C. Staff Honors
H. What’s Ahead
A. Legislation, Budget, and Policy
The NIAAA is currently closing out FY 2010. The FY 2010 annual appropriation for the Institute is $462.3 million, excluding transfers, and reflects an increase of approximately 2.7% over the FY 2009 comparable level.
The NIAAA is also in the process of closing out year two of the $113.9 million provided under the American Recovery and Reinvestment Act (ARRA) for the purposes of creating jobs, increase efficiency in science and health, and promoting economic recovery by investing in areas most impacted by the recession. This apportionment was made available over a 2 year period ending September 30th, 2010. Using the ARRA apportionment, NIAAA was able to fund additional approved and highly meritorious projects that could not have been supported under our regular annual appropriation.
House Action: On July 15th, the House Labor HHS Appropriations Subcommittee marked-up a bill that provided both the NIH and the NIAAA with the same level as the President’s budget request. For the NIH, this amount is $32 billion, an increase of $1.0 billion or 3.2% over FY 2010. For NIAAA, the recommended amount is $474.6 million, a $12.4 million or 2.7% increase over the FY 2010 comparable level.
Senate Action: On July 29th, the Senate Appropriations Committee completed their mark-up of the NIH budget. The NIH level proposed by the Senate Committee is $32.0 billion, approximately the same level as the House. The NIAAA level is $473.9 million, which reflects a .7 million decrease from both the House Subcommittee’s and the President’s budget requests.
Once again, the NIH is anticipating beginning the new fiscal year under a Continuing Resolution.
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.
B. Director’s Activities
French National Institute of Health and Medical Research (INSERM) / International Society for Biomedical Research on Alcoholism (ISBRA) Mtgs., Paris
September 10-13, 2010
At INSERM headquarters in Paris on September 10, Dr. Warren introduced and facilitated discussions about establishing collaborative research activities between NIAAA-supported investigators in the U.S., and INSERM-supported investigators in France on four topic areas: alcoholic-related liver disease; alcohol and cancer; phenotypes of alcohol dependence of importance in the development of target specific medications; and alcohol and violence prevention. On September 13, also in Paris, Dr. Warren gave a talk on NIAAA’s global research mission at the opening ceremony of the ISBRA meeting.
FASD Site Visit, Seoul, South Korea
Dr. Warren was among a team of fetal alcohol spectrum disorder (FASD) researchers who completed an exploratory site visit to Seoul, South Korea to lay the groundwork for adding Korea as a site for the NIAAA-funded Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). Accompanying Dr. Warren were Dr. Peggy Murray, NIAAA Senior Advisor for International Research, as well as Dr. Edward Riley, San Diego State University, and Drs. Christine Chambers and Kenneth Lyons Jones of San Diego. Reports on women’s drinking in South Korea have led experts to believe that there was a possibility for high rates of FASD. The preliminary research on alcohol consumption among pregnant women in South Korea was lead by Dr. So Hee Lee of the Department of Psychiatry, National Medical Center in Seoul and was recently published in Psychiatry Investigations, 2010. She has recently finished a post doctoral position in the laboratory of Dr. Riley. The team visited a total of eight sites including residential homes for children with mental retardation, special education centers, and orphanages. Dr. Jones trained a group of Korean pediatricians and psychiatrists on the diagnosis of FAS and FASD during the visits. A number of children were identified as having FAS, and a greater number had fewer symptoms but enough to defer for further assessment for partial FAS or other FASD diagnoses. The trip ended with a workshop for Research on FASD, sponsored by the Korean CDC and St. Mary’s Hospital of the Catholic University of Seoul. Dr. Hae Kook Lee, who had just finished a fellowship with NIAAA, organized the site visit and symposium and will lead the FASD research collaboration with CIFASD in South Korea. Drs. Warren and Murray also visited the Korean Alcohol Research Foundation in Seoul and met with their clinical director as well as senior staff in prevention and rehabilitation programs.
Dr. Warren also attended and/or spoke or otherwise participated at the following recent meetings:
IOM Neuroscience Forum
June 22-23, 2010
33rd Annual RSA Scientific Meeting
June 26-30, 2010
NASADAD - 23rd Annual National
Aug 31-Sep 3, 2010
Prevention Network Conference
SMRB Full Board Meeting
September 14-15, 2010
The NIH Scientific Management Review Board (SMRB) discussed, and voted on, two potential options for optimizing addictions research across NIH. The two options presented were: a functional merger, which would consolidate addictions research across NIH through an Addictions Blueprint similar to the Neuroscience Blueprint or the Basic Behavioral and Social Sciences Network (OPPNET); and a structural merger that would abolish the NIAAA and NIDA and create a new Institute on Addictions that will encompass addictions to alcohol and drugs as well as to tobacco, compulsive eating, gambling, etc. The SMRB voted (12 to 3, with 6 members not present) to recommend to the Director of NIH, Dr. Collins, the structural option as outlined by the Substance Use, Abuse and Addictions (SUAA) Working Group. Dr. Collins will now consider the SMRB’s recommendation and decide whether to accept or modify it. Dr. Collins’ recommendation will go to DHHS Secretary Sebelius and the Congress. If there is no opposition to the proposed change, it will take effect after 180 days.
C. Staff Honors
Dr. Joe Hibbeln (Laboratory of Membrane Biochemistry and Biophysics) received the Special Assignment Award from the USPHS in recognition of his 3 years as a 'first responder' to Federal disasters on Mental Health Team #1 for the USPHS.
Dr. Laura Bevilacqua (Laboratory of Neurogenetics) received the Italian Foundation Award that will allow her to engage in a collaborative research and teaching activity with Columbia University.
D. Press Releases
September 1, 2010: NIH awards grants to support biomedical research in space
The NIH awarded the first new grants under the Biomedical Research on the International Space Station (BioMed-ISS) initiative, a collaborative effort between NIH and NASA. Using a special microgravity environment that Earth-based laboratories cannot replicate, researchers will explore fundamental questions about important health issues, such as how bones and the immune system get weak. The National Laboratory at the ISS provides a virtually gravity-free — or microgravity — environment where the cellular and molecular mechanisms that underlie human diseases can be explored. NIAAA is among the NIH Institutes and Centers participating in BioMed-ISS, funding a grant to Declan McCole, Ph.D., of the University of California, San Diego. Dr. McCole will use microgravity three-dimensional cell culture models to generate insights regarding the barrier properties of the intestines. A major factor in alcohol-related disease stems from the ability of alcohol to compromise the natural barrier function of cells in the gastrointestinal tract, increasing the movement of toxins from the intestines to other organs in the body.
August 26, 2010: Studies on combat related substance use and abuse to be funded by NIH and VA
NIAAA and other federal agencies will provide more than $6 million to support research on substance abuse and associated problems among U.S. military personnel, veterans, and their families. Most of the research is directed at substance abuse and related conditions experienced by veterans returning from wars in Iraq and Afghanistan. There is a growing awareness that military personnel returning from these prolonged conflicts have a variety of serious problems, including depression, anxiety, sleep disturbances, and substance abuse. For example, NIAAA-supported research has documented a significant association between combat deployment of U.S. military personnel to Iraq and Afghanistan and the onset of alcohol problems upon their return to the U.S.
July 26, 2010: New Compound Improves Obesity-Related Health Complications in NIH-Led Study
A preliminary study led by researchers at the NIAAA found that an experimental compound appeared to improve metabolic abnormalities associated with obesity. NIAAA Scientific Director, George Kunos, M.D., Ph.D., and Joseph Tam, D.D.S., Ph.D., of the NIAAA Laboratory of Physiologic Studies, collaborated with a team of scientists within and outside NIH. They investigated an endocannabinoid-blocking compound that had been designed to avoid the side effects that have stymied the development of similar compounds. Their results suggest that the compound could perhaps provide clinical benefits for obese individuals without the liabilities seen thus far with similar compounds. A report of the study, which was conducted with obese mice, appeared in the Journal of Clinical Investigation.
July 22, 2010: Scientists Identify Brain Circuits Related to the Initiation of Termination of Movement Sequences in NIH-Supported Study
Scientists at NIAAA and the Gulbenkian Institute in Portugal identified brain activity in mice that can signal the initiation and termination of newly learned action sequences. The study was conducted by Xin Jin, Ph.D. an investigator in the NIAAA Laboratory for Integrative Neuroscience, and Rui M. Costa, D.V.M, Ph.D., of the Gulbenkian Institute. The researchers trained mice to press a lever to receive a sugar-water reward. As the mice learned this task, the researchers monitored brain cell activity in the animals’ basal ganglia, deep brain structures that are known to help start and control movement. The findings appeared in Nature.
E. Multi-Media Products from NIAAA
NIAAA Newsletter -- The Communications and Public Liaison Branch (CPLB) published issue 21 of the NIAAA Newsletter in… The newsletter features:
NIAAA Spectrum -- Issue 4 of the Institute's online webzine features lead stories on
Alcohol Research & Health – new issue on FASD
F. News Media Interactions
Recent News Media Interviews
Dr. Joseph Hibbeln, NIAAA Laboratory of Membrane Biochemistry and Biophysics, gave interviews regarding Omega 3 fatty acids and mental health to:
Medscape Psychiatry News
The Kojo Nnamdi Show
American Baby magazine
Los Angeles Times
Dr. Ralph Hingson, NIAAA Division Of Epidemiology and Prevention Research, gave interviews to:
Lansing, Mich., State Journal (regarding college drinking prevention programs)
San Diego Union-Tribune (regarding NIAAA ARRA-funded research project being conducted by James Lange at San Diego State on disclosing alcohol content of drinks)
Boston Globe (regarding underage drinking)
Radio Pennsylvania (regarding college drinking)
bigthink.com (regarding minimum legal drinking age)
Dr. Sam Zakhari, NIAAA Division of Metabolism and Health Effects, gave interviews to:
endlessbeauty.com (regarding women's drinking and breast cancer risk)
Consumer Reports magazine (regarding Hangover "cures")
Dr. PJ Brooks, NIAAA Laboratory of Neurogenetics, was interviewed by:
ABC World News Tonight with Diane Sawyer (regarding alcohol and cancer)
livescience.com (regarding Asian flushing reponse to alcohol and esophageal cancer risk)
Dr. George Kunos, Scientific Director, NIAAA, gave interviews regarding his recent paper on an experimental compound that improves obesity-related health complications to:
Science-Business eXchange (cover story)
BHMA-GREECE (Greek newspaper)
Dr. Raye Z. Litten, Division of Treatment and Recovery Research, was interviewed by Newsweek magazine regarding medications for alcohol use disorders.
Dr. Mike Hilton, Division of Epidemiology and Prevention Research, was interviewed by the Boston Globe Magazine regarding per capita alcohol consumption statistics, and by the Iowa City Press-Citizen regarding alcohol and violence.
Dr. Deborah Dawson, Laboratory of Epidemiology and Biometry, was interviewed by Health.com and CNN.com regarding alcohol consumption trends among minorities.
Dr. David Goldman, Chief, NIAAA Laboratory of Neurogenetics, provided listener feedback to a National Public Radio news story which stated that the facial flushing variant of ALDH2 [aldehyde dehydrogenase 2] is "not associated with a disease." Dr. Goldman noted that “This is factually wrong both with regard to alcoholism and cancer.”
Dr. Goldman was also interviewed by livescience.com regarding the Asian flushing reponse to alcohol and esophageal cancer risk.
Dr. David Lovinger, NIAAA Laboratory of Integrative Neuroscience, was interviewed by a freelance science writer and author regarding the neurobiology of alcohol addiction.
Dr. Kathy Jung, Division of Metabolism and Health Effects, was interviewed by ProteoMonitor about a recent NIAAA biomarkers RFA.
Dr. Lindsey Grandison, Division of Neuroscience and Behavior, was interviewed by myhealthnewsdaily.com regarding the consequences of repeated alcohol withdrawal on stress.
G. NIAAA Staff and Organization
Troy Zarcone, Ph.D. joined the Science Policy Branch on July 19th as a Health Scientist Administrator. He was previously an associate research professor at the University of Rochester Medical Center where he served as the Scientific Director of the Animal Behavioral Assessment Unit. Dr. Zarcone received his Ph.D. in psychology from the University of Florida in 1994.
Extramural Staff Activities
Dr. Antonio Noronha co-organized and chaired a symposium with Dr. Subhash Pandey from The University of Illinois, Chicago at the 33rd Annual Meeting of the Research Society on Alcoholism in San Antonio, Texas, June 26-30, 2010. The Symposium was entitled “Potential Therapeutic targets for the Treatment of Alcoholism: A Perspective from Preclinical Studies.” Dr. Noronha gave an overview on NIAAAs Preclinical Program including research findings as an Introduction to the symposium.
Dr. Noronha co-organized Satellite Symposiums on the 2 Integrative Neuroscience Initiatives on Alcoholism (INIA) consortiums at the RSA meeting in San Antonio.
Dr. Noronha organized and co-chaired a session on “Alcohol and Stress” at the International Behavioral Science Society (IBNS) Meeting held in Sardinia, Italy, June 7-13, 2010
NIAAA Advisory Panel Meeting- Phase 2 - Longitudinal Studies of the Impact of Adolescent Drinking on the Developing Brain.
Organized by Dr. Ellen Witt, the meeting took place July 20, 2010 at NIAAA. In 2007, NIAAA began a two-phase initiative to study the effects of human child and adolescent alcohol use on the developing brain using neuroimaging and neurocognitive techniques. In Phase 1, five investigators were funded under RFA-AA-07-006 to do feasibility studies for undertaking a much larger longitudinal study to determine 1) what are the long-term and short-term effects of alcohol on the developing brain; 2)the effects of timing dose, and duration of exposure on the developing brain; and 3) if any changes are persistent or reversible. The goal of this workshop was to convene an NIAAA Advisory Panel comprised of experts in longitudinal design and developmental neuroimaging to 1) evaluate progress and lessons learned from studies funded under the original RFA; and 2) to have a discussion with the invited experts and grantees, based on the presented results and their own experience, as to the potential problems and pitfalls as well as constructive recommendations for pursuing a much larger longitudinal study (Phase 2).
Drs. Qi-Ying Liu, Mathew Reilly and John Matochik of the Division of Neuroscience and Behavior organized and presented at a workshop entitled “A Systems Biology Approach to Understanding the Effects of Alcohol on the Brain” that was held on June 26, 2010 as a satellite meeting of the 33th Annual Scientific Meeting of the Research Society on Alcoholism in San Antonio, Texas. This workshop featured an overview of systems biology approaches and their applications in studying the effects of alcohol on the brain and presentations by invited speakers. The workshop covered principles and the most recent progress in areas such as “Transcriptome Organization in the Human Brain”, “Epigenomics and Complex Disease Research”, “Transcriptomics, Proteomics and Alcoholism”, “Brain Connectomics and Functional Neural Connectivity”, “Signaling Pathways and Synaptic Interactions in the Hippocampus”, “Systems Biology of Alcohol and Stress” and “Data Integration Across Genomic Studies of Alcoholism.”
Dr. Qi-Ying Liu represented NIAAA on the NIH Blueprint Neurotherapeutics Grand Challenge Team. The gap in drug development between where NIH-funded research typically leaves off and industry development begins has become known as the “valley of death.” The goal of the Neurotherapeutics Grand Challenge Team is to establish a Blueprint Neurotherapeutics Network that will span this region of the drug development pipeline, providing funding and research services to advance promising hit compounds through lead optimization, candidate selection, preclinical safety, and phase I clinical testing. As part of the efforts, an RFA was published: (RFA-NS-11-002: NIH Blueprint for Neuroscience Research Grand Challenge: Developing Novel Drugs for Disorders of the Nervous System (U01)).
Dr. Abbas Parsian, program director for human genetics /genomics in the Division of Neuroscience & Behavior co-organized and co-chaired a Symposium with Dr. Alison Goate from Washington University School of Medicine in St. Louis at the annual meeting of the Research Society on Alcoholism held on June 26-30, 2010 in San Antonio, Texas. The Symposium was entitled, “Identifying Genes Affecting Alcoholism Using Different Strategies.” Dr. Parsian gave an overview of the challenges in gene mapping for complex human disorders including alcoholism and the introduction to the symposium.
Dr. Samir Zakhari co-chaired a symposium during the 33rd Annual Scientific Meeting of the Research Society on Alcoholism, entitled: Charles Lieber – a life dedicated to research on alcoholism – Alcoholic Liver Disease: from Pathophysiology to Therapy. He also gave a presentation entitled: Charles S. Lieber: A Pioneer in Alcohol-Induced Liver Disease, on June 26, 2010. During the same meeting, Dr, Zakhari was a discussant on a symposium entitled “Alcohol and the Cardiovascular System Mitochondrial Dynamics and Oxidative Stress”.
Dr. Zakhari served on a Search Committee to interview potential candidates for a Scientific Advisor for Viral Hepatitis and Liver Diseases, for NIDDK.
Dr. Zakhari gave a presentation at the 29th Annual Conference of the Association of American Indian Physicians, entitled “Fetal Alcohol Spectrum Disorders: a Preventable Affliction,” on August 8, 2010, in Santa Ana Peublo, CO.
Dr. Zakhari co-chaired a session on “Progenitor Cells, Liver Development and Regeneration” during the 15th ISCHS meeting in Los Angeles, CA on August 31, 2010.
Dr. Bill Dunty presented introductory remarks for the symposium entitled "Role of Alcohol and Interacting Factors on Tumor Progression" held during the 33rd annual RSA meeting in San Antonio, Texas.
Dr. Dale Hereld delivered a presentation on NIAAA's FASD-related activities to the FASD Study Group, which met on June 26, 2010, in San Antonio, TX, in conjunction with the annual RSA meeting.
Dr. Dale Hereld gave a talk titled "Fetal Alcohol Spectrum Disorders: Potential Therapies Emerging from the Lab," to NIAAA's Laboratory of Neurogenetics on September 9, 2010.
Dr. Svetlana Radaeva prepared and submitted the NIAAA response to the Office of Research on Women's Health’s (ORWH) request for submissions of highlights of research progress in women’s health in preparation for the ORWH 20th Anniversary celebration.
Dr. Andras Orosz co-organized a RSA symposium with Dr. Daria Mochly-Rosen titled “Alcohol and the cardiovascular system: mitochondrial dynamics and oxidative stress” that was well received during the June RSA meeting in San Antonio.
Dr. Raye Litten presented “Research Opportunities for the Treatment of Alcohol Comorbidity,” Research Society on Alcoholism, San Antonio, Texas, June 2010.
Mechanisms of Behavior Change Interdisciplinary Research Consortium (MIRC) In July 2010, NIAAA held a kickoff meeting for the Mechanisms of Behavior Change Interdisciplinary Research Consortium (MIRC). The MIRC represents NIAAA’s most progressive effort to support highly innovative, foundational research to investigate the causal mechanisms and processes underlying the initiation of behavior change from a maladaptive to a more healthful state. More specifically, NIAAA sought to develop practical models of the drinking behavior control system (DBCS) that might elucidate how to effect positive behavior change within the spectrum of behavioral modes and define what is achievable within any given individual’s local context. These models would involve three levels of observation and analysis:
Neurophysiologic Factors: Individual neurophysiology and relevant biology;
Intrapersonal Factors: Individual intrapersonal factors (cognition, affect and behavior); and
Interpersonal Factors: Individual immediate social ecology (e.g. family, friends).
The focus of the MIRC is to develop and assess the feasibility of, novel methods and approaches applicable for conducting multidisciplinary research on mechanisms of behavior change.
American College of Neuropsychology (ACNP) Medications Development Group In August 2010, Drs. Daniel Falk and Raye Litten made two presentations during a meeting of the ACNP Medications Development Group—a group that consists of representatives from NIAAA, the pharmaceutical industry, the FDA, and academia. The group aims 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. Dr. Falk presented new secondary data analyses from the COMBINE study on the sensitivity of objective outcomes such as blood pressure and drinking biomarkers to detect treatment effects in alcohol clinical trials. Dr. Litten gave an overview of the placebo effect and how it may impact the treatment effects found in alcohol clinical trials. The ACNP Medications Development Group is currently drafting two manuscripts based on a number of secondary data analyses conducted by DTRR staff.
Substance Use and Abuse among U.S. Military Personnel, Veterans and their Families In July of 2009, NIAAA partnered with NIDA, NCI, and the Department of Veterans Affairs and released a funding opportunity announcement to support research on substance abuse and associated problems among U.S. military personnel, veterans, and their families. The funding opportunity announcement solicited applications on the causes, screening, identification, prevention, and treatment of substance use and abuse - including alcohol, tobacco, illicit and prescription drugs and associated problems. In August 2010, NIAAA funded four applications:
Dr. Andrew Golub at the National Development and Research Institutes, Inc. will conduct a longitudinal analysis of the dynamic interactions of substance, mental health, and reintegration problems with treatment and life experiences on the predominately African American veterans returning to the inner city.
Dr. Amanda Amstadter and her team at Virginia Commonwealth University are investigating the role of a history of exposure to combat trauma on reactivity to stress and on stress- induced voluntary drinking.
Drs. Andrew Rosenblum and Stephen Maisto at National Development Research Institute and Syracuse University are modifying the content of an efficacious web-based Cognitive Behavioral Therapy for individuals with substance use disorders to target substance use, PTSD and other problems common among Operation Enduring Freedom and Operation Iraqi Freedom veterans.
Dr. Matthew Martens and his team at University of Missouri-Columbia will assess the efficacy of a computer delivered personalized drinking feedback intervention among veterans of the wars in Afghanistan and Iraq.
Dr. Ralph Hingson presented:
“Alcohol and Drug Use in Fatally Injured Drivers in U.S. States that Test Over 80% of Deceased Drivers for Both Alcohol and Drugs,” at the 2010 Tri-Annual Meeting of the International Conference on Alcohol, Drugs and Traffic Safety, in Oslo, Norway, on August 22, 2010.
“Actively Building Community-Researcher Partnerships: The Road to Achieving True Community-Based Participatory Research,” at the Society of Prevention Research’s 18th Annual Meeting, Denver, CO, on June 2, 2010.
“Recent Trends and Findings Regarding the Magnitude and Prevention of College and Underage Drinking Problems,” at the Community Anti-Drug Coalitions of America’s (CADCA) Mid-Year Training Institute, in Phoenix, AZ, on July 28, 2010.
“Prevention of Alcohol-Related Injuries Among Youth: From Global to Local,” Social Welfare Policy and Services II Class, at Catholic University of America, Washington, D.C., on July 13, 2010.
Dr. Robert Freeman organized and moderated two panels at the Society for Prevention Research’s 18th Annual Meeting in Denver, CO, from June 1-4, 2010: “Promises and Pitfalls in Research Collaborations with City Hall Targeting Alcohol-Related Violence: Case Studies Drawn from 3 East Coast Cities,” and “Brain Research in the Context of Adolescent Development Research: Implications for Prevention Policy Aimed at Reducing High-Risk Behaviors.”
Dr. Robert Freeman organized and moderated a panel at the Research Society on Alcoholism Annual Meeting in San Antonio, TX, from June 26-30, 2010: “New Developments in Understanding Alcohol-Related Intimate Partner Violence: Evidence from 4 Ongoing Investigations”.
Mr. Greg Bloss attended the 3rd Biennial Conference of the American Society of Health Economists (ASHEcon) at Cornell University, June 20-23, 2010. Mr. Bloss conducted a grantsmanship workshop at the conference in coordination with staff members from NIDA, NIMH, and NIDCR to encourage successful grant applications by health economists.
Mr. Greg Bloss participated in the Institute for Systems Science and Health, sponsored by the NIH Office of Behavioral and Social Science Research, the Centers for Disease Control and Prevention, and Columbia University, in New York, June 13-17, 2010. He attended intensive workshops on methods and applications of systems modeling and participated in a “Funders’ Panel” by giving a presentation and participating in a Q&A session on research opportunities at NIH and NIAAA.
Mr. Greg Bloss participated in the trans-NIH working group on Health Economics for Health Care Reform chaired by Dr. Hodes and Dr. Insel. The group developed a successful proposal for a Common Fund initiative, from which the first two Requests For Applications (RFAs) have been developed and released: RFA-RM-10-015, “Economics of Prevention (R21)” and RFA-RM-10-016, “Science of Structure, Organization and Practice Design in the Efficient Delivery of Effective Healthcare (R21)”. The group will continue to meet through the coming year and plans to develop several additional FOAs.
Dr. Marcia Scott was a Planning Committee Member on the 2010 NIH Summer Institute on Transdisciplinary Research: Integrating Genetic and Social Work Research, sponsored by the NIH Office of Behavioral and Social Sciences Research (OBSSR), August 8-13, 2010, in Bethesda, MD. Dr. Scott was also a member of the NIH OppNet “Social Environment” Concept Development Team, and lead author on two OppNet RFAs:
RFA-NR-11-001, NIH Basic Behavioral and Social Science Opportunity Network (OppNet) Short-term Small b-BSSR Grants for New and Early-Stage Investigators (R03);
RFA-NR-11-002, NIH Basic Behavioral and Social Science Opportunity Network (OppNet) Short-term Interdisciplinary Research Education Program for New and Early-Stage Investigators (R25);
Dr. Scott serves as a member of the Planning Committee for: Building Bridges: Advancing AI/AN Substance Abuse Research A State of the Science and Grant Development Workshop, sponsored by NIDA and NIAAA, scheduled for October 5-7, 2010, in Bethesda, MD.
Dr. Mariela Shirley served as Chair, OppNet Capacity Building Concept Team. In this role, Dr. Shirley led efforts to develop RFA- CA-10-017 “Scientific meetings for creating interdisciplinary research teams in basic behavioral and social science research (R13)”. NIAAA is a participating Institute in this RFA. Applicants must propose developmental activities (i.e., meetings/workshops) that will build the capacity of interdisciplinary teams to accelerate, expand, and/or strengthen fundamental knowledge in b-BSSR as relevant to the Nation’s health and well-being. Proposed interdisciplinary teams must include at least one investigator from the basic social and/or behavioral sciences, and must include investigators from at least one additional discipline. Applicants are encouraged to either: (1) accelerate, expand, and/or strengthen the scope of investigation of a specific b-BSSR research domain through the integration of disparate approaches from b-BSSR and allied disciplines; or (2) increase the sophistication of theoretical, methodological, and analytical approaches in b-BSSR. These goals may be accomplished by fostering the development of shared scientific terminology, approaches, and methodologies across disciplines in order to address a common b-BSSR research question. Letters of Intent Due: November 14, 2010; Application Due: December 14, 2010. More information on OppNet and Funding Opportunities may be found at http://oppnet.nih.gov/.
H. What’s Ahead
Division of Neuroscience and Behavior: "Neuroimmune Mechanisms of Brain Functions and Alcohol Related Disorders", Satellite Symposium at Society for Neuroscience, November 12, 2010, San Diego, CA.
Division of Neuroscience and Behavior: A NIH-sponsored social will be held at the Society for Neuroscience meeting in November 2010 to highlight recent progress in the mouse Cre-driver line project. This social will provide the latest information on currently and soon-to-be available Cre-driver lines, their recombination patterns, and how they can be obtained by neuroscience researchers. Dr. Matthew Reilly is the NIAAA representative for this trans-NIH initiative.
Dr. Ralph Hingson will be the Keynote speaker at the Mothers Against Drunk Driving’s (MADD) 30th Anniversary in Arlington, VA, on September 25, 2010. Dr. Hingson will discuss the importance of parents in preventing and reducing underage drinking as well as trends in and the magnitude of alcohol-related driving injuries and interventions shown through research to prevent drunk driving.
Dr. Ralph Hingson will present “The Magnitude and Prevention of Underage and College Age Drinking Problems,” at the Carolinas Conference on Addiction and Recovery at Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill’s School of Medicine, on October 29, 2010.
Dr. Ralph Hingson will present “Alcohol, Tobacco, and Other Drug Use: Predictors of Prescription Drug Misuse: A Prospective National Analysis,” at the American Public Health Administration’s 138th Annual Meeting and Exposition, in Denver, Colorado on November 9, 2010.
The NIAAA Alcohol Research Center (ARC) Directors Meeting and Scientific Conference will take place on October 19-20, 2010 in Berkeley, California. The topic for this meeting will focus on Innovative Alcohol Intake Pattern Measurement for Human and Animal Model Research. NIAAA currently funds 27 ARCs.
Dr. BJ Song will present at the Mitochondrial Proteomics Session of the NIH Research Festival in October.
I. NIAAA Program Announcement, Request for Application, and CRADA Information
PA-10-255 & PA-10-256 Behavioral Regulation Mechanisms of Alcohol Dependence and Related Phenotypes This announcement promotes research to study the mechanisms of behavioral regulation contributing to the behavioral characteristics of alcohol dependence. It seeks proposals to promote research to study 1) how chronic and acute alcohol consumption affect behavioral regulation processes at the epigenetic, cellular, systems (neurocircuitry) and behavioral level, 2) how these effects lead to propensity to develop alcohol dependence, and 3) the influence of genetic and environmental factors on behavioral regulation processes contributing to risk for alcoholism.
PA-10-249 & 250 Endocannabinoid Signaling in Alcohol Consumption, Intoxication and Alcohol Use Disorders (R01 and R21, respectively) This announcement encourages Research Project Grants (R01 & R21) applications from institutions/organizations that propose to study the roles and underlying mechanisms of endocannabinoid signaling in alcohol preference, consumption, intoxication and alcohol use disorders, and to explore endocannabinoid signaling system as potential targets for alcohol pharmacotherapy. With increasing knowledge of the function of eCBs in the developing and adult brain and recent behavioral and pharmacological evidence linking alcohol and eCB signaling system, there is now great potential to explore the role of eCB signaling system in alcohol-related behaviors and alcohol use disorders. Studies supported with this FOA will help to gain knowledge about the role and underlying mechanisms of eCB signaling in alcohol preference and consumption; the interactions of acute and chronic alcohol exposure with eCBs at synapses; the effects of such interactions on short- and long-term synaptic plasticity; the role of eCB signaling in the development and maturation of the central nervous system; and the eCB signaling system in fetal alcohol spectrum disorders.
PAS-10-215: Expanding and Personalizing Treatment Options for Alcohol Use Disorders Including Pharmacogenomics (R01). This announcement invites research grant applications to study how genetic variation affects responses to medications for the treatment of Alcohol Use Disorders (AUD). Both human and animal studies are encouraged to determine the full range of genetic variation affecting both pharmacodynamic and pharmacokinetic parameters resulting in altered drug efficacy and toxicity. Mechanistic studies using animal models and/or in vitro/ex vivo preparations are also encouraged.
RFA-AA-11-004: Biomarkers of Alcohol Consumption and Alcohol-induced Tissue Injury (SBIR [R43/R44]). This announcement solicits Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) that propose to stimulate the discovery and development of biomarkers of alcohol consumption, biomarkers for early detection of alcohol-induced organ damage, and biomarkers of fetal alcohol exposure. Approaches using high throughput technologies leading to the discovery of biomarker signatures are encouraged. Proposals leading to rapid translation of candidates to marketable clinically useful biomarker assays are also encouraged.
RFA-AA-11-005: Biomarkers of Alcohol Consumption and Alcohol-induced Tissue Injury (STTR [R41/R42]). This Funding Opportunity Announcement (FOA) solicits Small Business Technology Transfer (STTR) grant applications from small business concerns (SBCs) that propose to stimulate the discovery and development of biomarkers of alcohol consumption, biomarkers for early detection of alcohol-induced organ damage, and biomarkers of fetal alcohol exposure. Approaches using high throughput technologies leading to the discovery of biomarker signatures are encouraged. Proposals leading to rapid translation of candidates to marketable clinically useful biomarker assays are also encouraged.
RFA-AA-11-002 “Alcohol-induced Metabolic and Hepatic Injury.” The goal of this announcement is to stimulate innovative research that will determine the key cellular and molecular events responsible for the progression of alcohol-induced fatty liver to fibrosis and cirrhosis in patients with alcoholic liver disease (ALD) alone or in combination with obesity, diabetes or Hepatitis C infection. We anticipate that the results of such research will identify the mechanisms responsible for the increased susceptibility to the progression of ALD to end-stage liver disease and help identify promising molecular targets for early detection of the most at-risk population.
The Division of Treatment and Recovery Research released a SBIR contract, “Interventions to Prevent and Treat Substance Abuse Among Children, Adolescent and Adults with Fetal Alcohol Spectrum Disorder (FASD).” In recent years, new interventions to improve functioning and life skills have begun to emerge for those afflicted with FASD. An element absent from these new interventions is an approach specifically for alcohol and other drug abuse. Adolescents and adults with FASD are at especially high risk for substance abuse, and are unlikely to seek treatment, or to benefit from traditional forms of therapy. We have announced an SBIR contract opportunity to develop tools to engage, inform, teach and reinforce skills to avoid substance use in FASD subgroups of all ages. Required features for these programs are: (1) suitability for delivery in a variety of settings, including those where special education professionals may not be available, (2) modularized format allowing ready incorporation into broader interventions for FASD persons such as those that teach social skills, safety, and other life skills, (3) inclusion of teacher training methods and development of curriculum materials and tools, and (4) provision for the fact that many along the FASD spectrum also have co-occurring psychiatric conditions.
DTRR also released a SBIR contract “Medications Development for the Treatment of Alcohol Use Disorders and Alcohol-Induced Tissue Damage.” Efforts to develop medications for alcohol use disorders have expanded rapidly in recent years. Three agents—disulfiram, naltrexone, and acamprosate—are now approved for use in the United States and many other countries. Recently, topiramate also has been shown to be effective in treating alcohol-dependent patients. However, because of the heterogeneous nature of alcohol use disorders, many patients have limited or no response to these medications. Therefore, developing new medications and evaluating their use in combination with other medications and with behavioral therapies are important steps toward improving treatment outcomes for all individuals with alcohol use disorders.
In addition, DTRR recently released a PAS, “Treatment for Alcohol Use Disorders in Young Adults,” to support new research on the treatment of young adults (18-25 years of age) with alcohol use disorders. Compared to all other age groups, the prevalence of periodic heavy or high-risk drinking is greatest among young adults aged 18 to 25. Alcohol use disorders, including alcohol dependence, also peak during this critical period during which profound developmental changes occur. Despite having the highest prevalence of drinking, interventions for this group have been understudied. Gaps exist in understanding how to effectively engage this group in treatment, which treatments are the most effective, and how to maintain treatment gains in the longer term after treatment. The PAS was released for 3 funding mechanisms: R01, R21, and R03.
J. NIAAA Research Programs
The following items represent examples of the breadth and quality of research conducted and supported by NIAAA.
Heavy alcohol consumption during adolescence compromises hippocampal development
Binge drinking is common during adolescence, a period of rapid brain development. In this study, researchers used adolescent nonhuman primates to examine the effects of long-term binge alcohol consumption on brain development. They found that an 11-month period of heavy binge alcohol consumption by nonhuman primates led to a significant and persistent reduction in neurogenesis — the birth and maturation of new neurons – in the hippocampus, a brain region involved in learning and memory formation. Alcohol specifically interfered with the division and migration of hippocampal precursor cells. The lasting reduction in hippocampal neurogenesis was paralleled by an increase in neural degeneration. The findings demonstrate that hippocampal development during adolescence is highly vulnerable to alcohol, and suggests that alcohol-induced hippocampal degeneration is one of several factors that may increase the vulnerability to alcohol use disorders. (Taffe M, et al. Pro Nat Acad Sci, 2010, 107:11104-9).
Scientists find evidence of functional heterogeneity in the precuneus
The precuneus is a brain structure within the parietal cortex, which sits on top of the brain. Though traditionally one of the least understood structures in the human brain, the precuneus is thought to help regulate episodic memory, self-awareness, and consciousness. Very recent anatomical studies have demonstrated that it is composed of three different sub-regions. In the current study, researchers used arterial imaging techniques to measure activity in the precuneus during both rest and task performance. The investigators reported some of the first evidence of functional heterogeneity within the precuneus. It will be important to investigate in subsequent studies how alcohol abuse may affect this structure and the functions it mediates. (Pfefferbaum A et al. Cerebral Cortex, Epub ahead of print May 19, 2010).
Dissociation of genetic and hormonal influences on sex differences in alcoholism-related behaviors
Differences between men and women in the prevalence of alcohol related disorders have long been known. Such differences have been attributed to gender-related social influences on behavior and also to hormonal influences. The current study examined sex differences in alcohol consumption in mice and distinguished the biological influences deriving from either the chromosomal make up, or hormonal factors. Females consumed greater amounts of alcohol than males, a finding that was linked to the presence of female gonads. Gonadal steroids act in two manners, organizationally to modulate brain development within a critical time period and activationally to regulate physiological response throughout life. Elimination of gonadal steroids during adulthood had marginal effects on alcohol consumption in mice, suggesting that the effect of gonadal steroids on consumption may involve both organizational and activational effects. In contrast to consumption, males were found to develop a habitual pattern of consumption more quickly than females. This sex-related behavioral difference was not influenced by gonadal steroids, but was determined by the chromosomal make up of either XY or XX. This report provides novel evidence of the distinct mechanisms by which sex differences are manifested in various parameters of alcohol-related behaviors (Barker JM, et al. J Neurosci., 2010, 30(27):9140-4)
Low concentrations of alcohol inhibit development of hippocampal neurons
The learning and memory disabilities associated with fetal alcohol spectrum disorder (FASD) are due, in part, to hippocampal damage caused by ethanol exposure during prenatal development. However, the mechanism by which alcohol damages the developing hippocampus remains poorly understood. In the current study, researchers examined how ethanol exposure in neonatal rats – a period that is developmentally equivalent to the third trimester of pregnancy in humans -- affects neuronal activities in the hippocampus. They report that in vivo and in vitro ethanol exposure potently inhibits molecular processes that are vital for the proper function and maturation of hippocampal neurons. Most importantly, the ethanol effect reaches significance at concentrations that can be achieved by a pregnant woman consuming less than a single standard drink in an hour. Although many other studies have shown effects of ethanol on synaptic function in developing neurons, this study reveals the most potent effect of ethanol to date. It suggests that even low amounts of alcohol consumption during pregnancy may cause irreversible effects on hippocampal neurons and contribute to FASD (Zucca S and Valenzuela CF. Journal of Neuroscience 2010; 30:6776-81).
Study advances understanding of varenicline-induced reduction of alcohol consumption.
Increasing evidence indicates that the activation of neuronal nicotinic acetylcholine receptors (nAChRs) modulates alcohol consumption and reinforcement. Varenicline, a nAChR partial agonist, has been shown to reduce alcohol consumption in rats and heavy drinking smokers. However, the underlying mechanism of varenicline action is not clear; particularly regarding nAChR subtypes and brain regions that varenicline may target to reduce alcohol consumption. In this study, researchers demonstrated that the activation of nicotinic receptors containing alpha 4 nAChR subunit is necessary and sufficient for varenicline-induced reduction of alcohol consumption. Varenicline selectively activates dopaminergic neurons within the posterior, but not the anterior, ventral tegmental area (VTA). These data highlight the importance of alpha4 nAChRs and the posterior VTA in mediating the actions of varenicline and alcohol. Together with other results, this study indicates the potential therapeutic value of varenicline on the treatment of alcohol dependence (Hendrickson LM et al. Journal of Neuroscience, 2010; 30:10169-76).
Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse
Previous studies suggest that neuronal activities in the dorsal striatum play an important role in compulsive drug seeking and alcohol withdrawal-induced synaptic adaptation. However, it is not clear how the sub-regions of the dorsal striatum, which have distinct anatomical connectivity and function, contribute to alcohol consumption and relapse. In this study, researchers used electrophysiological recordings combined with biochemical analysis and systematic ethanol administration, to demonstrate that repeated ethanol exposure or large ethanol intake causes long-lasting facilitation of NMDA receptor-mediated synaptic activity in the dorsomedial striatum (DMS), but not in the dorsolateral striatum (DLS). These data provide evidence for a dorsostriatal mechanism underlying the maladaptive synaptic changes following repeated ethanol exposure and suggest an important role that DMS NMDA receptors play in the excessive alcohol consumption and relapse (Wang et al. Journal of Neuroscience, 2010; 30:10187-98).
Mitochondrial cytochrome P450 2E1 induces oxidative damage and augments alcohol-mediated oxidative stress.
The ethanol-inducible cytochrome P450 2E1 (CYP2E1) is also induced under different pathological and physiological conditions. Studies have shown that CYP2E1 is targeted to both the endoplasmic reticulum and mitochondria. In the current study researchers used cell culture techniques to investigate the role of mitochondrial CYP2E1 in ethanol-mediated oxidative stress. Their results strongly suggest that mitochondrial CYP2E1 induces oxidative stress and augments alcohol-mediated cell and tissue injury.
(Bansal S, et al. J Biol Chem 2010 Aug 6; 285(32):24609-19.)
Binge alcohol exposure affects spinal gene expression in adolescent rats.
Alcohol consumption in adolescent rats has been previously shown to prevent the achievement of peak bone mass during a critical time in bone development. Adult bone fails to overcome the reduced peak bone mass, and long-term skeletal integrity is compromised, showing that the effects of alcohol on bone density extend beyond the period of alcohol consumption. In the current study, researchers examined gene expression patterns in the vertebrae of adolescent rats following alcohol treatment and abstinence to identify any long-term molecular changes in the lumbar spine. They identified clusters of binge alcohol-sensitive genes displaying differential expression patterns starting before bone damage was seen and persisting after alcohol treatment was discontinued. The results demonstrate that binge alcohol exposure can produce disruptions of normal bone gene expression patterns in the adolescent rat that persist well beyond the period of active intoxication. The findings may have relevance to peak bone mass attainment and future risk of skeletal disease in adolescents who engage in repeated episodes of binge-drinking. (Callaci JJ, Himes R, Lauing K, Roper P. Alcohol Alcohol. 2010 Jul-Aug; 45(4):332-46. Epub 2010 Jun 16.)
Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.
Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, researchers explored whether ethanol-induced apoptosis would lead to activation of complement via the classical pathway. For the first time, they demonstrated that ethanol does indeed activate the classical complement pathway via C1q binding to apoptotic cells in the liver and that C1q contributes to the pathogenesis of ethanol-induced liver injury.
(Cohen JI, et al. Gastroenterology. 2010 Aug;139(2):664-74)
Imaging Interorganelle Contacts and Local Calcium Dynamics at the ER-Mitochondrial Interface.
The ER-mitochondrial junction provides a local calcium signaling domain that is critical for both matching energy production with demand and the control of apoptosis. ER-mitochondrial contacts can be resolved in vivo using inducible interorganelle linkers. A deeper exploration of the ER-mitochondrial coupling in live cells was made possible by the invention of drug-inducible interorganellar linkers that can accommodate different fluorescent proteins for colocalization, FRET, and chemical signal measurements. This genetic approach offers a powerful toolkit for the study of various interorganellar contact sites in live cells. In this study investigators visualized ER-mitochondrial contact sites and monitored the localized [Ca2+] changes ([Ca2+]ER-mt) using drug-inducible fluorescent interorganelle linkers. They showed that all mitochondria have contacts with the ER, but plasma membrane (PM)-mitochondrial contacts are less frequent because of interleaving ER stacks in both RBL-2H3 and H9c2 cells. Single mitochondria display discrete patches of ER contacts and show heterogeneity in the ER-mitochondrial Ca2+ transfer. The IP3-induced local ER-mitochondrial interface [Ca2+] reaches >10-fold above the global [Ca2+]. The high-Ca2+ microdomains require an optimal space between the ER and mitochondria. These studies provide direct evidence for the existence of high-Ca2+ microdomains between the ER and mitochondria and suggest an optimal gap width for efficient Ca2+ transfer. It is likely that the different functions of the ER-mitochondrial associations are assigned to contacts with distinct physical properties. Collectively, these results suggest that both the area and gap width of the ER-mitochondrial interface are important determinants of the [Ca2+]ER-mt signaling and are likely to affect differently the other functions of the junctions. (Csordás G, et al. Molecular Cell 2010; 39: 121-132. (Partly funded by RC2-AA019416)
Phosphodiesterase inhibitors may be potential treatment for FASD learning deficits.
Learning and memory deficits are common in children with fetal alcohol spectrum disorders (FASD). Such deficits are also seen in animal models of FASD. Critical to learning is synaptic plasticity, the ability to form new neural connections. In previous studies, investigators have shown that synaptic plasticity is impaired in the visual cortex of ferrets exposed in utero to ethanol. They then showed that plasticity could be restored in this animal by vinpocetine, one of a group of drugs known as phosphodiesterase (PDE) inhibitors. In the current study, the researchers used a rat model of FASD to demonstrate that vinpocetine could mitigate the learning deficits of young rats that had been exposed to alcohol during the equivalent of the third trimester of human gestation. Demonstration of the beneficial effects of vinpocetine in both ferret and now rat models of FASD suggests that this agent may be "translatable" to humans as a treatment for children with FASD. (Filgueiras CC, Krahe TE, Medina AE. Neurosci Lett 2010; 473:202-7.)
Delayed neonatal lung macrophage differentiation in a mouse model of in utero ethanol exposure.
Prenatal alcohol exposure (PAE) is thought to increase the newborn's risk for infection by impairing immune function. Consistent with this, investigators have previously established that lung alveolar macrophages (AM) of offspring are poorly differentiated and functionally impaired in an animal model of PAE. The current study demonstrates that PAE also impairs differentiation of lung interstitial macrophages (IM), the precursors of AM, and results in oxidative stress in the lung, which was found to induce both AM and IM to express TGFβ1. Furthermore, TGFβ1, in turn, was shown to cause dedifferentiation and impair phagocytic function of both IM and AM. Importantly, this cascade of events in the offspring could be prevented by administering S-adenosylmethionine (SAM), which protects against oxidative stress, to the alcohol-consuming pregnant animal. Thus, these findings extend our mechanistic understanding of alveolar macrophage dysfunction in prenatal-alcohol-exposed newborns and suggests strategies to prevent this adverse outcome of PAE. (Gauthier TW, et al. Am J Physiol Lung Cell Mol Physiol 2010; 299:L8-16.)
Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice.
Chronic alcohol consumption impairs innate and adaptive immunity, leading to increased severity of pulmonary infections, including influenza A virus. During influenza outbreaks, infected chronic alcoholics have more profound lung pathology, greater viral titers and viral shedding, and increased mortality. The neuraminidase inhibitor oseltamivir is an anti-influenza drug that is effective in healthy populations, but less effective in immune compromised individuals. In the current study, researchers found that, despite the severe immune defect of mice chronically fed ethanol, treatment with oseltamivir improved the prognosis and survival of influenza –infected chronically alcohol-fed mice. The experimental design incorporated a prophylactic dose of anti-viral coupled with concurrent treatment, so the animal results are not entirely relevant to community acquired infections. Nevertheless, these results may be translatable to instances of influenza pandemic, during which prophylactic treatment of compromised populations may reduce morbidity, mortality and medical costs. (Langlois RA, et al. Alcohol Clin Exp Res. 2010 Aug;34(8):1425-31. Epub 2010 May 21.)
Toward a Neurobehavioral Profile of Fetal Alcohol Spectrum Disorders.
FASD is characterized by craniofacial malformations, neurological and motor deficits, intrauterine growth retardation, learning disabilities, and behavioral and social deficits. In the current study, researchers analyzed neuropsychological assessments given at two sites of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), an interdisciplinary consortium of investigators funded by NIAAA. Subjects were children with heavy prenatal alcohol exposure (PAE) and unexposed children. Out of 547 neuropsychological variables, 22 were selected for analysis based on their ability to distinguish among these two groups. The resulting profile was successful at distinguishing subjects with fetal alcohol syndrome (FAS), which falls at the severe end of the FASD spectrum, from non-exposed controls with a high degree of accuracy (92%). Furthermore, and perhaps more importantly, this same profile was used to accurately distinguish children with heavy PAE who do not meet the physical criteria for FAS from non-exposed controls (85% overall classification accuracy). The authors suggest that measures of executive function and spatial processing are especially sensitive to PAE. Collectively, these findings should improve the ability to accurately identify children affected by maternal alcohol consumption. (Mattson SN, et al. Alcohol Clin Exp Res. 2010 Jun 21. [Epub ahead of print])
Effects of moderate drinking during pregnancy on placental gene expression.
Many children adversely affected by maternal drinking during pregnancy cannot be identified early in life using current diagnostic criteria for fetal alcohol spectrum disorder (FASD). In the current study, conducted with pregnant rats, researchers examined whether ethanol-induced alterations in placental gene expression may have some utility as a diagnostic indicator of maternal drinking during pregnancy and as a prognostic indicator of risk for adverse neurobehavioral outcomes in affected offspring. Microarray analysis of more than 28,000 genes revealed that the expression of 304 known genes was altered twofold or greater in placenta from ethanol-consuming pregnant rats compared with controls. About 76% of these genes were repressed in ethanol-exposed placentas. Gene expression changes involved proteins associated with central nervous system development; organ morphogenesis; immunological responses; endocrine function; ion homeostasis; and skeletal, cardiovascular, and cartilage development. These results suggest that the expression of a sufficiently large number of placental mRNAs is altered after moderate drinking during pregnancy to warrant more detailed investigation of the placenta as a biomarker system for maternal drinking during pregnancy and as an early indicator of FASD. Furthermore, these results provide new insights into novel mechanisms on how ethanol may directly or indirectly mediate its teratogenic effects through alterations in placental function during pregnancy. Given the accessibility of placentas following child birth, the gene changes identified in this study have the potential to serve as practical biomarkers of prenatal alcohol exposure and/or predictors of FASD in offspring. In addition, the identity of these genes could inform our understanding of alcohol's effects on placental function. (Rosenberg MJ, et al. Alcohol 2010 Jan 4. [Epub ahead of print].)
Chronic alcohol exposure increases circulating bioactive oxidized phospholipids.
Ethanol metabolism by the liver generates short-lived reactive oxygen species that can damage the liver and affect other organs through unknown mechanisms. In studies directed toward the understanding of the link between alcohol use, oxidative stress and tissue damage, researchers report an important temporal distinction between alcohol-induced reactive oxygen species and the appearance of oxidized phospholipids. The latter were identified as markers of developing steatohepatitis temporally distinct from oxidant stress with the potential to systemically distribute the effect of chronic ethanol exposure. Drugs that suppress endoplasmic reticulum stress and hepatic inflammation without any antioxidant capability were shown to reduce the circulating oxidized phospholipids and abolish liver damage, pointing the way toward potentially new therapy for alcoholic liver disease. The conclusion that the reactive oxygen species are not the proximate cause for liver damage is a potential paradigm shift in the understanding of alcohol induced tissue damage. (Yang L, et al. J Biol Chem. 2010 285(29):22211-20. Epub 2010 May 11.)
Evaluation of a brief web-based genetic feedback intervention for reducing alcohol-related health risks associated with ALDH2.
There is increasing interest in health interventions that incorporate genetic risk information. Although genetic feedback has been evaluated as an adjunct to smoking cessation interventions, its efficacy for reducing alcohol-related risks is unknown. The current study evaluated the feasibility, acceptability, and efficacy of a web-based alcohol intervention incorporating genetic feedback and risk information specific to ALDH2 genotype. The ALDH2*2 variant is associated with partial protection against alcohol dependence but confers significantly increased risk for alcohol-related cancers as a function of alcohol exposure. Two hundred Asian-American young adults were randomly assigned to receive web-based personalized genetic feedback or attention-control feedback. Genetic feedback included health risk information specific to alcohol-related cancer or alcohol dependence, depending on genotype. Genetic feedback and risk information resulted in significant reductions in 30-day drinking frequency and quantity among participants with the ALDH2*1/*2 genotype. Genetic feedback was rated highly by participants and also showed some effects on theoretical correlates of behavior change. Results provide initial evidence of the feasibility, acceptability, and brief efficacy of web-based genetic feedback for reducing alcohol-related health risks associated with ALDH2 genotype. Results also highlight the utility of targeting preventive interventions based on genetically-related risk and protective factors and specific environmental exposures. (Hendershot CS, et al. Ann Behav Med. 2010 Aug; 40 (1):77-88.)
Revised NESARC personality disorder diagnoses: gender, prevalence, and comorbidity with substance dependence disorders.
In this study, researchers applied different diagnostic rules for diagnosing personality disorders (PDs) to the NESARC epidemiological study of over 40,000 individuals. Results demonstrated significant reductions in prevalence rates for PDs (9.1% versus 21.5% using original NESARC algorithms), and these revised prevalence rates were much more consistent with recent epidemiological studies in the U.S. and Great Britain. We also found gender differences in the prevalence rate for most PDs. Comorbidity analyses revealed strong associations between PDs and alcohol dependence, drug dependence, and tobacco dependence. PD diagnoses were also associated with scores on dysfunction and impairment, perceived stress and less social support, lifetime history of suicide attempts, interpersonal difficulties, and problems with legal authorities.
Use of this approach in future research may help to identify individuals whose comorbid psychiatric diagnoses may place them at greater risk for AUD and the need for changes in assessment and treatment of those at risk. (Trull TJ, et al. J Pers Disord. 2010 Aug;24 (4):412-26.)
A genetic determinant of the striatal dopamine response to alcohol in men
Excessive alcohol use, a major cause of morbidity and mortality, is less-well understood
than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. In the current study, investigators report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, researchers generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.
(Ramchandani VA, et al. Molecular Psychiatry advance online publication, 18 May 2010.)
Polymorphisms Modify the Effect of Breastfeeding on Child IQ
Breastfeeding is important for child cognitive development. A recent study has suggested that rs174575 within the FADS2 gene moderates this effect so that children homozygous in the minor allele (GG genotype) have similar IQs irrespective of feeding method.
In this study of 5934 children aged 8 years, no genetic main effect with IQ was found for rs174575. In contrast to previous findings, GG children exhibited the greatest difference between feeding methods such that breastfed children performed similarly irrespective of child genotype whereas formula fed GG children performed worse than other children on formula milk. Further studies are required to replicate these findings. (Steer CD, et al. PLoS ONE 2010 5(7):e11570.)
Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. In this study, researchers demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.
(Tam J, et al. J Clin Invest Epub ahead of print July 26, 2010.)
Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor
Alcoholism can result in fatty liver that can progress to steatohepatitis, cirrhosis, and liver cancer. Mice fed alcohol develop fatty liver through endocannabinoid activation of hepatic CB1 cannabinoid receptors (CB1R), which increases lipogenesis and decreases
fatty acid oxidation. Chronic alcohol feeding also up-regulates CB1R in hepatocytes in vivo, which could be replicated in vitro by co-culturing control hepatocytes with hepatic stellate cells (HSC) isolated from ethanol-fed mice, implicating HSC-derived mediator(
s) in the regulation of hepatic CB1R. HSCbeing a rich source of retinoic
acid (RA), researchers in this study tested whether RA and its receptors may regulate CB1R expression in cultured mouse hepatocytes. Incubation of hepatocytes with RA or RA receptor (RAR) agonists increased CB1R mRNA and protein, the most efficacious being the RAR agonist CD437 and the pan-RAR agonist TTNPB. The endocannabinoid 2-arachidonoylglycerol (2-AG) also increased hepatic CB1R expression, which was mediated indirectly via RA, because it was absent in hepatocytes from mice lacking retinaldehyde dehydrogenase 1, the enzyme catalyzing the generation of RA from retinaldehyde. The binding of RAR to the CB1R gene 5 upstream domain in hepatocytes treated with RAR agonists or 2-AG was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift and antibody supershift assays. Finally, TTNPB-induced CB1R expression was attenuated by small interfering RNA
knockdown of RAR in hepatocytes. We conclude that RAR regulates CB1R expression and is thus involved in the control of hepatic fat metabolism by endocannabinoids.
(Mukhopadhyay, B et al. J Biol Chem. 2010 Jun 18;285(25):19002-11. Epub 2010 Apr 21.)
Publications by Extramural Staff
Matthew Reilly, PhD, a program director in the Division of Neuroscience & Behavior, co-edited a special volume on alcohol with David Lovinger, PhD (Chief, Laboratory for Integrative Neuroscience, NIAAA) in the International Review of Neurobiology entitled: Functional Plasticity and Genetic Variation: Insights into the Neurobiology of Alcoholism, Vol 91, 2010.
Dr. Ralph Hingson published a Commentary on Nelson, Toomey, Lenk, et al. (2010): “Implementation of NIAAA College Drinking Task Force Recommendations: How are Colleges Doing 6 Years Later?” in Alcoholism: Clinical and Experimental Research 34(10): 1-5, 2010.
Dr. Howard Moss published a NIAAA Update column in the Summer 2010 issue of the AAAP newsletter entitled “What’s In a Name? Labeling and Stigma in Alcohol and Drug Dependence.”