NIAAA Directors Report on Institute Activities to the 135th Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism

Wednesday, February 5, 2014

Table of Contents

• NIAAA WELCOMES NEW DIRECTOR

• NIAAA BUDGET

• DIRECTOR’S ACTIVITIES

• STAFF TRANSITIONS & AWARDS

• HONORS & AWARDS

• NEW RFA’S/PA’S

• NIAAA COMMUNICATIONS & MEDIA COVERAGE

• SELECT NIAAA STAFF ACTIVITIES

• WHAT’S AHEAD

• NIAAA RESEARCH HIGHLIGHTS

NIAAA Welcomes New Director

On January 27, 2014, George F. Koob, Ph.D., joined NIH as Director of the National Institute on Alcohol Abuse and Alcoholism. Dr. Koob is one of the world’s authorities on the neurobiology of alcohol and drug addiction.
He comes to NIAAA from The Scripps Research Institute, California Campus, where he orked for three decades, most recently serving as Chairman of the Committee on the Neurobiology of Addictive Disorders, and Director of the Alcohol Research Center. He earned his Ph.D. in Behavioral Physiology at Johns Hopkins University.

Dr. Koob’s early research interests were directed at the neurobiology of emotion, with a focus on the theoretical constructs of reward and stress. His contributions have led to the understanding of the anatomical connections of emotional systems and the neurochemistry of emotional function.  

He has contributed to the understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and more recently on the neuroadaptations of these reward circuits associated with the transition to dependence.
After five years of service as Acting Director, Dr. Kenneth R. Warren will return to his position as Deputy Director.

Photo: On January 28, 2014, Dr. George Koob was sworn in as the new Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) by NIH Director Dr. Francis Collins.

NIAAA BUDGET

FY 2013
The total FY 2013 appropriation for NIAAA was $433.4 million.  Within this appropriation, NIAAA awarded 648 research project grants (RPGs), including 166 competing awards, which corresponds to a success rate of 20%.  FY 2013 support levels for other key extramural funding mechanisms included 18 research centers for $26.0 million, 135 other research grants for $35.0 million, 270 full-time training positions for $11.4 million; and $37.6 million for research and development contracts.

FY 2014
After a lengthy continuing resolution, the Consolidated Appropriation Act, 2014 (H.R. 3547) was signed by the President on January 17th.  NIH received a total of $29.9 billion, $1 billion above the fiscal year 2013 post-sequestration level. This funding will continue support for basic bio-medical research and translational research through the programs like the Clinical and Translational Science Awards (CTSA) and Institutional Development Award (IDeA) to support scientists as they conduct research to discover cures. Further, it provides full support for the NIH Office of Science Education and programs like the Science Education and Partnership Awards (SEPA) to support bio-medical research for the future.

The FY 2014 appropriation for NIAAA provides $444.9 million.  This represents a $11.5 million or a 2.7% increase over the FY 2013 post-sequestration budget level. NIAAA estimates it will support a total of 652 RPGs in FY 2014, including 175 competing awards.

FY 2015
Preliminary work on the budget for FY 2015 is beginning.  After intermediate stages of review, the President’s budget request for FY 2015 will be presented to Congress on March 3, 2014, at which time it will become available to the public.

NIAAA Budget (Dollars in Thousands)

DIRECTOR’S ACTIVITIES

STAFF TRANSITIONS

Howard B. Moss, M.D., Associate Director for Clinical and Translational Research, has retired from NIAAA after nine years in this capacity. Dr. Moss was one of NIAAA's first Medical Staff Fellows in the Intramural Program in the early 1980s.  He went on to become a Professor of Psychiatry at University of Pittsburgh School of Medicine for 15 years, and Professor of Psychiatry at University of Pennsylvania School of Medicine for five years. He was recruited by then Director, T.K. Li, and returned to NIAAA in 2004 to work in the Office of the Director. Dr. Moss is a board-certified psychiatrist with added qualifications in addiction psychiatry. His research has focused on the clinical manifestations of substance use disorders, their etiology, and the intergenerational transmission of risk and resilience.  This work has employed diverse methodologies that include psychiatric epidemiology, advanced statistical methods, neurochemistry/neuropharmacology, psychophysiology, biomarker development, neuroimaging, and molecular and behavioral genetics. Dr. Moss is moving to San Diego where he hopes to continue his research endeavors.

Peter Silverman, Ph.D., J.D., Deputy Scientific Director, has retired effective January 13, 2014. Dr. Silverman has a unique set of expertise: he is an accomplished Ph.D. neuroscientist, an outstanding expert of technology transfer issues buttressed by a law degree, superb interpersonal skills that have served him well as our training director, and a sense of humor that has endeared him to all. His wise counsel to the Scientific Director on all kinds of matter has been particularly appreciated. His contribution to NIAAA’s intramural program has been invaluable and its loss will be keenly felt. Fortunately, he has graciously agreed to continue to look after tech transfer issues as a part-time contractor.

Nancy Diazgranados, M.D., M.Sc., joins the Section of Clinical Assessment & Treatment Evaluation as a Staff Clinician. Her current work is in clinical research, mood dis orders, clinical pharmacology and experimental therapeutics. Dr. Diazgranados received her Doctoral Degree in Medicine and Surgery from the Pontificia Universidad Javeriana in Bogota, Colombia. She completed her Psychiatry residency at Albert Einstein Medical Center and a Master in Science Degree in Pharmacology at Thomas Jefferson University. In 2008, she became a diplomat of the American Board of Psychiatry and Neurology. She continued her training as a Post-Doctoral Clinical-Research Fellow at the intramural program at NIMH; there she worked at the Experimental Therapeutics and Pathophysiology Branch in the Mood and Anxiety Disorders Program.  In 2010, she joined the University of Texas Health Science Center at San Antonio as a tenure track assistant professor within the Division of Mood and Anxiety Disorders. In 2012, she joined a private practice and relocated to Maryland.

Bonnie L. Ellis joins the Administrative Services Branch as a Section Chief, Administrative Officer.  She has been in the federal government and at NIH for 24 years.  Seventeen of these years were at the Center for Scientific Review, with a break in service to the Office of the Director for seven years.  Her last position before NIAAA was as an Administrative Officer at CSR.  She has spent over 10 years as supervisor/manager.  In her current position she will support the OD and Extramural.

HONORS & AWARDS

• Dr. Abraham Bautista, Director of the Office of Extramural Activities, received from the NIH Asian Pacific Islander American Organization, the 2013 Leadership Excellence Award for leadership excellence, mentorship and empowerment of Asian and Pacific Americans to promote diversity and support of the overall mission of NIH.
• Dr. Ralph Hingson, Director of the Division of Epidemiology and Prevention Research received the University of Pittsburgh Legacy Laureate Award on September 27, 2013. The University of Pittsburgh gives this award to alumni recognized for their outstanding professional and personal accomplishments.
• Dr. Lorenzo Leggio, Chief of the joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN), Laboratory of Clinical and Translational Studies (LCTS), was appointed as Editor-in-Chief for North America for Alcohol and Alcoholism, the official Journal of the European Society for Biomedical Research on Alcoholism (ESBRA).
• Dr. Lorenzo Leggio, together with Dr. Fatemeh Akhlaghi from the University of Rhode Island received one of the 9 NCATS grant awards of the “Discovering New Therapeutic Uses for Existing Molecules” initiative. This is a translational project that will look at the effects of a ghrelin receptor antagonism in alcoholism. The project involves the NIH Intramural Research Program (NIAAA/LCTS, NIDA IRP, CC), the NIA Extramural Programs (NCATS and NIAAA), the University of Rhode Island, and Pfizer.
• Dr. Mary Lee and Dr. Lorenzo Leggio, respectively Staff Clinician and Chief at the joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN), LCTS, received one of the “Bench-to-Bedside” (B2B) grant award selected for funding in the behavioral and social sciences category. This is a translational project that will look at the effects of oxytocin in alcoholism. The project involves the NIH Intramural Research Program, i.e. NIAAA/LCTS, NIDA IRP, NIAAA/LNI, NIMH, and CC.
• Dr. Cheryl Marietta, a Senior Research Assistant in the Laboratory of Neurogenetics and the lab’s safety guru, won an “NIH Mission First, Safety Always” award.

NIAAA’s Annual Sen. Harold Hughes Award
Mr. Tom Donaldson, president of the National Organization on Fetal Alcohol Syndrome (NOFAS), will receive NIAAA’s 2014 Senator Harold Hughes Memorial Award. For more than a decade Donaldson has served in leadership role at NOFAS, first as chief executive officer and, since 2002, as the nonprofit organization’s president. NOFAS provides resources for people living with fetal alcohol spectrum disorders (FASD) and advocates for improved public policy for those affected by FASD. The organization also educates the public about FASD and the risks of drinking alcohol while pregnant.  

The Hughes Award recognizes the contributions of a non-researcher whose achievements have helped to translates research into practice by building bridges across the alcohol prevention, treatment and policy-making communities. The award recalls the legacy of U.S. Senator Harold Hughes, the force behind the Comprehensive Alcohol Abuse and Alcoholism Prevention, Treatment and Rehabilitation Act of 1970, which established the NIAAA. 
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NEW RFA’S/PA’S

• NPA-13-359, PA-13-360 and PA-13-361: Nutrition and Alcohol-Related Health Outcomes (R01, R03, R21).  This solicitation encourages applications that propose to examine associations between nutrition and alcohol-related health outcomes in humans and animal models. The goal of this NOFO is to stimulate a broad range of research on the role of nutrition in the development, prevention, and treatment of a variety of alcohol-related health outcomes including alcohol use disorder and chronic disease. Dr. Peter Gao, Dr. Rosalind Breslow, and Dr. John Matochik are program contacts.
• RFA-AA-14-002, RFA-AA-14-003: Limited Competition: Alcohol-HIV/AIDS Program Project on Behavioral Interactions and Intervention (P01, P60). This NOFO encourages renewal applications for a research center grant to conduct cross-cutting research on alcohol and HIV/AIDS. Through this NOFO, NIAAA seeks to encourage research that can be translated into interventions in order to reduce infection and transmission of HIV. 
• Program Announcement PA-13-339 (R01) and PA-13-340 (R21): Mechanisms of Alcohol and Stimulant Co-Addiction were issued to promote research on the neurobiology and behavioral mechanisms that might explain how alcohol and stimulants interact at genetic, epigenetic, cellular, neurocircuitry, and behavioral levels to promote co-addiction. Drs. Ivana Grakalic and Matthew Reilly are the program contacts. 
• Program Announcement PA-14-038 (R01), PA-14-036 (R21), and PA-14-037(R03): Women, & Sex/Gender Differences in Drug and Alcohol Abuse/Dependence  were re-issued jointly with NIDA to advance research on male-female differences in drug and alcohol abuse and addiction and on factors specific to women. Both human and animal model studies are sought. Dr. Ellen Witt is the program contact from NIAAA. 
• NIAAA participated in the NIH initiative PAR-13-364 (R01): Development of Assay for High-Throughput Screening for use in Probe and Pre-therapeutic Discovery.  The purpose of this NOFO is to 1) develop assays for specific biological targets and disease mechanisms relevant to the mission of participating NIH Institutes with the intent to screen for small molecule compounds that show potential as probes for use in advancing knowledge about the known targets, identifying new targets, or as pre-therapeutic leads; and 2) establish collaborations with screening centers that have the requisite expertise and experience needed in implementation of HTS assays for the discovery and development of small molecule chemical probes. Dr. Changhai Cui is the NIAAA scientific contact for this announcement. 
• NIAAA will continue participation in the “Collaborative Research in Computational Neuroscience:  Innovative Approaches to Science and Engineering Research on Brain Function” (CRCNS) program for FY2014-16.  The CRCNS program is a joint initiative between the National Science Foundation, the National Institutes of Health, the German Federal Ministry of Education and Research, the French National Research Agency, and the U.S.-Israel Binational Science Foundation. The current funding announcement is NSF-14-504.  Dr. John Matochik is the program contact.  
• The NIH Has released its first round of funding opportunities in support of the President’s BRAIN Initiative. Collectively, these opportunities focus on building a new arsenal of tools and technologies for helping scientists unlock the mysteries of the brain. Six funding announcements (see http://www.nih.gov/science/brain/funding.htm) were developed in response to one or more of the high priority areas identified by the NIH Advisory Committee to the Director’s BRAIN Working Group in its interim report.  NIH investments will total $40 million in Fiscal Year 2014 and will involve a coordinated, cooperative effort between interdisciplinary scientific teams and with NIH program staff. NIAAA staff from the Division of Neuroscience and Behavior (Drs. Antonio Noronha, Changhai Cui, Lindsey Grandison, Qi-ying Liu, and John Matochik) have participated in the discussion and development of these RFAs. 
• Dr. Robert Freeman is the NIAAA Scientific Contact on trans-NIH PA-13-363, which is titled Research on the Health Determinants and Consequences of Violence and its Prevention, Particularly Firearm Violence (released in September 2013). Under this PA, NIAAA welcomes applications that explore the etiology, epidemiology, prevention, and treatment of alcohol-related violence, but particular consideration will be given to applications that propose studies of the intersection of various types of violence (homicide, suicide, youth, IPV) and firearms. 
• Dr. Robert Freeman is the NIAAA Scientific Contact on RFA-CA-14-008 (R01): Using Social Media to Understand and Address Substance Use and Addiction. This is part of a trans-NIH initiative Collaborative Research on Addiction at NIH (CRAN, http://addictionresearch.nih.gov/). 
• PAR-14-051, PAR-14-052, and PAR-14-053: Mechanisms of Behavior Change in the Treatment of Alcohol Use Disorders (R01, R03, R21). This notice of funding opportunity (NOFO) encourages grant applications from institutions or organizations that propose to investigate the underlying mechanisms that facilitate behavior change within our current empirically-supported behavioral treatments for alcohol use disorders.  A further goal of this NOFO is to enhance translational research efforts by identifying potential neurobiological or cognitive processes that may act as potential mechanisms of therapeutic change or mediate the direct link between specific “active ingredients” and alcohol use treatment outcomes.  
• PAR-13-383 (U01): Replication of Key Clinical Trials Initiative. In response to the significant need to replicate influential behavioral and pharmacological clinical trials of therapeutic approaches to the treatment of Alcohol Use Disorders and alcoholic liver disease, this Notice of Funding Opportunity (NOFO) invites applications for a limited number of Cooperative Agreements (U01) for the purpose of conducting replication studies of key single-site “proof of concept” clinical trials of a behavioral or pharmacologic nature. 

Research & Development (R&D) Sources Sought

Ms. Megan Ryan and Dr. Raye Litten (in conjunction with Contract Officers Alice Pagan and David Fitton – NICHD) released a Sources Sought announcement on November 25, 2013 for an upcoming solicitation entitled “Human Laboratory Paradigms” (Solicitation Number: NIH-NIAAA-RDSS-14-005). NIAAA seeks capability statements from interested and qualified potential laboratory sites capable of conducting human laboratory paradigms in non-treatment seeking individuals with alcohol use disorder, paradigms that can serve as a screening model for medications development. 

NIAAA COMMUNICATIONS & MEDIA COVERAGE 

Seasonal Outreach Series – Projects and Results

Winter Holidays

As part of the seasonal outreach around the Christmas and New Year’s holidays, NIAAA used a multipronged approach focusing on traffic fatality statistics (from the National Highway Traffic Safety Administration), health messages on moderate drinking, and a link to NIAAA’s Rethinking Drinking website.  Expanded efforts this year included:

• The NIAAA fact sheet titled “New Year, Old Myths, New Fatalities: Alcohol-Related Traffic Deaths Jump During Christmas and New Year’s,” was disseminated to the media via PR Newswire on December 2 and 23, 2013. Across both dates, the release was linked by a total of 334 unique media outlets including Yahoo!, The Boston Globe, The Cincinnati Inquirer, The Sacramento Bee, and Reuters, as well as numerous major television network (FOX, NBC, CBS, ABC) local affiliates nationwide, representing a total potential audience of 57,852,000 people.

• NIAAA provided the fact sheet electronically to the Washington Regional Alcohol Program (WRAP), as well as numerous state and county police departments. Hard copies of the fact sheet were sent to the Delaware Office of Highway Safety and Utah Office of Highway Safety.

• Additionally, NIAAA ran a 15-second animated holiday-themed PSA on the CBS Times Square billboard during the month of December.  More than 2 million people pass through the Times Square area each day. 

Photo: Video still from the 15-second NIAAA spot that appeared in Times Square over the holidays.

• Social Media Outreach:  Photo messages were included on NIAAA and NIH websites and in Twitter messages, distributed among NIH and liaison community for possible additional placements, and pitched to online food and entertaining media for free placement on their websites.

• Twitter Chat:  On December 12, 2013, NIAAA hosted a Twitter chat, “Alcohol & the Holidays: What You Need to Know.” The chat, co-hosted by the National Council on Alcohol and Drug Dependence (NCADD) and featuring NIAAA researcher Dr. Aaron White, covered tips for celebrating the season safely if you choose to drink, vital stats about drunk driving, and evidence-based advice for those thinking about reducing their drinking in the New Year. The chat had 121 contributors and a potential reach of 480,000 people.

Halloween: “People” social media pick-up

As part of NIAAA’s seasonal awareness efforts, NIAAA reached out to several high-profile magazines for possible free placement of our graphic messages. People.com featured NIAAA’s Halloween risky-drinking prevention PSAs from October 29 through October 31, 2013. People Magazine is the #4 magazine for women, and reaches 16 million unique users a month, with 882 million pages viewed on average monthly. The donated ad value was $12,000.

Back to School Outreach

In conjunction with the start of the fall college semester, NIAAA disseminated its fact sheet “Fall Semester: A Time for Parents to Revisit Discussions About College Drinking” through PR Newswire on August 19, August 26, and September 3, 2013. The fact sheet was picked up by 350 media outlets including Yahoo!, The Boston Globe, The Cincinnati Inquirer, The Sacramento Bee, and Reuters, as well as numerous major television network (FOX, NBC, CBS, ABC) local affiliates nationwide, with a total audience of more than 58 million people. The fact sheet was also disseminated to colleges and universities nationwide.

Super Bowl Outreach

As part of the arrangement for the holiday PSA on the CBS Times Square billboard, NIAAA was given the opportunity, free of charge, to change the graphic on January 1 for the final days of the contract period.  As a result, NIAAA replaced the holiday theme with a 15-second PSA focusing on risky drinking during the Super Bowl (February 2). NIAAA is also promoting three static images to the media for use in social media and websites. According to NHTSA, on Super Bowl Sunday, 36 percent of fatalities from motor vehicle crashes were connected to drunk driving in 2011.

AP REPORTER VISIT

In early November, the communications and public liaison branch (CPLB) submitted a proposal to the NIH Communications Office to showcase NIAAA’s clinical center activity for a visiting reporter from the Associated Press.  The recommendation, which highlighted the work of Drs. Markus Heilig and Lorenzo Leggio, was one of only four selected for the reporter’s day-long visit to NIH. NIAAA continues to be in contact with the reporter to provide resources for a possible future article.    

EXHIBITS & PUBLICATIONS

NIAAA’s exhibits are being revised for use at health fairs, conferences, professional meetings, and other events. Several of these exhibits are tailored to specific audiences, including a tabletop designed to spotlight NIAAA’s work in ending health disparities in alcohol research and another tabletop drawing attention to the Institute’s important research in fetal alcohol spectrum disorders. Other new exhibits include:

• A full-sized traveling exhibit
• A pop-up exhibit featuring the NIAAA logo for use at press events
• A small tabletop that mirrors the large, permanent exhibit on display at NIH
• Banner stands and table drapes with the Institute’s logo

Publications:

• Alcohol Alert, No. 86 (“Epigenetics—New Frontier for Alcohol Research”) was printed and mailed to subscribers at the end of October. The issue is also available on the NIAAA website.
• A new fact sheet comparing criteria from DSM–IV and DSM–5 has been developed to provide a quick summary of the differences and similarities between these two sets of criteria.
• The holiday drinking fact sheet, “Rethinking Holiday Drinking: New Year, Old Myths, New Fatalities,” has been revised and posted on the NIAAA website.
• Five issues of Alcohol Research: Current Reviews are now underway. Topics include “m-Health,” “Translating Research into Practice,” “Defining Special Populations for Alcohol Use and Its Consequences,” “Alcohol and the Immune System,” and “Alcohol–Organ Interactions.”

Publication Statistics:
As of November 30, there were 24,071 subscribers to the Alcohol Alert; 23,733 to Alcohol Research: Current Reviews; 15,850 to the Spectrum; and 15,691 to receive general information.

PRESS RELEASES & RESEARCH NEWS

NIH study identifies gene for alcohol preference in rats (September 30, 2013)

Selectively bred strains of laboratory rats that either prefer or avoid alcohol have been a mainstay of alcohol research for decades.  So-called alcohol-preferring rats voluntarily consume much greater amounts of alcohol than do non-preferring rats.  Scientists at the National Institutes of Health now report that a specific gene plays an important role in the alcohol-consuming tendencies of both types of rats.

NIH Names Dr. George Koob Director of the National Institute on Alcohol Abuse and Alcoholism (October 31, 2013)

National Institutes of Health Director Francis S. Collins, M.D., Ph.D., announced today the selection of George F. Koob, Ph.D., as Director of the National Institute on Alcohol Abuse and Alcoholism.  Dr. Koob is expected to join the NIH in January 2014.

NIH-funded study finds that gabapentin may treat alcohol dependence (November 04, 2013)
Promising results from a randomized, controlled clinical trial of the medication  

The generic anticonvulsant medication gabapentin shows promise as an effective treatment for alcohol dependence, based on the results of a 150-patient clinical trial of the medication. Conducted by scientists supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, the study found that alcohol dependent patients using gabapentin were more likely to stop drinking or refrain from heavy drinking than those taking placebo. Gabapentin is already widely prescribed to treat pain conditions and epilepsy.

NIAAA to Host Twitter Chat on Holiday Drinking (November 22, 2013)

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) will be hosting a Twitter Chat, “Alcohol & the Holidays: What You Need to Know.” The chat will cover tips for celebrating the season safely if you choose to drink, vital stats about drunk driving, and evidence-based advice for those thinking about reducing their drinking in the New Year. The chat will also explore the after-effects of a night of overconsumption (apart from those professionally damaging dance moves at the office holiday party), as well as the intriguing “holiday heart” phenomenon.

Twitter Chat on Holiday Drinking (January 2, 2014)

Read our Twitter Chat, “Alcohol & the Holidays: What You Need to Know,” transcript here: http://sfy.co/pKyy. The National Council on Alcoholism and Drug Dependence (NCADD) co-hosted the December 12 event.

NIH study: Research-based strategies help reduce underage drinking (January 14, 2014)

Strategies recommended by the Surgeon General to reduce underage drinking have shown promise when put into practice, according to scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. These approaches include nighttime restrictions on young drivers and strict license suspension policies, interventions focused on partnerships between college campuses and the community, and routine screening by physicians to identify and counsel underage drinkers.

RECENT NEWS MEDIA INTERVIEWS

Dr. Judy Arroyo, NIAAA Minority Health and Health Disparities Coordinator, spoke with Rose Arce of CNN.com about alcohol-related cirrhosis mortality among Hispanics. (12/4/13)

Dr. Arroyo subsequently gave a live on-camera interview on this topic (in Spanish) to CNN en Español. (12/17/13)

Mr. Greg Bloss, Division of Epidemiology and Prevention Research, provided expert input to an inquiry received by the NIH Press Office from Adam Ulbricht of Watchdog.org regarding an NIH grant to the Public Health Institute's Alcohol Research Group. (12/6/13)

Dr. Rosalind Breslow, Division of Epidemiology and Prevention Research, spoke with Ben Court of Men’s Health on the topic of drinking and nutrition. (9/17/13)

Dr. Robert Freeman, Division of Epidemiology and Prevention Research, spoke with Jaime Fuller of The American Prospect magazine about NIAAA involvement in planned studies on violence. (10/29/13)

Dr. Markus Heilig, NIAAA Laboratory of Clinical and Translational Studies, spoke with Stefanie Schramm of Die Zeit about calcium as the possible mechanism of action for acamprosate’s effectiveness. (10/25/13)

Dr. Heilig also spoke with Jonathan Rockoff of the Wall Street Journal about alcoholism treatments that target brain stress systems. (12/17/13)

Dr. Joe Hibbeln of the NIAAA Laboratory of Membrane Biochemistry and Biophysics spoke with Lucy Johnston of the Sunday Express (UK) about the relationship of omega 3 fatty acid consumption to mental health and human behavior.  (10/24/13)

Dr. Hibbeln also spoke with Kenneth Chang of the New York Times for a story about a study on omega 3 and 6 fatty acids in milk. (12/6/13).

Dr. Ralph Hingson, Division of Epidemiology and Prevention Research, spoke with the following outlets about a JAMA Pediatrics study on extreme binge drinking among high school seniors.  Dr. Hingson and Dr. Aaron White wrote an editorial on this topic in the same issue of the journal:

• Nicole Ostrow, Bloomberg News (9/16/13)
• Melissa Pandika, LA Times (9/16/13)
• Lindsay Tanner, Associated Press (9/16/13)
• Bahar Gholipour, LiveScience (9/16/13)
• Lisa De Bode, Al Jazeera America (9/17/13)

Dr. Hingson also spoke with Yoeri Vugts of RTL Netherlands Television about the effects of raising the drinking age to 21 in U.S., for a story about plans to raise the legal drinking age in the Netherlands. (11/8/13)

Dr. Andrew Holmes, NIAAA Laboratory of Behavioral and Genomic Neuroscience, spoke with Jon Hamilton of National Public Radio about his lab’s investigations of brain changes that occur with chronic drinking. (11/26/13)

Dr. Bob Huebner and Dr. Raye Litten, Division of Treatment and Recovery Research, spoke with Elizabeth Bromstein of Toronto NOW magazine regarding available treatments for alcohol problems and recent research developments. (11/8/13)

Dr. Lorenzo Leggio, chief, section on clinical psychoneuroendocrinology and neuropsychopharmacology, NIAAA Laboratory of Clinical and Translational Studies, spoke with Alison Knopf of Alcoholism & Drug Abuse Weekly and Ben Court of Men’s Health magazine about the link between alcoholism and obesity. (9/18/13)

Dr. Raye Litten, Division of Treatment and Recovery Research, spoke with Julia Bain of ABC News, about naltrexone as a therapy for alcohol abuse, including its mechanism of action, how often it is used in practice, and how it works in conjunction with other treatments. (1/3/14)

Dr. John Matochik, NIAAA Division of Neuroscience and Behavior, spoke with Aleisha Fetters of Men’s Health magazine about the mechanisms through which alcohol leads to impaired judgement. (1/15/14)

Dr. Gary Murray, Division of Metabolism and Health Effects, spoke with:

• Astrid Van Den Broek of Best Health magazine about how to prevent alcohol hangovers. (10/22/13)
• Merritt Watts of Self Magazine about how alcohol’s effect on metabolism can contribute to weight gain. (10/25/13)
• Andrea Petersen of the Wall Street Journal about alcohol’s effects on the aging body. (11/14/13)
• Tom de Castella of the BBC News, regarding the health impact of giving up alcohol for a month. (12/13/13)
• Drake Baer of Fast Company.com about the Mechanisms of an alcohol hangover. (12/16/13)
• Joe Brownstein of LiveScience.com, about alcohol health effects – positive and negative, for article about relative harms and benefits of alcohol and marijuana. (1/13/14)
• Aleisha Fetters of Men’s Health magazine, about alcohol's metabolic pathway. (1/15/14)

Dr. Antonio Noronha, Division of Neuroscience and Behavior, spoke with Elise Oberliesen of the Connecticut Health I-Team, about the Collaborative Studies on Genetics of Alcoholism. (10/24/13)

Dr. Deidra Roach of the Division of Treatment and Recovery Research spoke with Susan Donaldson James, ABCNews.com about alcohol problems among women. (10/21/13)

Dr. Roach also discussed alcohol problems among women with:

• Alena Hall, NYU journalism graduate student (11/8/13)
• Kim Krisberg,Fredericksburg FreeLance Star (12/4/13)

Dr. Ken Warren and Mr. Keith Lamirande gave interviews about the NIH Combined Federal Campaign to:

• Josh Hicks, Washington Post (11/5/13)
• Agnes Blum, The Bethesda Gazette (11/4/13)

Dr. Aaron White, Division of Epidemiology and Prevention Research, was interviewed about risky drinking, alcohol poisoning, and blackouts by:

• Shereen Jegtvig, Reuters Health (11/6/13)
• Taylor-Rae Collins-Headley, Howard University News Service (11/19/13)
• Dillon Phillips, Univ. of Oklahoma (11/22/13)
• Arwen Nicks, KUOW (NPR affiliate in Seattle) (11/6/13)
• Taylor Ryan, Mercy College Impact News (12/4/13)
• Dave Mason, Santa Barbara News-Press (12/16/13)

SELECT NIAAA STAFF ACTIVITIES

Dr. Andras Orosz co-chaired the session entitled “Translational Applications” in the workshop “Protein Homeostasis & Viral Infection: Mechanisms to Therapy” organized and co-sponsored by the National Institute of Allergy and Infectious Diseases and the University of California, San Francisco that was held at NIH on September 18-19, 2013.

Dr. Ralph Hingson gave the University of Pittsburgh School of Public Health Legacy Laureate Presentation in Pittsburgh, PA, on September 27, 2013. His talk was titled “New Research Since the Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking.”

Dr. Raye Litten and Ms. Megan Ryan served on the NIH Clinical Trials Working Group. Dr. Litten served as the chair for the subcommittee “GCP Training for Clinical Trials Investigators and NIH Staff Managing Clinical Trials.” The Committee met with Dr. Collins to discuss the final report and later the final report was presented to the ICD Steering Committee and then to the IC Directors and Deputy Directors.

Dr. Abbas Parsian co-organized and chaired a symposium entitled, “New Findings on the Genomic Basis of Substance Use Disorders,” at the XXI World Congress on Psychiatric Genetics held on October 17 – 21, 2013 in Boston, MA. The goal of the symposium was to update the meeting attendees on the new genetic and genomic findings related to alcoholism using high through put technologies and new methodologies.  The symposium included the latest GWAS (Genome -wide Association Study) findings, the results of first international GWAS meta-analysis, genotype-phenotype correlation using candidate genes, and microarray analysis using mouse and human brain. The speakers included Joel Gelernter, Arpana Agrawal, John Nurnberger, Dyne Mayfield and Kenneth Kendler.

Drs. Raye Litten, Joanne Fertig, and Bob Huebner served as chairs for the planning committee for ASAM State of the Art Course in Addiction Medicine. The course was held on October 24-26, 2013 in Arlington, VA. Drs. Fertig and Litten served as co-chairs for the session, “Alcohol Pharmacotherapy: Translation and Barriers to Use.”  In that session, Dr. Fertig presented “A Double-Blind, Placebo-Controlled Trial Assessing the Efficacy of Varenicline Tartrate for Alcohol Dependence” and Dr. Litten served as the discussant. Dr. Litten also served as moderator and discussant for the following sessions: “NIAAA, NIDA, and SAMHSA Address Emerging Problems” and “Advances in Addiction Treatment; Screening and Drug Testing; and Behavioral Intervention in Addiction Treatment.”

Dr. Gary Murray participated in the Federal Focus at the American Association for the Study of Liver Disease, held in November 2013 in Washington, DC.  Dr. Murray presented, “The Goals and Structure of U01 Translational Research in Alcoholic Hepatitis” and “Funding opportunities to support research on ALD.”  Dr. Murray also presented “Challenges in North America” in the Global Forum on Fatty Liver Disease - Alcoholic and Nutritional held at the same symposium.

Dr. P.J. Brooks presented an invited lecture entitled “Gene therapy for neurologic diseases,” in the Department of Psychology and Neuroscience program at Bucknell University on November 6, 2013.  Dr. Brooks also gave an oral presentation at the NIH Research Festival entitled “Targeting and delivering nucleic acids for the treatment of rare genetic diseases” on November 7, 2013. 

Dr. Andras Orosz served as the moderator of the “Proteostasis” NIH Scientific Interest Group organized and co-chaired the NIH Research Festival Symposium entitled “The Role of Proteostasis (Protein Homeostasis) in Health and Disease,” held at NIH on November 7, 2013.

Dr. Raye Litten presented “Advances in Medications Development in Patients with Alcohol Dependence,” at the University of Kansas on November 7, 2013.

Dr. Changhai Cui, together with Drs. Antonio Noronha, Mark Egli and John Matochik, organized a NIAAA sponsored satellite symposium on "Brain Pathways to Recovery from Alcohol Dependence" to the Society for Neuroscience Annual Meeting, November 8, 2013, San Diego, CA. This symposium highlighted multilevel studies that explore the mechanisms contributing to recovery from alcohol dependence and the mechanisms driving relapse and craving associated with sustained alcohol abstinence. Dr. Cui gave an introduction to the symposium by reviewing the current knowledge on brain pathways to recovery from alcohol dependence and co-chaired sessions with Drs. Noronha, Egli and Matochik.

Dr. Matthew Reilly organized a symposium for the 2013 Society for Neuroscience meeting entitled, “The Role of Transposable Elements in Health and Diseases of the Central Nervous System.”  This symposium occurred on November 11, 2013, in San Diego, CA.  Several prominent neuroscientists, including Dr. Fred Gage, presented their latest findings on somatic retrotransposition in the brain. Somatic retrotransposition may serve as a novel mechanism that generates neuronal diversity and influences a number of psychiatric disorders including alcoholism. 

Dr. Antonio Noronha attended the American College of Neuropsychopharmacology (ACNP) 52^nd Annual Meeting in Hollywood, Florida, December 8-12, 2013, and was the discussant for the symposium entitled, “Behavioral, Endocrine, and Neural Plasticity Changes Reflecting Stress Associated with Mouse and Monkey Models of Heavy Alcohol Drinking.”

Ms. Megan Ryan participated in the Trans-NIH DSM Working Group on Sept 27, October 15, and December 13. This Working Group was assigned an important two-fold charge: 1) address recommendations issued by the HHS Office of the Inspector General (OIG) regarding NIH DSMB policies and procedures; and 2) initiate discussion of broader DSMB issues, including conflict of interest issues.  

Dr. Bill Dunty and Dr. Dale Hereld traveled to Cape Town, South Africa, to conduct site visits of four NIAAA-funded studies related to Fetal Alcohol Spectrum Disorders (FASD).  Drs. Dunty and Hereld gave presentations highlighting both animal and human research on the etiology and potential therapeutic prevention of FASD to the staff of the Prenatal Alcohol in Sudden Infant Death Syndrome and Stillbirth (PASS) Network.

Dr. Antonio Noronha was invited to a meeting entitled, “The Adolescent Brain and Mental Disorders,” at the Banbury Center at Cold Spring Harbor Laboratory in Long Island, NY. The focus of the meeting, attended by 25 researchers on adolescent health, was to discuss gaps and opportunities for research in the developing brain during a period when a variety of mental and behavioral disorders can manifest themselves.

Dr. John Matochik served as an expert reviewer for abstracts submitted to the 10^th Anniversary of the Brain Disorders in the Developing World Program symposium, which is sponsored by the NIH Fogarty International Center and will be held in February 2014 on the NIH main campus. 

Dr. Matthew Reilly represents NIAAA on the NIH Common Fund’s Library of Integrated Network-based Cellular Signatures (LINCS) program and is a science officer for LINCS.  Dr. Reilly attended the annual LINCS retreat in Boston, MA, November 18-19, 2013. Day 1 consisted of hands-on workshops which demonstrated the web-tools available to access and analysis LINCS data. Day 2 consisted of presentations by LINCS funded investigators as well as scientists that are using LINCS data to inform their own research. Finally, a presentation on data visualization was given by two employees at Google, who lead their data visualization program.   

Dr. Mike Hilton organized the NIAAA workshop titled, “Barriers to Implementing College Prevention,” which was held on December 6, 2013. The purpose of this workshop was to gather information from college administrators who have attempted to implement model prevention strategies with a special focus on learning more about the barriers that impeded implementation and determining whether additional research can reduce those barriers.

Dr. Robert Freeman was the moderator and chair of the “Intervention in the Clinical Setting” panel at the Trans-HHS Intimate Partner Violence Screening and Counseling: Research Symposium, held at the Neuroscience Center Building (NSC) on December 9, 2013. The purpose of the symposium was to identify gaps in research on screening and counseling for intimate partner violence, which often is related to alcohol use and abuse, and to shape priorities for a public health research agenda moving forward.

Dr. Robert Freeman was the moderator of the “Substance Use” panel at the 2013 mHealth Summit in Washington, DC, on December 11, 2013. This session addressed assessment and intervention findings from studies that use mobile applications for investigating nicotine dependence, alcohol dependence, and illicit drug use. The session included presentation of ecological momentary assessments of real-time tracking of alcohol and drug use.

NEW AND UPCOMING PUBLICATIONS/MULTI-MEDIA PRODUCTS

The November-December issue of the NIH Catalyst published a feature article entitled, “One Name, Many Fields: “Proteostasis” Research at NIH,” about the ongoing proteostasis research at NIH highlighting the contribution of Dr. Andras Orosz, Division of Metabolism and Health Effects, as the organizer of this important new initiative.

Drs. Ralph Hingson and Aaron White’s article titled “New Research Findings Since the 2007 Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking” was published in the Journal of Studies on Alcohol and Drugs in mid-January 2014. This report reviews underage drinking and related traffic fatality trends and new research on social determinants, consequences, and prevention interventions published since the 2007 Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking.

Dr. Ralph Hingson co-authored a paper with Drs. Kaigang Li and Bruce Simons-Morton titled, “Impaired Driving Prevalence Among U.S. High School Students and Risky Driving Behavior,” which was published by the American Journal of Public Health in November 2013. 

Dr. Marcia Scott co-authored an article entitled, “PhenX: A consensus process to establish common measures for collaborative research,” published in the RTI Press in October 2013. This article discusses the development and implementation of the PhenX Toolkit, an NHGRI-supported tool to encourage scientists to collaborate on use of common measures of biological and environmental exposures and disease phenotypes in clinical, epidemiological and GWAS studies.  NIAAA-supported scientists and staff participated in a Substance Abuse and Addiction Scientific Panel that identified collections of 44 SAA measures that were added to the toolkit to facilitate data sharing and harmonization across multiple studies and datasets.

Brooks PJ, Zakhari S. Acetaldehyde and the genome: Beyond nuclear DNA adducts and carcinogenesis. Environ Mol Mutagen. 2013 Nov 27. [Epub ahead of print]

Reilly MT, Faulkner GJ, Dubnau J, Ponomarev I, Gage FH. The role of transposable elements in health and diseases of the central nervous system.  Journal of Neuroscience. 2013 Nov 6;33(45):17577-86.

New Multi-Media Products

The data set from NIAAA’s Clinical Investigation Group’s (NCIG) multi-site clinical trial of levetiracetam is now available to alcohol researchers. Application and data access agreement are on the NIAAA’s website. This data set now joins the data sets of multi-site clinical trials of quetiapine and COMBINE.

WHAT’S AHEAD?

2014 Alcohol and the Nervous System Gordon Research Conference

A new Gordon Research Conference on Alcohol & the Nervous System has been established with the first meeting on February 16-21, 2014 at the Hotel Galvez, Galveston, TX. The Conference Chairs, David Lovinger and Changhai Cui, and Vice Chair, Dorit Ron, have developed a cutting edge program which will focus on research addressing various aspects of the neurobiological actions of alcohol that contribute to excessive drinking and alcohol addiction. Dr. George Koob, will give the opening keynote lecture to discuss the newest developments in alcohol and addiction research. This highly interactive conference will draw scientists from around the world to present the newest and most exciting developments in alcohol and the relevant research fields http://www.grc.org/programs.aspx?year=2014&program=alcohol.

2014 NIAAA Mark Keller Honorary Lecture Series

The annual NIAAA Mark Keller Lecture will be given by Edith V. Sullivan, Ph.D., of the Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, on March 25, 2014 at 1:30 p.m. The lecture is titled, “Functional Compromise and Compensation in Alcoholism: Neuropsychology Meets Neuroimaging.” The event will be held at Lipsett Amphitheater, NIH Clinical Center (Bldg. 10), in Bethesda, MD.

 
NIAAA RESEARCH HIGHLIGHTS

INTRAMURAL RESEARCH

50 YEARS OF HURDLES AND HOPE IN ANXIOLYTIC DRUG DISCOVERY

Significance: Researchers highlight various key issues that may have hampered progress in the development of new medications for anxiety disorders and offer recommendations for how anxiolytic drug discovery can be more effective in the future.

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)-benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. (Griebel G, Holmes A. Nat Rev Drug Discov. 2013 Sep;12(9):667-87.)

THE TOUCHSCREEN OPERANT PLATFORM FOR TESTING LEARNING AND MEMORY IN RATS AND MICE

Significance: This protocol describes an automated touchscreen platform with which a remarkable diversity of cognitive functions may be tested in rodents.

An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive rather than aversive reinforcement), has high translational potential and lends itself to a high degree of standardization and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer's disease, schizophrenia, Huntington's disease, frontotemporal dementia), as well as the characterization of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: visual discrimination, object-location paired-associates learning, visuomotor conditional learning and autoshaping. It is accompanied by two further protocols (also published in this issue) that use the touchscreen platform to assess executive function, working memory and pattern separation. (Horner AE, Heath CJ, Hvoslef-Eide M, Kent BA, Kim CH, Nilsson SR, Alsiö J, Oomen CA, Holmes A, Saksida LM, Bussey TJ. Nat Protoc. 2013 Oct;8(10):1961-84.)

MONOUNSATURATED FATTY ACIDS GENERATED VIA STEAROYL COA DESATURASE-1 ARE ENDOGENOUS INHIBITORS OF FATTY ACID AMIDE HYDROLASE

Significance: Researchers investigated the interrelationship between the endocannabinoid AEA and SCD1 activity, two key players in the development of HFD-induced hepatic steatosis and insulin resistance, and identified hepatic MUFAs generated via SCD1 activity as endogenous inhibitors of the AEA degrading enzyme FAAH in the liver, responsible for the elevated hepatic levels of AEA in DIO mice and the resulting CB1R-mediated insulin resistance.

High-fat diet (HFD)-induced obesity and insulin resistance are associated with increased activity of the endocannabinoid/CB1 receptor (CB1R) system that promotes the hepatic expression of lipogenic genes, including stearoyl-CoA desaturase-1 (SCD1). Mice deficient in CB1R or SCD1 remain lean and insulin-sensitive on an HFD, suggesting a functional link between the two systems. The HFD-induced increase in the hepatic levels of the endocannabinoid anandamide [i.e., arachidonoylethanolamide (AEA)] has been attributed to reduced activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH). Here we show that HFD-induced increased hepatic AEA levels and decreased FAAH activity are absent in SCD1(-/-) mice, and the monounsaturated fatty acid (MUFA) products of SCD1, palmitoleic and oleic acid, inhibit FAAH activity in vitro at low micromolar concentrations. HFD markedly increases hepatic SCD1 activity in WT mice as well as in CB1R(-/-) mice with transgenic reexpression of CB1R in hepatocytes, but not in global CB1R(-/-) mice. Treatment of HFD-fed mice with the SCD1 inhibitor A939572 prevents the diet-induced reduction of hepatic FAAH activity, normalizes hepatic AEA levels, and improves insulin sensitivity. SCD1(-/-) mice on an HFD remain insulin-sensitive, but develop glucose intolerance and insulin resistance in response to chronic treatment with the FAAH inhibitor URB597. An HFD rich in MUFA or feeding mice pure oleic acid fail to inhibit hepatic FAAH activity. We conclude that MUFAs generated via SCD1 activity, but not diet-derived MUFAs, function as endogenous FAAH inhibitors mediating the HFD-induced increase in hepatic AEA, which then activates hepatic CB1R to induce insulin resistance. (Liu J, Cinar R, Xiong K, Godlewski G, Jourdan T, Lin Y, Ntambi JM, Kunos G. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):18832-7.)

THE TOUCHSCREEN OPERANT PLATFORM FOR ASSESSING EXECUTIVE FUNCTION IN RATS AND MICE

Significance: This protocol details a subset of assays developed within the touchscreen platform to measure various aspects of executive function in rodents.

Three main procedures are included: extinction, measuring the rate and extent of curtailing a response that was previously, but is no longer, associated with reward; reversal learning, measuring the rate and extent of switching a response toward a visual stimulus that was previously not, but has become, associated with reward (and away from a visual stimulus that was previously, but is no longer, rewarded); and the 5-choice serial reaction time (5-CSRT) task, gauging the ability to selectively detect and appropriately respond to briefly presented, spatially unpredictable visual stimuli. These protocols were designed to assess both complementary and overlapping constructs including selective and divided visual attention, inhibitory control, flexibility, impulsivity and compulsivity. The procedures comprise part of a wider touchscreen test battery assessing cognition in rodents with high potential for translation to human studies. (Mar AC, Horner AE, Nilsson SR, Alsiö J, Kent BA, Kim CH, Holmes A, Saksida LM, Bussey TJ. Nat Protoc. 2013 Oct;8(10):1985-2005.)

LOSS OF METABOTROPIC GLUTAMATE RECEPTOR 2 ESCALATES ALCOHOL CONSUMPTION

Significance: The study provides evidence that metabotropic glutamate receptor 2 (mGluR2) plays a key role in alcohol preference and may serve as a potential therapeutic target.

Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 (-/-) mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target. (Zhou Z, Karlsson C, Liang T, Xiong W, Kimura M, Tapocik JD, Yuan Q, Barbier E, Feng A, Flanigan M, Augier E, Enoch MA, Hodgkinson CA, Shen PH, Lovinger DM, Edenberg HJ, Heilig M, Goldman D. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16963-8.)

EXTRAMURAL RESEARCH

IBUDILAST REDUCES ALCOHOL DRINKING IN MULTIPLE ANIMAL MODELS OF ALCOHOL DEPENDENCE

Significance: These findings support the viability of the medication ibudilast as a possible treatment for alcohol dependence. Ibudilast, an anti-inflammatory medication that acts as a non-selective phosphodiesterase inhibitor, reduces alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure.

Neuroinflammatory signaling pathways in the central nervous system are of current interest as potential pharmacotherapy targets for alcohol dependence. In this study, we examined the ability of ibudilast, a non-selective phosphodiesterase inhibitor, to reduce alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure. When administered twice daily, ibudilast reduced alcohol drinking in rats by approximately 50% and reduced drinking by alcohol-dependent mice at doses which had no effect in non-dependent mice. These findings support the viability of ibudilast as a possible treatment for alcohol dependence. (Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, Becker HC. Addict Biol. 2013 Nov 11. [Epub ahead of print])

PROTEIN TYROSINE PHOSPHATASE Α IN THE DORSOMEDIAL STRIATUM PROMOTES EXCESSIVE ETHANOL-DRINKING BEHAVIORS

Significance: This study reveals that protein tyrosine phosphatase (PTP), a novel ethanol target, contributes to the neuroadaptation driving excessive ethanol intake. Silencing PTP in the DMS attenuated the activation of the Fyn/GluN2B signaling and reduced ethanol intake in both rats and mice.

We previously found that excessive ethanol drinking activates Fyn in the dorsomedial striatum (DMS) (Wang et al., 2010; Gibb et al., 2011). Ethanol-mediated Fyn activation in the DMS leads to the phosphorylation of the GluN2B subunit of the NMDA receptor, to the enhancement of the channel's activity, and to the development and/or maintenance of ethanol drinking behaviors (Wang et al., 2007, 2010). Protein tyrosine phosphatase α (PTPα) is essential for Fyn kinase activation (Bhandari et al., 1998), and we showed that ethanol-mediated Fyn activation is facilitated by the recruitment of PTPα to synaptic membranes, the compartment where Fyn resides (Gibb et al., 2011). Here we tested the hypothesis that PTPα in the DMS is part of the Fyn/GluN2B pathway and is thus a major contributor to the neuroadaptations underlying excessive ethanol intake behaviors. We found that RNA interference (RNAi)-mediated PTPα knockdown in the DMS reduces excessive ethanol intake and preference in rodents. Importantly, no alterations in water, saccharine/sucrose, or quinine intake were observed. Furthermore, downregulation of PTPα in the DMS of mice significantly reduces ethanol-mediated Fyn activation, GluN2B phosphorylation, and ethanol withdrawal-induced long-term facilitation of NMDAR activity without altering the intrinsic features of DMS neurons. Together, these results position PTPα upstream of Fyn within the DMS and demonstrate the important contribution of the phosphatase to the maladaptive synaptic changes that lead to excessive ethanol intake. (Ben Hamida S, Darcq E, Wang J, Wu S, Phamluong K, Kharazia V, Ron D.  J Neuroscience. 2013, 33(36):14369-78.

MOLECULAR MECHANISM UNDERLYING ETHANOL ACTIVATION OF G-PROTEIN-GATED INWARDLY RECTIFYING POTASSIUM CHANNELS.

Significance: Alcohol modulation of G-protein-gated inwardly rectifying potassium (GIRK) channels is known to regulate neuronal excitability in the brain’s reward circuit and underlie forms of alcohol addiction. This study investigated the chemical nature of the alcohol pocket, and examined the chemical diversity of ligands compatible with the alcohol pocket and the role of other signaling molecules, phosphatidylinositol 4,5-bisphosphate (PIP2) and G-protein Gβγ subunits, which also regulate the activity of GIRK channels. Understanding this mechanism will be critical for developing alcohol-selective therapeutics that can perhaps prevent alcohol abuse and treat addiction.

Alcohol (ethanol) produces a wide range of pharmacological effects on the nervous system through its actions on ion channels. The molecular mechanism underlying ethanol modulation of ion channels is poorly understood. Here we used a unique method of alcohol-tagging to demonstrate that alcohol activation of a G-protein-gated inwardly rectifying potassium (GIRK or Kir3) channel is mediated by a defined alcohol pocket through changes in affinity for the membrane phospholipid signaling molecule phosphatidylinositol 4,5-bisphosphate. Surprisingly, hydrophobicity and size, but not the canonical hydroxyl, were important determinants of alcohol-dependent activation. Altering levels of G protein Gβγ subunits, conversely, did not affect alcohol-dependent activation, suggesting a fundamental distinction between receptor and alcohol gating of GIRK channels. The chemical properties of the alcohol pocket revealed here might extend to other alcohol-sensitive proteins, revealing a unique protein microdomain for targeting alcohol-selective therapeutics in the treatment of alcoholism and addiction. (Bodhinathan K, Slesinger PA. Proc Natl Acad Sci U S A. 2013 Oct. [Epub ahead of print])

ALTERATIONS IN ETHANOL-INDUCED BEHAVIORS AND CONSUMPTION IN KNOCK-IN MICE EXPRESSING ETHANOL-RESISTANT NMDA RECEPTORS

Significance: This study demonstrates that knock-in mice expressing a mutant NMDA subunit with reduced ethanol inhibition showed task-specific alterations in their responses to alcohol. It provides the most direct evidence to support the long-standing hypothesis that NMDARs are key mediators of the behavioral actions of ethanol.

Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p.) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol. (den Hartog CR, Beckley JT, Smothers TC, Lench DH, Holseberg ZL, Fedarovich H, Gilstrap MJ, Homanics GE, Woodward JJ. PLoS One. 2013 Nov 14;8(11): e80541.)

SEXUAL ORIENTATION DIFFERENCES IN THE RELATIONSHIP BETWEEN VICTIMIZATION AND HAZARDOUS DRINKING AMONG WOMEN IN THE NATIONAL ALCOHOL SURVEY

Significance:  Findings from this study underscore the importance of adopting approaches to treatment that are sensitive to the histories of victimization among sexual minority women. Although psychological distress associated with victimization may be similar across sexual orientation groups, health care providers need to consider additional complexities that may be particularly relevant to sexual minorities such as ongoing traumatic stressors in the form of bias-related harassment, discrimination, or rejection.

This study examined relationships between past experiences of victimization (sexual abuse and physical abuse in childhood, sexual abuse and physical abuse in adulthood, and lifetime victimization) and hazardous drinking among sexual minority women compared to exclusively heterosexual women. Data were from 11,169 women responding to sexual identity and sexual behavior questions from three National Alcohol Survey waves: 2000 (n = 3,880), 2005 (n = 3,464), and 2010 (n = 3,825). A hazardous drinking index was constructed from five dichotomous variables (5+ drinking in the past year, drinking two or more drinks daily, drinking to intoxication in the past year, two or more lifetime dependence symptoms, and two or more lifetime drinking-related negative consequences). Exclusively heterosexual women were compared with three groups of sexual minority women: lesbian, bisexual, and women who identified as heterosexual but reported same-sex partners. Each of the sexual minority groups reported significantly higher rates of lifetime victimization (59.1% lesbians, 76% bisexuals, and 64.4% heterosexual women reporting same-sex partners) than exclusively heterosexual women (42.3%). Odds for hazardous drinking among sexual minority women were attenuated when measures of victimization were included in the regression models. Sexual minority groups had significantly higher odds of hazardous drinking, even after controlling for demographic and victimization variables: lesbian (ORadj = 2.0, CI = 1.1-3.9, p < .01; bisexual (ORadj = 1.8, CI = 1.0-3.3, p < .05; heterosexual with same-sex partners (ORadj = 2.7; CI = 1.7-4.3, p < .001). Higher rates of victimization likely contribute to, but do not fully explain, higher rates ofhazardous drinking among sexual minority women. (Drabble L, Trocki KF, Hughes TL, Korcha RA, Lown AE. Psychol Addict Behav. 2013 Sep;27(3):639-48.)

ETHANOL METABOLISM MODIFIES HEPATIC PROTEIN ACYLATION IN MICE

Significance: The importance of ethanol in regulating protein acetylation, has been documented previously.  In this work, the authors employed cutting edge mass spectrometry-based analyses to identify multiple new types of post-translation modifications of the proteins that are regulated by ethanol.  These findings have potential implications for the pathogenesis of alcohol-related liver injury. 

Mitochondrial protein acetylation increases in response to chronic ethanol ingestion in mice, and is thought to reduce mitochondrial function and contribute to the pathogenesis of alcoholic liver disease. The mitochondrial deacetylase SIRT3 regulates the acetylation status of several mitochondrial proteins, including those involved in ethanol metabolism. The newly discovered desuccinylase activity of the mitochondrial sirtuin SIRT5 suggests that protein succinylation could be an important post-translational modification regulating mitochondrial metabolism. To assess the possible role of protein succinylation in ethanol metabolism, we surveyed hepatic sub-cellular protein fractions from mice fed a control or ethanol-supplemented diet for succinyl-lysine, as well as acetyl-, propionyl-, and butyryl-lysine post-translational modifications. We found mitochondrial protein propionylation increases, similar to mitochondrial protein acetylation. In contrast, mitochondrial protein succinylation is reduced. These mitochondrial protein modifications appear to be primarily driven by ethanol metabolism, and not by changes in mitochondrial sirtuin levels. Similar trends in acyl modifications were observed in the nucleus. However, comparatively fewer acyl modifications were observed in the cytoplasmic or the microsomal compartments, and were generally unchanged by ethanol metabolism. Using a mass spectrometry proteomics approach, we identified several candidate acetylated, propionylated, and succinylated proteins, which were enriched using antibodies against each modification. Additionally, we identified several acetyl and propionyl lysine residues on the same sites for a number of proteins and supports the idea of the overlapping nature of lysine-specific acylation. Thus, we show that novel post-translational modifications are present in hepatic mitochondrial, nuclear, cytoplasmic, and microsomal compartments and ethanol ingestion, and its associated metabolism, induce specific changes in these acyl modifications. These data suggest that protein acylation, beyond protein acetylation, contributes to the overall metabolic regulatory network and could play an important role in the pathogenesis of alcoholic liver disease. (Fritz KS, Green MF, Petersen DR, Hirschey MD. PLoS One. 2013;8(9):e75868)

INTEGRATING GWASS AND HUMAN PROTEIN INTERACTION NETWORKS IDENTIFIES A GENE SUBNETWORK UNDERLYING ALCOHOL DEPENDENCE

Significance: Genome-wide association studies (GWAS) for alcohol dependence have been used to identify common genetic variants that influence risk for this disease.   Although there are examples of successful identification of novel genetic variants associated with alcohol dependence using traditional GWAS, many challenges remain.  In the present article, Han et al (2013) use a network-based analysis that integrates data from protein-protein interactions with GWAS data, a method that allows more direct conclusions that are biologically relevant.  A network of 39 genes was identified that contributes to alcohol dependence in two ethic populations (European Americans and African Americans).  This network was specific for alcohol dependence and was highly reproducible across independent samples.  This network-based approach has tremendous potential for discovering genetic variants that are biologically relevant, which greatly improves traditional forms of analyses of GWAS data. 

Despite a significant genetic contribution to alcohol dependence (AD), few AD-risk genes have been identified to date. In the current study, we aimed to integrate genome-wide association studies (GWASs) and human protein interaction networks to investigate whether a subnetwork of genes whose protein products interact with one another might collectively contribute to AD. By using two discovery GWAS data sets of the Study of Addiction: Genetics and Environment (SAGE) and the Collaborative Study on the Genetics of Alcoholism (COGA), we identified a subnetwork of 39 genes that not only was enriched for genes associated with AD, but also collectively associated with AD in both European Americans (p < 0.0001) and African Americans (p = 0.0008). We replicated the association of the gene subnetwork with AD in three independent samples, including two samples of European descent (p = 0.001 and p = 0.006) and one sample of African descent (p = 0.0069). To evaluate whether the significant associations are likely to be false-positive findings and to ascertain their specificity, we examined the same gene subnetwork in three other human complex disorders (bipolar disorder, major depressive disorder, and type 2 diabetes) and found no significant associations. Functional enrichment analysis revealed that the gene subnetwork was enriched for genes involved in cation transport, synaptic transmission, and transmission of nerve impulses, all of which are biologically meaningful processes that may underlie the risk for AD. In conclusion, we identified a gene subnetwork underlying AD that is biologically meaningful and highly reproducible, providing important clues for future research into AD etiology and treatment. (Han S, Bao-Zhu Y, Kranzler HR, Liu X, Zhao H, Farrer LA, Boerwinkle E, Potash JB, Gelernter J. Am J Hum Genet. 2013 Dec 5;93(6):1027-34.)

FUNCTIONAL VALIDATION OF VIRTUAL SCREENING FOR NOVEL AGENTS WITH GENERAL ANESTHETIC ACTION AT LIGAND-GATED ION CHANNELS

Significance: The findings support the feasibility of the use of virtual screening to discover allosteric modulators of pLGICs, and suggest that GLIC is a valid model system to identify novel ligands of GABAA receptors which are primary targets of alcohol in the central nervous system.

GABA_A receptors play a crucial role in the actions of general anesthetics and alcohol. The recently published crystal structure of the general anesthetic propofol bound to a bacterial homolog of GABA_A receptors (GLIC), provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). In this study, molecular docking of 153,000 commercially available compounds was used to identify molecules that interact with the propofol binding site in GLIC. (Heusser SA, Howard RJ, Borghese CM, Cullins MA, Broemstrup T, Lee US, Lindahl E, Carlsson J, Harris RA. Molecular Pharmacology. 2013 Nov; 84:670-678.)

MICRORNA EXPRESSION PROFILE AND FUNCTIONAL ANALYSIS REVEAL THAT MIR-382 IS A CRITICAL NOVEL GENE OF ALCOHOL ADDICTION.

Significance: This study demonstrated that alcohol significantly regulated the expressions of multiple miRNAs in the NAc. Overexpression of miRNA-382 in the NAc significantly reduced the voluntary alcohol intake and preference, possibly via inhibition of Dopamine D1 receptor and DetalFosB mediated signaling.

Alcohol addiction is a major social and health concern. Here, we determined the expression profile of microRNAs (miRNAs) in the nucleus accumbens (NAc) of rats treated with alcohol. The results suggest that multiple miRNAs were aberrantly expressed in rat NAc after alcohol injection. Among them, miR-382 was down-regulated in alcohol-treated rats. In both cultured neuronal cells in vitro and in the NAc in vivo, we identified that the dopamine receptor D1 (Drd1) is a direct target gene of miR-382. Via this target gene, miR-382 strongly modulated the expression of DeltaFosB. Moreover, overexpression of miR-382 significantly attenuated alcohol-induced up-regulation of DRD1 and DeltaFosB, decreased voluntary intake of and preference for alcohol and inhibited the DRD1-induced action potential responses. The results indicated that miRNAs are involved in and may represent novel therapeutic targets for alcoholism. (Li J et al. EMBO Mol Med. 2013, 5(9):1402-14.)

THE PLACEBO EFFECT IN CLINICAL TRIALS FOR ALCOHOL DEPENDENCE: AN ANALYSIS OF 51 NALTREXONE AND ACAMPROSATE STUDIES

Significance: The placebo response varied considerably across naltrexone and acamprosate trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects.

The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (rp) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients (rs ) were used to examine the strength of associations between study characteristics and placebo response. For the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (rp  = -0.55, p < 0.01 and rp  = -0.20, p = 0.35, respectively) as well as in the acamprosate trials (rp  = -0.45, p = 0.09 and rp  = -0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (rs  = -0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (rs  = 0.57, p = 0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size. (Litten RZ, Pan I-J, Falk D, Ryan M, Fertig J, Chen CM, and Yi H. Alcohol Clin  Exp Res. 2013 Dec;37(12):2128-2137.)

GABAPENTIN TREATMENT FOR ALCOHOL DEPENDENCE: A RANDOMIZED CLINICAL TRIAL

Significance: Gabapentin was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile.

IMPORTANCE Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics. OBJECTIVE To determine ifgabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner. DESIGN, PARTICIPANTS AND SETTING A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital. INTERVENTIONS Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling. MAIN OUTCOMES AND MEASURES Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study. RESULTS Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P &lt; .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups. CONCLUSIONS AND RELEVANCE Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence. (Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. JAMA Intern Med. 2014 Jan 1;174(1):70-7.)

A NEW SCALE OF THE U.S. ALCOHOL POLICY ENVIRONMENT AND ITS RELATIONSHIP TO BINGE DRINKING

Significance: This innovative study reports the first effort to develop and validate a composite measure of state-level alcohol policy environments in U.S. states, and finds that the resulting measure is a robust predictor of binge drinking prevalence rates.

BACKGROUND: Of outcomes related to excessive drinking, binge drinking accounts for approximately half of alcohol-attributable deaths, two thirds of years of potential life lost, and three fourths of economic costs. The extent to which the alcohol policy environment accounts for differences in binge drinking in U.S. states is unknown. PURPOSE: The goal of the study was to describe the development of an Alcohol Policy Scale (APS) designed to measure the aggregate state-levelalcohol policy environment in the U.S. and assess the relationship of APS scores to state-level adult binge drinking prevalence in U.S. states. METHODS: Policy efficacy and implementation ratings were developed with assistance from a panel of policy experts. Data on 29 policies in 50 states and Washington DC from 2000-2010 were collected from multiple sources and analyzed between January 2012 and January 2013. Five methods of aggregating policy data to calculate APS scores were explored; all but one was weighted for relative policy efficacy and/or implementation. Adult (aged ≥18 years) binge drinking prevalence data from 2001-2010 was obtained from the Behavioral Risk Factor Surveillance System surveys. APS scores from a particular state-year were used to predict binge drinking prevalence during the following year. RESULTS: All methods of calculating APS scores were significantly correlated (r >0.50), and all APS scores were significantly inversely associated with adult binge drinking prevalence. Introducing efficacy and implementation ratings optimized goodness of fit in statistical models (e.g., unadjusted beta=-3.90, p<0.0001, R(2)=0.31). CONCLUSIONS: The composite measure(s) of the alcohol policy environment have internal and construct validity. Higher APS scores (representing stronger policy environments) were associated with less adult binge drinking and accounted for a substantial proportion of the state-level variation in binge drinking among U.S. states. (Naimi TS, Blanchette J, Nelson TF, Nguyen T, Oussayef N, Heeren TC, Gruenewald P, Mosher J, Xuan Z. Am J Prev Med. 2014 Jan;46(1):10-6.)

CRITICAL ROLE OF FOXO3A IN ALCOHOL-INDUCED AUTOPHAGY AND HEPATOTOXICITY

Significance: This study suggests one possible explanation for the observation that in alcoholic liver disease progression to a more severe clinical phenotype occurs in only a small minority of those who drink heavily, namely the presence of an impaired protective response, exemplified here by the absence of FOXO3.

Autophagy is a lysosomal degradation process that degrades long-lived cellular proteins and damaged organelles as a critical cell survival mechanism in response to stress. We recently reported that acute ethanol induces autophagy, which then reduces ethanol-induced liver injury. However, the mechanisms by which ethanol induces autophagy are not known. In the present study, ethanol treatment significantly increased both mRNA and protein levels of various essential autophagy-related genes in primary cultured mouse hepatocytes and in mouse liver. Both nuclear translocation of FoxO3a and expression of FoxO3a target genes were increased in ethanol-treated primary hepatocytes and mouse liver. Overexpression of a dominant negative form of FoxO3a inhibited ethanol-induced autophagy-related gene expression and enhanced ethanol-induced cell death in primary hepatocytes, which suggests that FoxO3a is a key factor in regulating ethanol-induced autophagy and cell survival. Resveratrol, a well-known SIRT1 agonist, further enhanced ethanol-induced expression of autophagy-related genes, likely via increased deacetylation of FoxO3a. Moreover, acute ethanol-treated Foxo3a(-/-) mice exhibited decreased autophagy-related gene expression, but enhanced steatosis and liver injury, compared with wild-type mice. FoxO3a thus plays a critical role in ethanol-induced autophagy in mouse liver. Modulating the FoxO3a autophagy pathway may offer novel therapeutic approaches for treating alcoholic liver pathogenesis.  (Ni HM, Du K, You M, Ding WX. Am J Pathol. 2013;183(6):1815-25.)

STING-IRF3 PATHWAY LINKS ENDOPLASMIC RETICULUM STRESS WITH HEPATOCYTE APOPTOSIS IN EARLY ALCOHOLIC LIVER DISEASE

Significance: This paper provides previously undescribed evidence that STING, an endoplasmic reticulum (ER)-resident protein involved in DNA sensing, couples ER stress with apoptotic signaling in alcoholic liver disease. The proapoptotic role of STING is mediated by the interferon regulatory factor 3 (IRF3), and is independent of inflammation or Type-I interferons. Activation of STING and IRF3, originally reported in the context of antiviral response, determines survival of hepatocytes in early alcoholic liver disease suggesting that innate immunity regulates hepatocyte pathophysiology independent of inflammation.

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis. (Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, Fitzgerald KA, Szabo G.  Proc Natl Acad Sci U S A. 2013,110:16544-9)

ABSENCE OF RECEPTOR INTERACTING PROTEIN KINASE 3 PREVENTS ETHANOL-INDUCED LIVER INJURY

Significance: The histopathology of alcoholic hepatitis, previously characterized to be apoptotic and necrotic is shown here to also involve necroptosis as a major form of cell injury in eliciting the inflammatory response. The observations in this study have revealed a new therapeutic target for treatment of patients with alcoholic hepatitis.

Hepatocyte cell death via apoptosis and necrosis are major hallmarks of ethanol-induced liver injury. However, inhibition of apoptosis is not sufficient to prevent ethanol-induced hepatocyte injury or inflammation. Because receptor-interacting protein kinase (RIP) 3-mediated necroptosis, a nonapoptotic cell death pathway, is implicated in a variety of pathological conditions, we tested the hypothesis that ethanol-induced liver injury is RIP3-dependent and RIP1-independent. Increased expression of RIP3 was detected in livers of mice after chronic ethanol feeding, as well as in liver biopsies from patients with alcoholic liver disease. Chronic ethanol feeding failed to induce RIP3 in the livers of cytochrome P450 2E1 (CYP2E1)-deficient mice, indicating CYP2E1-mediated ethanol metabolism is critical for RIP3 expression in response to ethanol feeding. Mice lacking RIP3 were protected from ethanol-induced steatosis, hepatocyte injury, and expression of proinflammatory cytokines. In contrast, RIP1 expression in mouse liver remained unchanged following ethanol feeding, and inhibition of RIP1 kinase by necrostatin-1 did not attenuate ethanol-induced hepatocyte injury. Ethanol-induced apoptosis, assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive nuclei and accumulation of cytokeratin-18 fragments in the liver, was independent of RIP3. Conclusion: CYP2E1-dependent RIP3 expression induces hepatocyte necroptosis during ethanol feeding. Ethanol-induced hepatocyte injury is RIP3-dependent, but independent of RIP1 kinase activity; intervention of this pathway could be targeted as a potential therapeutic strategy. (Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. Hepatology. 2013 57(5):1773-83.)

THE ASSOCIATIONS OF FINANCIAL STRESS AND PARENTING SUPPORT FACTORS WITH ALCOHOL BEHAVIORS DURING YOUNG ADULTHOOD

Significance: Living with parents in young adulthood is associated with lower levels of alcohol use, heavy drinking, and problematic drinking both concurrently and 5 years later, as well as decreased alcohol use and problematic drinking 5 years later.  As parents give more money, young adults engage in more alcohol use, heavy drinking, and problematic drinking. Further, financial support from parents during young adulthood is associated with higher levels of alcohol use and heavy drinking 5 years later, as well increased alcohol use.

This study examined concurrent and prospective associations of financial stress (financial strain, lack of financial access, public assistance) and parenting support factors (relationship quality, living at home, financial support) with young adults’ alcohol behaviors (alcohol use, heavy drinking, and problematic drinking) over a 5-year period. Analyses of National Longitudinal Study of Adolescent Health (Add Health) data (N = 7,159) showed that, over the study period, alcohol use and heavy drinking declined while problematic drinking increased. In addition, living at home and parental relationship quality were associated with fewer concurrent and prospective alcohol behaviors whereas financial strain and parents’ financial support were associated with more alcohol behaviors. The implications for minimizing alcohol misuse in young adults amid uncertain economic conditions are discussed. (Serido J, Lawry C, Gu L, Konger KJ, Russell ST.  J Fam Econ Iss. 2013 Oct 18. [Epub ahead of print]) 

HEPATITIS C AND ALCOHOL EXACERBATE LIVER INJURY BY SUPPRESSION OF FOXO3

Significance: The working hypothesis to explain the progression from mild (fatty liver) to more severe clinical disease in ALD, including fibrosis, cirrhosis, alcoholic hepatitis and hepatocellular carcinoma, has been that alcohol requires a secondary initiator or trigger for this progression or that alcohol is secondary to some other initiating event.  HCV has been a strong candidate for this role.  Dr. Weinman’s paper provides mechanistic details for this pathway and identifies FOXO3 as potential target for therapeutic intervention in alcoholic liver disease.

Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury. (Tumurbaatar B, Tikhanovich I, Li Z, Ren J, Ralston R, Kuravi S, Campbell R, Chaturvedi G, Huang TT, Zhao J, Hao J, O'Neil M, Weinman SA.  Am J Pathol. 2013;183(6):1803-14.)