scientific Review Officer of a Mock Study Section at the 2010 Surgical Investigators Conference in Bethesda, MD on March 7, 2010.

Dr. Abe Bautista, Director of the NIAAA Office of Extramural Activities, co-chaired the scientific session on “Effects of HIV-1 in Promoting Alcohol Addiction and Mechanisms of Associated Neurodegeneration” and “Technical Workshop on Grantsmanship and Funding Opportunities at NIH” during the 16^th Annual Scientific Conference of the Society on Neuroimmune Pharmacology, in Manhattan Beach, California on April 13-17, 2010.

Dr. RV Srinivas, Chief of the Extramural Project Review Branch in the Office of Extramural Activities, presented a lecture on “The Review Process at NIAAA/NIH” during the 16^th Annual Scientific Conference of the Society on Neuroimmune Pharmacology, in Manhattan Beach California on April 13-17, 2010.

Dr. Ralph Hingson, director of the Division of Epidemiology and Prevention Research, presented “Recent Trends and Findings Regarding the Magnitude and Prevention of College and Underage Drinking Problems,” at:

• Grand Rounds of the Department of Psychiatry, University Hospitals of Cleveland, Case School of Medicine, Cleveland, OH, May 14, 2010.

• Northeast Ohio University and College Counseling Centers Association at Baldwin College, Berea, OH, May 13, 2010.

• 18th Annual Virginia S. DeHann Lecture on Health Promotion and Education, Rollins School of Public Health at Emory University, Atlanta, GA, March 23, 2010.

• Community Anti-Drug Coalitions of America’s (CADCA) 20th National Forum, National Harbor, MD, February 9, 2010.

• Virginia Commonwealth University, Richmond, VA, January 26, 2010.

• Webinar sponsored by the Substance Abuse and Mental Health Services Administration, Rockville, MD, January 21, 2010.

Dr. Ralph Hingson presented “Lending Support to Educational and Enforcement Campaigns and Other Safety Programs,” at the Association of State and Territorial Health Officials (ASTHO): Presidential Challenge Meeting, Washington, D.C., May 11, 2010.

Dr. Ralph Hingson presented “Alcohol-Impaired Driving and Other Injury Prevention: From Global to Local,” to the Alcohol, Drug Addiction & Mental Health Services (ADAMHS) Board of Cleveland, OH, on May 13, 2010.

Dr. Ralph Hingson presented “Prevention of Alcohol-Related Injuries Among Youth,” at The Center for Injury Research and Prevention in Philadelphia, PA on March 30, 2010 and at the Department of Pediatrics: Grand Rounds, Children’s Hospital of Philadelphia, on March 31, 2010.

F. News Media Interactions

NIAAA Press Releases

May 18, 2010: Receptor Variant Influences Dopamine Response to Alcohol

A genetic variant of a receptor in the brain’s reward circuitry plays an important role in determining whether the neurotransmitter dopamine is released in the brain following alcohol intake, according to a study led by Vijay A. Ramchandani, Ph.D, and Markus Heilig, M.D., Ph.D., of the NIAAA Laboratory of Clinical and Translational Studies. A report of the findings, which help explain the diverse genetic susceptibility for alcohol use disorders, appeared online in Molecular Psychiatry on May 18, 2010.

April 26, 2010: Scientists Find Genes That Influence Brain Wave Patterns

Scientists led by Colin A. Hodgkinson, Ph.D., and David Goldman, M.D., of the NIAAA Laboratory of Neurogenetics identified new genes and pathways that influence an individual’s typical pattern of brain electrical activity, a trait that may serve as a useful surrogate marker for more genetically complex traits and diseases. One of the genes, for example, was found to be associated with alcoholism. A report of the findings appeared in the Proceedings of the National Academy of Sciences.

March 25, 2010: Diet Quality Worsens as Alcohol Intake Increases

People who drink more are also likely to eat less fruit and consume more calories from a combination of alcoholic beverages and foods high in unhealthy fats and added sugars, according to a new study by Rosalind Breslow, Ph.D., M.P.H., of the NIAAA Division of Epidemiology and Prevention Research and researchers at the National Cancer Institute (NCI), and the U.S. Department of Agriculture (USDA). The study of more than 15,000 adults in the United States found that increased alcoholic beverage consumption was associated with decreased diet quality. The article was published in the April 2010 issue of the Journal of the American Dietetic Association.

Interviews and Articles

Dr. Sam Zakhari gave interviews to CNN Health online and to Men’s Health Magazine about alcohol and hangover remedies that were published in March, 2010.

Joseph Hibbeln, M.D., acting chief of the section on nutritional neurochemistry in the NIAAA Laboratory of Membrane Biochemistry and Biophysics, was featured in a lengthy article in the May/June, 2010 issue of Eating Well magazine. The article explored Dr. Hibbeln’s research on the mental health effects of omega-3 fatty acids. Dr. Hibbeln was also interviewed by the Washington Post and Prairie Public Broadcasting for upcoming stories about his research.

NIAAA clinical director Markus Heilig, M.D., Ph.D. was featured in the May 14, 2010 issue of the NIH Record in an article titled: Pharmacogenomics and Alcoholism: Why Meds Work for Some People, but Not for Others.

G. What’s Ahead

NIAAA Acting Director Kenneth R. Warren, Ph.D. is scheduled to speak or otherwise participate at the following meetings:

• 33rd Annual RSA Scientific Meeting June 26-30, 2010

• NASADAD - 23rd Annual National Prevention Aug 31-Sep 3, 2010

Network Conference (Denver, CO)

• INSERM – ISBRA - Paris September 9, 2010

• International Society for Biomedical September 13, 2010

Research on Alcoholism

The Division of Neuroscience and Behavior has organized these upcoming meetings:

• “A Systems Biology Approach to Understanding the Effects of Alcohol on the Brain,” Satellite Meeting at the Research Society for Alcoholism, June 26,2010, San Antonio, TX.

• NIAAA Workshop, “Phase 2 - Longitudinal Studies of the Impact of Adolescent Drinking on the Developing Brain,” July 20, 2010, Rockville, MD

H. NIAAA Program Announcement, Request for Application, and CRADA Information

RFA-AA-11-001: Multi-Component Youth/Young Adult Alcohol Prevention Trials (R01). This announcement invites research grant applications that will advance the science of alcohol prevention and treatment through evaluations of multi-component community programs, with a specific focus on adolescents and young adults. It seeks proposals to test the relative effectiveness and costs of: (1) Community based programs comprised of environmental interventions to reduce underage and binge drinking among young adults and related harmful behaviors; (2) Community based programs that increase alcohol screening, brief intervention, and access to formal treatment for adolescents and young adults in multiple community settings (e.g. primary care, emergency departments, school- and work-based settings, and web-based venues); and (3) Programs that combine both strategies.

PAR-10-187: Program Project on Alcohol-Related Research (P01) The NIAAA Program Project Initiative provides leadership in conducting and fostering interdisciplinary research on a wide variety of topics including, but not limited to: the nature, causes, consequences, diagnosis, treatment, and prevention of alcohol abuse and alcoholism; and in developing new topics, approaches and methodologies to pursue these areas of research.

PA-10-085 & 086: The Role of Cellular Organelles in Alcohol-Induced Tissue Injury (R01 and R21, respectively) This announcement encourages Research Project Grant applications (R01) that propose to study biological processes involving the cellular organelles in alcohol-induced tissue injury. The purpose is to: (1) better understand how acute or chronic alcohol consumption affects the structure and function of cellular organelles, and in turn, how these changes contribute to alcohol-induced injury; (2) investigate how variations of proteins in cellular organelles, or their regulation and function, including cellular signaling pathways, contribute to an individual’s response to acute or chronic alcohol intake and alcohol-induced tissue injury; (3) develop potential biomarkers for prognosis and diagnosis of tissue injury, or identify new targets for therapeutic interventions.

PA-10-093 & 094: Stress Pathways in Alcohol Induced Organ Injury and Protection (R01 and R21, respectively) This announcement encourages Research Project Grant (R01) applications that propose studying the role of cellular stress responses, the cytoplasmic classical stress response or heat shock response (HSR) and the endoplasmic reticulum (ER) stress, in alcohol-induced tissue injury and tissue protection. The purpose of this NOFO is to: (1) acquire insight into how acute or chronic alcohol consumption affects cellular stress pathways and in turn, how these changes contribute to alcohol-induced injury/protection; (2) investigate how alcohol induced stress responses mediate cell survival and death signaling pathways at macromolecular, organelle, cellular and organism level contributing to alcohol-induced tissue injury/protection; (3) develop potential stress related biomarkers for prognosis, diagnosis of tissue injury/protection, furthermore identify new targets for their therapeutic interventions.

PA-10-100, 101 & 102): Alcohol Use Disorders: Treatment, Services Research, and Recovery (R01, R03 and R21, respectively) This announcement encourages grant applications from institutions/organizations that propose to support research on behavioral and pharmacological treatment for alcohol use disorders; organizational, financial, and management factors that facilitate or inhibit the delivery of services for alcohol use disorders; and phenomenon of recovery from alcohol use disorders. It will utilize the NIH Research Project Grant (R01) award mechanism and runs in parallel with two announcements of identical scientific scope: PA-10-102 that encourages applications under the R21 mechanism and PA-10-101 that encourages applications under the R03 mechanism.

I. NIAAA Research Programs

RESEARCH REPORTS

The following items represent examples of the breadth and quality of research conducted and supported by NIAAA.

The Endocannabinoid System Depresses Alcohol’s Effect in the Central Amygdala.

The central amygdala is a brain region that plays a major role in alcohol dependence and reinforcement. Behavioral and neurochemical evidence suggests a role for the endocannabinoid system in ethanol use and dependence. In this study, researchers found that type 1 cannabinoid (CB1) receptor agonists decrease gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission in central amygdala neurons. Interestingly, CB1 receptor antagonists increased baseline GABAergic neurotransmission in the absence of exogenous agonists. These data indicate a prominent role for the endocannabinoid system in regulating synaptic transmission in the central amygdala. Further studies to delineate the cellular effects of endocannabinoids and CB1 ligands and their modulation by acute and chronic alcohol exposure may lead to a better understanding of the cellular mechanisms of addiction and dependence. (Roberto M, Cruz1 M, Bajo M, Siggins GR, Parsons LH, Schweitzer P. Neuropsychopharmacology 2010. advance online publication).

Visualization of Dynamic Dopamine Changes in the Human Brain.

In this report, researchers describe mathematical modeling and visualization methods to follow the time course of the dopamine concentration in the human brain during positron emission tomography (PET) studies. Previously, receptor modeling methods with PET could measure an average value of a neurotransmitter concentration during the course of a study. The new modeling method detects neurotransmitter changes on a minute-to-minute basis, and has important implications for the study of alcohol and drug abuse, since dopamine kinetics in the brain has been implicated in addiction liability. Understanding the temporal dynamics of dopamine will resolve more clearly our understanding of dopamine action in the brain. This new modeling method can also be applied to other neurotransmitters, such as serotonin, to more fully characterize their actions in the brain and their effects on addictive behaviors.(Morris ED et al. NeuroImage 2010; 51:135-144)

Study Reveals Differences in Brain Wave Patterns in ADHD Young Adults with and without Prenatal Alcohol Exposure.

Investigators reported a difference in the P3 brain wave activity during performance of a response inhibition task between young adults with idiopathic ADHD and young adults with a history of prenatal alcohol exposure and ADHD. This difference in brain electrical activity during response inhibition may be a unique biomarker for differentiating these clinical groups. The P3 difference also suggests a possible mechanism as to why individuals with ADHD symptoms and prenatal alcohol exposure do not respond as well to psychostimulant medications as those with ADHD but with no history of prenatal exposure to alcohol. This study highlights the importance of obtaining information about prenatal alcohol exposure in studies of ADHD. Such information may help to guide more effective and individualized treatment approaches. (Burden MJ et al. Alcohol Clin Exp Res 2010; 34:617-627)

Differential expression of proteins in fetal brains of alcohol-treated mice.

Previous studies have shown that moderate prenatal alcohol exposure results in brain defects at different stages of development. In the current study, researchers used quantitative proteomic analyses to investigate differential protein expression in fetal brains of alcohol-treated mice. The down-regulation of several important mitochondrial enzymes explains the mitochondrial dysfunction induced by alcohol exposure, and the down-regulation of some cytoskeletal proteins provides information about the effects of prenatal alcohol exposure on cell migration and neurite extension. Understanding the regulation of proteins in fetal alcohol exposure or fetal alcohol syndrome models will ultimately provide new mechanistic explanations for alcohol-related brain abnormalities. Taken together, these findings may provide important information for identifying mechanisms of neuroprotection, and may also allow for the development of intervention strategies to could protect or attenuate the deleterious effects of alcohol exposure during pregnancy. (Sari Y, Zhang M, Mechref Y. Electrophoresis 2010; 31, 483–496)

Hippocampal Activity May Reveal Long-Term Effects of Adolescent Alcohol. Previous studies in rats have shown that ethanol exposure can produce long-term changes in hippocampal electroencephalogram and event-related potential activity. Recently in humans, it was shown that event-related oscillations (EROs) may be good indices of alcoholism risk. However, the effect of adolescent alcohol exposure on EROs has not been evaluated. The results from this study suggest that the decrease in P3 event-related potential amplitudes found in adult rats following adolescent alcohol exposure is associated with increases in hippocampal evoked theta EROs. These studies suggest that EROs are suitable for characterizing long-term effects of adolescent alcohol exposure. (Criado J, Ehlers C. Behav Brain Res., 2010 Jul 210(2):164-70).

Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity

Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. In this study researchers show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. The investigators conclude that an interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. (Wang H, et al. Hepatology, 2010 April 51(4): 1354-1362).

Study Points to NK1R Blocker as Possible Alcoholism Treatment

Neurokinin-1 receptors (NK1R) are highly expressed in brain areas involved in stress responses and drug reward. In recent years, mounting research evidence has suggested that they may help regulate important aspects of alcohol use. In a new study, researchers in the NIAAA Laboratory of Clinical and Translational Studies report that a compound that blocks NK1R suppresses alcohol drinking in mice. NIAAA Clinical Director Markus Heilig, M.D., Ph.D., and colleagues also showed that mice that lack the gene for NK1R have a lower preference for alcohol than do normal mice, and score lower on measures of alcohol reward, a key aspect of its addictive effects. Taken together, the data from the new study supports further investigation of NK1R blockade as a potential treatment for alcoholism.

(Thorsell A, Schank JR, Singley E, Hunt SP, and Heilig M. Psychopharmacology (Berl). 2010 Mar;209(1):103-11.)

NPY Suppresses Stress-Induced Alcohol Relapse in Rats

Neuropeptide Y (NPY) is a naturally-occurring brain molecule that helps regulate emotional behavior, stress responses, and other functions. Much research evidence suggests that NPY also plays an important role in regulating alcohol consumption. Scientists led by NIAAA Clinical Director Markus Heilig, M.D., Ph.D., recently investigated the effect of NPY on stress-induced relapse to alcohol use. Relapse prevention is an important aspect of alcoholism treatment, and researchers who study this phenomenon often rely on animal models of relapse-like behavior. Such models usually involve training laboratory rats to obtain alcohol by pressing a lever. Later, the lever-pressing behavior is "extinguished," or unlearned, by removing the alcohol reward. Researchers then simulate alcohol relapse by exposing the animals to stress, which causes them to again seek alcohol by lever-pressing. Stress in rats is reliably induced by injections of yohimbine, a drug that causes anxiety and panic. Using this approach, Dr. Heilig and colleagues from the NIAAA Laboratory of Clinical and Translational Studies found that by injecting rats with NPY, they could suppress the relapse-like alcohol-seeking behavior brought on by yohimbine. The findings, they note, support further study of NPY as a potential treatment for alcoholism. (Cippitelli A, Damadzic R, Hansson AC, Singley E, Sommer WH, Eskay R, Thorsell A, and Heilig M. Psychopharmacology (Berl). 2010 Feb;208(3):417-26.)

Classification of Alcohol Abuse by Plasma Protein Biomarkers.

Improved biochemical diagnostics for ethanol intake would aid alcohol abuse treatment and have applications in clinical trial and public safety settings. To address this unmet need, plasma protein biomarker discovery and validation were performed with an alcohol self-administering nonhuman primate model system to develop a diagnostic that accurately classifies subjects into nondrinking, nonabusive drinking, and abusive drinking categories. This model system provides the closest animal model to human alcoholism with similar physiology and durations of drinking. A 17-plasma protein panel was determined that correctly classifies abusive drinking with 100% sensitivity and also differentiates any level of drinking from alcohol abstinence with 88% accuracy. The biomarker panel reflects changes in multiple organ systems and suggests robust changes in the plasma proteome with drinking that might serve as a sensitive and specific diagnostic test. The specific plasma proteins altered with alcohol self-administration might represent indicators of alcohol-induced stress on a variety of organ systems. (Freeman WM, Salzberg AC, Gonzales SW, Grant KA, Vrana KE.

Biol Psychiatry. 2010 Mar 16. [Epub ahead of print])

Researchers Explore Mechanism of Alcohol-Related Melanoma Progression.

Chronic alcohol consumption decreases the survival of mice bearing subcutaneous B16BL6 melanoma. The underlying mechanism is still not completely understood. Antitumor T cell immune responses are important to inhibiting tumor progression and extending survival. Therefore, in this study researchers examined the effects of chronic alcohol consumption on the functionality and regulation of antitumor T cell in C57BL/6 mice that chronically consumed 20% (w/v) alcohol and subsequently were inoculated subcutaneously with B16BL6 melanoma cells. Chronic alcohol consumption inhibited melanoma-induced memory T cell expansion and accelerated the decay of interferon (IFN)-γ producing T cells in the tumor-bearing mice. Foxp3+CD4+CD25+ regulatory T cells were not affected; however, the percentage of myeloid-derived suppressor cells (MDSC) was significantly increased in the peripheral blood and spleen. T cell proliferation in vitro was inhibited by alcohol consumption relative to control water-drinking melanoma-bearing mice. Collectively, these data show that chronic alcohol consumption inhibits proliferation of memory T cells, accelerates the decay of IFN-γ producing CD8+ T cells, and increases MDSC, all of which could be associated with melanoma progression and reduced survival. (Zhang H, Meadows GG. Cancer Immunol Immunother. 2010 Mar 13. [Epub ahead of print])

Molecule Repairs Alcohol Metabolism Enzyme

An estimated 1 billion people worldwide carry a genetic mutation that produces an inactive form of ALDH2, an important enzyme involved in alcohol metabolism. When individuals with the ALDH2 mutation drink alcohol, the toxic compound acetaldehyde accumulates in the body. The inactive form of ALDH2 is linked to increased risk for cancer, neurodegenerative diseases, and death following myocardial infarction. In the current study, researchers found that an experimental compound—Alda-1--- restores the structure and function of the inactive enzyme. The findings suggest the possibility of a treatment to reduce the health problems associated with the enzyme defect.

(Perez-Miller S, Younus H, Vanam R, Chen CH, Mochly-Rosen D, Thomas D. Hurley TD. Nat Struct Mol Biol. 2010 17(2):159-64.)

Induction of Antioxidant Response Prevents Ethanol-Induced Damage to Embryonic Nerve Cells.

Reactive oxygen species (ROS) derived from alcohol metabolism can overwhelm endogenous antioxidant systems and thus damage cells and tissues, including those of the developing fetus. An important defense against oxidative stress involves the activation of transcription factor Nrf2 and its subsequent induction of enzymes capable of eliminating ROS. In this in vitro study, researchers demonstrate that artificial activation of Nrf2 (nuclear factor-erythroid 2-related factor 2) by tert-butylhydroquinone (tBHQ) can induce these protective enzymes in embryonic neural crest cells from mice, which are particularly vulnerable to alcohol, and can prevent their death by apoptosis. Given these findings and the fact that tBHQ is approved for human use, this agent holds promise as an intervention for the prevention of Fetal Alcohol Spectrum Disorders (FASD). (Yan D, Dong J, Sulik KK, Chen SY. Biochem Pharmacol 2010 80:144-9.)

Serum Response Factor Restores Ocular Dominance Plasticity in a Model of Fetal Alcohol Spectrum Disorders.

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Researchers recently showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity in ferrets, an effect that can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. In the current study, investigators used the same ferret model to examine whether the plasticity defect results from impaired activation of the cGMP-dependent transcription factor SRF, which is known to be important for many plasticity processes. They tested this by expressing activated SRF in the ferret visual cortex using a locally injected viral construct. They found that the SRF construct corrected the plasticity deficit. They also showed that astrocytes, not neurons, were targeted by the SRF construct and that the deficit was corrected well beyond the zone of SRF expression. The observations suggest that SRF activation in astrocytes gives rise to a factor that can restore alcohol-impaired plasticity of distant neurons. Once identified, this factor may prove to be an effective and much needed FASD treatment. (Paul AP, Pohl-Guimaraes F, Krahe TE, Filgueiras CC, Lantz CL, Colello RJ, Wang W, Medina AE. J Neurosci 2010 30:2513-20.)

Study Sheds Light on Interplay of Molecules Involved in Alcohol-Induced Liver Inflammation.

Accumulating evidence suggests that an imbalance between pro-inflammatory and anti-inflammatory mediators contributes to ethanol-induced liver injury. Among the pro-inflammatory mediators, tumor necrosis factor alpha (TNF-α) plays a critical role in the pathogenesis of alcoholic liver disease, while interleukin-10 (IL-10) is an immunomodulatory molecule with potent anti-inflammatory and immunosuppressive properties. Recent data suggest an important link between adiponectin, and IL-10, two critical anti-inflammatory mediators that may contribute to ethanol-induced liver injury. IL-10 mediates its anti-inflammatory functions via induction of IL-10–inducible genes, including heme oxygenase-1 (HO-1) and suppressor of cytokine signaling 3 (SOCS3). Because an inability to induce adequate anti-inflammatory responses likely contributes to chronic inflammation during long-term ethanol exposure, researchers in this study examined whether there is a beneficial interplay between globular adiponectin (gAcrp), IL-10, and HO-1 in the regulation of TNF-α expression by immune cells in the liver after chronic ethanol exposure. In experiments conducted in rats, they found that induction of both IL-10 and HO-1 expression are required for the anti-inflammatory effects of gAcrp. The identification of HO-1 as a downstream effector of gAcrp provides an exciting path for the design and development of novel therapeutic approaches for the resolution of chronic inflammation associated with alcoholic liver disease. (Mandal P, Park PH, McMullen MR, Pratt BT, Nagy LE. Hepatology. 2010 Apr;51(4):1420-9.)

Sertraline Plus Naltrexone Appears Effective for Treating Co-Occurring Depression and Alcohol Dependence.

Some studies have shown that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence. Most studies, however, have not found antidepressant treatment helpful in reducing excessive drinking in these patients. In this study, researchers evaluated the efficacy of combining approved medications for depression (sertraline) and alcohol dependence (naltrexone) in treating patients with both disorders. A total of 170 depressed alcohol-dependent patients were randomly assigned to receive 14 weeks of treatment with sertraline, naltrexone, the combination of sertraline plus naltrexone, or double placebo while receiving weekly cognitive-behavioral therapy. The sertraline plus naltrexone combination produced a higher alcohol abstinence rate and demonstrated a longer delay before relapse to heavy drinking than the naltrexone, sertraline, and placebo groups. The number of patients in the medication combination group not depressed by the end of treatment approached significance when compared with patients in the other treatment groups. (Pettinati HM, Oslin DW, Kampman KM, Dundon WD, Xie H, Gallis TL, Dackis CA, O'Brien CP. Am J Psychiatry. 2010 Mar 15.)

Study Defines Determinants of Brief Intervention Effects for Older At-Risk Drinkers. Investigators analyzed data from a randomized controlled trial of an alcohol abuse intervention for older at-risk drinkers delivered in a primary care setting. Study participants received personalized risk reports, booklets on alcohol-associated risks, and advice from physicians, followed by a health educator call. Researchers found that thirty-nine percent of the sample had reduced drinking within 2 weeks of receiving the initial intervention. Subjects who were concerned about alcohol-related risks, read through the educational booklet, or perceived that their physicians discussed risks and advised changing drinking behaviors had greater odds of reducing drinking by the first health educator call. The study results provide further evidence of reduced alcohol consumption from brief intervention delivered in a primary care setting and have important implications for replication and dissemination of this implementation design in other primary care settings. (Lin JC, Karno MP, Barry KL, Blow FC, Davis JW, Tang L, Moore AA. Addict Behav. 2010 May;35(5):533-6. Epub 2010 Jan 4.)

Researchers Identify Predictors of Drinking Problems Among Older Adults. This epidemiologic study focused on late-life and life history predictors of high-risk alcohol consumption and drinking problems in a sample of more than 700 adults as they matured from age 55-65 and 75-85. Researchers found that older adults who, at baseline, had more friends who approved of drinking, relied on substances for tension reduction, and had more financial resources were more likely to engage in high-risk alcohol consumption and to have experienced drinking problems at 10- and 20-year follow-ups. People who had drinking problems by age 50 had a higher likelihood of late-life high-risk alcohol consumption and drinking problems. Attempting to cut down on drinking and participation in Alcoholics Anonymous were associated with a lower likelihood of alcohol problems. The results have implications for targeted screening and intervention among older adults. (Moos RH, Schutte KK, Brennan PL, Moos BS. Drug Alcohol Depend. 2010 Apr 1;108(1-2):13-20. Epub 2009 Dec 6.)

Web-Based Alcohol Prevention Program for College Students Shows Promise.

In a study of more than 1,100 first-year college students, investigators assessed the efficacy of a web-based brief motivational alcohol prevention/intervention called Michigan Prevention and Alcohol Safety for Students (M-PASS). An intervention group attended 4 online M-PASS sessions, receiving feedback tailored to individual drinking patterns and concepts from 4 behavior change theories. Control group participants completed a mid-phase survey, and both groups were surveyed at baseline and posttest. Researchers found that the intervention was associated with advanced stage of change, lower tolerance of drinking and drink/driving, fewer reasons to drink, and use of more strategies to avoid at-risk drinking. The findings provide promising evidence that the M-PASS intervention is effective in reducing motivation to drink in risky ways, increasing knowledge of strategies to protect against the negative effects of drinking, and changing attitudes toward risky alcohol-related behaviors, like drinking and driving. This study adds to growing evidence that web-based prevention strategies can be effective at minimizing at-risk drinking among college students. (Bingham CR, Barretto AI, Walton MA, Bryant CM, Shope JT, Raghunathan TE. J Am Coll Health. 2010 Jan-Feb;58(4):349-56.)

Age of Drinking Onset Moderates the Efficacy of Alcohol Interventions Among College Students.

Age of onset is known to be a significant risk factor for developing alcohol use disorders. In the current study, researchers examined the efficacy of two intervention approaches, administered either in combination or alone, among college students, taking age of drinking onset into consideration. Researchers found that a combination of peer-delivered brief motivational interviewing and a parent-based intervention was found more effective, across all students, than either approach alone or a placebo approach. The combination was particularly beneficial for those students with an early age of onset; a group at heightened risk of developing alcohol problems. As such, the study provides important clues into how the enhanced risk of alcohol use disorders contributed by an early age of onset could be mitigated to prevent such problems from developing among college students. (Mallett KA, Ray AE, Turrisi R, Belden C, Bachrach RL, Larimer ME. Alcohol Clin Exp Res. 2010 May 7. [Epub ahead of print])

Publications by Extramural Staff

NIAAA UPDATE

Prenatal Exposure to Alcohol: The Role of Addiction Psychiatry
By Howard B. Moss, MD
AAAP News / Newsletter of the American Academy of Addiction Psychiatry
March 2010 / Volume 26, Number 1

Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development.
Wang HJ, Zakhari S, Jung MK.
World J Gastroenterol. 2010 Mar 21;16(11):1304-13.

A FOXA1-binding enhancer regulates Hoxb13 expression in the prostate gland.
McMullin RP, Dobi A, Mutton LN, Orosz A, Maheshwari S, Shashikant CS, Bieberich CJ.
Proc Natl Acad Sci USA. 2010 Jan 5;107(1):98-103. Epub 2009 Dec 14.

Research on alcohol and adolescent brain development: opportunities and future directions.
Witt ED.
Alcohol. 2010 Feb;44(1):119-24.

Alcohol Biomarkers in Applied Settings: Recent Advances and Future Research Opportunities.
Litten RZ, Bradley AM, Moss HB.
Alcohol Clin Exp Res. 2010 Apr 5

Prospective Follow-Up of Empirically Derived Alcohol Dependence Subtypes in Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC): Recovery Status, Alcohol Use Disorders and Diagnostic Criteria, Alcohol Consumption Behavior, Health Status, and Treatment Seeking.
Moss HB, Chen CM, Yi HY.
Alcohol Clin Exp Res. 2010 Apr 5.

Screening and brief intervention for underage drinkers.
Clark DB, Gordon AJ, Ettaro LR, Owens JM, Moss HB.
Mayo Clin Proc. 2010 Apr;85(4):380-91. Review.

Providing alcohol-related screening and brief interventions to adolescents through health care systems: obstacles and solutions.
Clark DB, Moss HB.
PLoS Med. 2010 Mar 9;7(3):e1000214.

Magnitude and prevention of college drinking and related problems.
Hingson, R.
Alcohol Research & Health, in press.

Alcoholic beverage consumption, nutrient intakes, and diet quality in the US adult population, 1999-2006.
Breslow RA, Guenther PM, Juan W, Graubard BI.
J Am Dietetic Assoc 110: 551-562, 2010.

Alcohol consumption and cardiovascular mortality among US adults, 1987-2002.
Mukamal KJ, Chen CM, Rao SR, Breslow RA.
J Am Coll Cardiol 55: 1328-1335, 2010.

Improving adolescent and young adult health–training the next generation of physician scientists in transdisciplinary research.
Emans SJ, Austin SB, Goodman E, Orr DP, Freeman R, Stoff D, Litt IF, Schuster MA, Haggerty R, Granger R, Irwin CE, Jr., and the participants of the W.T. Grant Foundation conference on Training Physician Scientists.
J Adol Hlth 46: 100-109, 2010.

Structure and mechanism of receptor sharing by the IL-10R2 common chain.
Yoon SI, Jones BC, Logsdon NJ, Harris BD, Deshpande A, Radaeva S, Halloran BA, Gao B, Walter MR.
Structure. 2010 May 12;18(5):638-48.

Is alcohol beneficial or harmful for cardioprotection?
Lakshman R, Garige M, Gong M, Leckey L, Varatharajalu R, Zakhari S.
Genes Nutr. Epub December 2009.

The NIH Human Microbiome Project.
Peterson J, Garges S, Giovanni M, McInnes P, Wang L, Schloss JA, Bonazzi V, McEwen JE, Wetterstrand KA, Deal C, Baker CC, Di Francesco V, Howcroft TK, Karp RW, Lunsford RD, Wellington CR, Belachew T, Wright M, Giblin C, David H, Mills M, Salomon R, Mullins C, Akolkar B, Begg L, Davis C, Grandison L, Humble M, Khalsa J, Little AR, Peavy H, Pontzer C, Portnoy M, Sayre MH, Starke-Reed P, Zakhari S, Read J, Watson B, Guyer M.
Genome Res. 2009 19(12):2317-23. Epub 2009 Oct 9.