A. Legislation, Budget, and Policy
In FY 2011, the NIAAA obligated $458.3 million in appropriated money. NIAAA awarded 707 research project grants (RPGs), including 150 competing awards with a success rate of 19%. FY 2011 support levels for other key extramural funding mechanisms included 21 research centers for $28.0 million; 124 other research grants for $30.7 million, 300 full-time training positions for $11.9 million; and $38.8 million for research and development contracts.
After a series of continuing resolutions, the Consolidated Appropriations Act, 2012 (P.L. 112-74) was signed by the President on December 23rd. NIH received a total of $30.6 billion after the -0.189% across the board reduction and the Secretary’s transfer of $8.7 million. Major features of the spending bill included the elimination of the National Center for Research Resources (NCRR) and the creation of the National Center for Advancing Translational Sciences (NCATS).
The FY 2012 appropriation for NIAAA provides $459.4 million. This represents a $1.5 million or a 0.3% increase over the FY 2011 comparable level of $457.9 million. NIAAA estimates it will support a total of 659 RPGs in FY 2012, including 156 competing awards.
For noncompeting grants, the new FY 2012 NIH funding policy is to eliminate the 2% inflationary increase provided between the FY 2011 award level and the FY 2012 commitment for all programs where such an increase was provided (including RPGs, Centers, Ks and Other Research Grants). For competing grants, the average cost is equal to the FY 2011 level.
The FY 2013 President’s budget request will be released on Monday, February 13, at which time it will become available to the public.
A budget mechanism distribution of NIAAA’s FY 2011 actual obligations is provided below.
FY 2011 ACTUAL
(dollars in thousands)
|Res. Centers in Minority Instit.|
|Cooperative Clinical Research||1||6,578|
|Biomedical Research Support|
|MInority Biomed. Res. Support|
|Subtotal, Other Research||124||30,732|
|Total Research Grants||852||329,544|
|Research & Develop. Contracts||69||38,763|
|Res. Management & Support||117||29,280|
B. Director’s Activities
NIAAA Acting Director Kenneth R. Warren, Ph.D. spoke or otherwise participated at the following recent meetings:
NACOA Board meeting September 9, 201
World Congress of Psychiatric Genetics September 10, 2011
First Joint NIAAA & NIDA Advisory Councils meeting September 12, 2011
NIAAA Advisory Council September 13, 2011
NIAAA T32 Directors/Trainee meeting September 23-25, 2011
Mayo Clinic Department of Psychiatry September 27, 2011
Alcohol Policy in Poland and around Europe October 11-12, 2011
World Health Organization Training Meeting on FASD October 13-15, 2011
Republican Research and Practical Center of Mental Health
Minsk, Belarus October 15, 2011
6th International Symposium on ALPD and Cirrhosis October 20-21, 2011
ARND Consensus Conference October 31 – November 2, 2011
AMERSA Annual National Conference November 4, 2011
IOM Neuroscience Forum Meeting November 29, 2011
American College on Neuropsychopharmacology
Annual Meeting December 4-8, 2011
Second International Conference on Fetal December 13-16, 2011
Alcohol Spectrum Disorders - Strasbourg, France
NIAAA Council January 19-20, 2012
Banff XLIV: Fetal Alcohol Spectrum March 18-21, 2012
IOM Neuroscience and Nervous System March 18-21, 2012
C. NIAAA Staff and Organization
Dr. Pal Pacher, Acting Chief of the Section on Oxidative Stress Tissue Injury in the NIAAA Laboratory of Physiologic Studies, was elected to the Steering Committee of the Cancer Redox Biology Faculty, National Cancer Institute/NIH.
Dr. Pacher was also elected to the Program Committee for The Society for Free Radical Biology and Medicine’s (SFRBM) 19th Annual Meeting to be held in San Diego, CA, November 14 - 18, 2012.
Dr. Bela Horvath, a Fellow in the Section on Oxidative Stress Tissue Injury in the NIAAA Laboratory of Physiologic Studies, was among the top 21 of 250 winners of a Fellows Award for Research Excellence (FARE) at the 2011 NIH Research Festival. The FARE Program recognizes outstanding scientific research performed by intramural fellows who have less than five years of research experience at NIH. Dr. Horvath was recognized for his presentation of the “Role of Poly (ADP-Ribose) Polymerase 1 (PARP-1) in Liver Injury, Inflammation and Fibrosis.”
Mr. Keith Lamirande was appointed NIAAA Executive Officer on January 24, 2012. Keith had served as the Acting Executive Officer and the Deputy Ethics Counselor since November 2009, in addition to his role as the Deputy Executive Officer, NIAAA.
Ms. Jennifer Czajkowski was appointed NIAAA Deputy Executive Officer on January 29, 2012. Jenny has been serving as the Acting Deputy Executive Officer on detail since July of 2011. Jenny has been at the NIH for over 15 years, most recently as the Chief of the Planning, Evaluation, and Communications Office and the Communications Director for the Center for Information Technology (CIT). She coordinated all communication policy and planning for the Center and the NIH CIO, managed all internal and external communications, maintained its web and intranet presences, and oversaw its service evaluation process. She also represented CIT on NIH-wide groups in the areas of FOIA, Privacy, Competencies, A76, and Section 508. Before becoming the Communication Director, Jenny spent 5 years as the Deputy Director for the Division of Customer Support (DCS) in CIT, responsible for 128 employees and contractors running day to day operations and administrative functions for DCS, including the NIH IT Help Desk, the CIT Training program, the Relationship Manager program, and other customer support functions. Her duties included budget execution, preparing HR actions, workforce planning and resource allocation, addressing EEO and employee relations issues, and working with subordinate managers on the same. She has been involved for 7 years with the NIH Administrative Training Committee’s intern programs, and is involved in the HHS Mentoring Program. She received a Bachelor of Arts in Business Information Systems from Messiah College in Grantham, Pennsylvania and a Master of Science in Information Technology and Telecommunications from Johns Hopkins University.
Ms. Monique Hill was appointed Committee Management Specialist in the NIAAA Office of Extramural Activities in January, 2012.
Extramural Staff Activities
Dr. RV Srinivas, Chief of the Extramural Project Review Branch and Dr. Beata Buzas, Scientific Review Officer, received the NIH Director’s Group award for their efforts on “Evergreening Peer Review Business Process Modeling (BPM).” This Trans-NIH effort developed a comprehensive business model of the NIH peer review process and identified opportunities to improve the supporting information technology infrastructure so that high quality reviews continue to be produced with optimized efficiency. The team included 56 NIH staff, primarily Scientific Review Officers with representation from the extramural support and Committee Management staffs. A minimum of twice-weekly meetings were held February through July 2010, contributing in total well over 4,000 hours of experience and expertise. The team produced two models; one encompasses the purposes of the peer review activities and one that depicts the peer review activities workflow.
Dr. Abe Bautista, Director OEA, Dr. RV Srinivas, EPRB Chief, Ms. Judy Fox, GMB Chief, Dr. Beata Buzas, SRO and Ms Heather Olusoga, GMS performed outreach activities on applications review and grant awards at the T32 Directors’ Meeting in Providence Rhode Island on September 30, 2011.
Dr. Changhai Cui organized and co-chaired a mini-symposium with Dr. Antonio Noronha at the Annual Meeting of Society for Neuroscience (SFN) in Washington DC, November 12 - 16, 2011. This mini-symposium, entitled “New Insights on Diverse Neural Mechanisms Underlying Alcohol Dependence/Addiction,” highlighted recent advances in understanding neural mechanisms of alcohol dependence from the perspectives of both reward and stress pathways. Dr. Cui also gave an overview on neurocircuits and pathways involved in alcohol dependence as an introduction to the mini-symposium.
Robert B. Huebner, Ph.D. presented an “NIAAA Update on Prevention and Treatment for Alcohol Problems among Active Duty Military Personnel and Veterans,” at a meeting of the National Academy of Science, Institute of Medicine Committee on Prevention, Diagnosis, Treatment and Management of Substance Use Disorders in the U.S. Armed Forces on November 16, 2011 in Washington, D.C.
Dr. Judy Arroyo, NIAAA Minority Health and Health Disparities Coordinator, presented an invited plenary lecture “Building a Culturally-Supportive Framework for the Indigenous Research Community: Engaging Future Generations of Alcohol Researchers” at the 23rd Annual Native Health Research Conference, June 27-30, 2011 in Niagara Falls, NY.
Dr. Judy Arroyo served as a faculty mentor for the American Psychological Association Summer Research Institute in Washington DC, July 20-24, 2011.
NIAAA co-sponsored, with NIDA, the meetings of the National Hispanic Science Network in Coral Gables, FL August 25-27th. NIAAA sponsored three alcohol related research symposia and a technical assistance workshop on application and review procedures for mid-level investigators.
NIAAA co- sponsored, with NICHD, NIDA, NIMH, and NINDS, the second in a lecture series “Addressing Health Disparities through Neuroscience: Views by Two” at NIH on September 19, 2011. Invited speakers included Dr. Bruce S. McEwen and Dr. James S. Jackson.
NIAAA co-sponsored with NIDA a mock review panel and technical assistance workshop for American Indian/Alaska Native new investigators in Bethesda, MD, on September 28 & 29, 2011.
Subsequent to NIAAA joining the PAR-11-346 “Interventions for Health Promotion in Native American Populations” Dr. Judy Arroyo and Lynn Morin of NINDS have participated in two Webinars, on December 8 and 12, 2011, to provide technical assistance for investigators hoping to apply on this FOA. Dr. Arroyo also participated in a workshop entitled “Technical assistance for researchers and Native American Partners” held at the Native American Research and Training Center at the University of Arizona, Tuscon, Az on January 25, 2011.
Dr. Daniel Falk presented “Cumulative Proportion of Responders Analysis (CPRA) for the Assessment of Treatment Outcomes in Alcohol Clinical Trials,” at the 50th Anniversary Meeting of the American College of Neuropsychopharmacology, on December 5, 2011. This work represented the latest product of the Alcohol Clinical Trials Initiative (ACTIVE) Group, a collaboration of representatives from NIAAA, NIDA, FDA, academia, and pharma dedicated to improving the methodology of alcohol pharmacotherapy trials. The presentation provided an overview of a novel application of a statistical technique useful for evaluating treatment outcomes in alcohol clinical trials.
Dr. Raye Litten presented NIAAA Breakthroughs in Alcohol Research, ASAM State of Art in Addiction Medicine, Washington, D.C., October 2011.
Dr. Raye Litten served as Co-Moderator for Genetics and presented: Shaping our Understanding of Addiction and its Treatment, at the ASAM State of Art in Addiction Medicine, Washington, D.C., October, 2011.
Dr. Raye Litten presented Clinical Use of Alcohol Biomarkers, Annual Meeting and Exposition of the American Association of Pharmaceutical Scientists, Washington, D.C., October, 2011.
Dr. Raye Litten presented Treatment Endpoints in Alcohol Clinical Trials, International Society for CNS Clinical Trials and Methodology (ISCTM), Amelia Island Florida, October 2011.
Dr. Ralph Hingson presented “Alcohol-Impaired Driving and Other Injury Prevention: From Global to Local,” at the Johns Hopkins Bloomberg School of Public Health, JHU Washington, D.C. Center, Washington, D.C., January 9. 2012.
Dr. Ralph Hingson presented “NIAAA Research Priorities in Epidemiological and Prevention Research,” at the U.S.-Russia Scientific Forum Meeting, Moscow, Russia, on November 18, 2011.
Dr. Ralph Hingson presented “Alcohol-Impaired Driving and Other Injury Prevention: From Global to Local,” at the U.S.-Russia Scientific Forum Meeting, Moscow, Russia, on November 16, 2011.
Dr. Ralph Hingson presented “Alcohol-Caffeine Combinations and Prevention of Other New Patterns of Alcohol Use and Underage Drinking,” at the American Society of Addiction Medicine’s (ASAM) 2011 Course on the State of the Art in Addiction Medicine, in Washington, DC, October 28, 2011.
Dr. Ralph Hingson presented “Drinking Age,” at the Northwestern University: Evidence-Based Interventions to Reduce Alcohol-Related Harm on College Campuses Conference, in Evanston, IL, on October 26, 2011.
Dr. Ralph Hingson presented “Magnitude of and Recent Trends in College Drinking,” at the Northwestern University: Evidence-Based Interventions to Reduce Alcohol-Related Harm on College Campuses Conference, in Evanston, IL, on October 25, 2011.
Dr. Ralph Hingson presented “Recent Trends and Findings Regarding the Magnitude and Prevention of College Drinking and Drug Use Problems,” to the Office of National Drug Control Policy, in Washington, D.C., on October 20, 2011.
Dr. Ralph Hingson presented “Priorities in Alcohol- and Drug-Related Research,” to the International Society of Addiction Journal Editors (ISAJE), at Hilton Head Island, SC, on September 13, 2011.
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 2011 Meeting of the International Council on Alcohol, Drugs & Traffic Safety (ICADTS), in Potsdam, Germany, on September 8, 2011.
Dr. Ralph Hingson and Dr. Peggy Murray will represent NIAAA in Bangkok, Thailand, at the Global Alcohol Policy (GAP) Conference from Feb. 13-15, 2012, and at the World Health Organization (WHO) Coordinating Council on global alcohol problems, which takes place before and after the GAP Conference, on Feb. 12, 2012, and Feb. 16, 2012.
Dr. Mariela Shirley served as a Mentor at the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Scholars Meeting, sponsored by the NIH Office of Research on Women’s Health, in Rockville, MD, on November 16, 2011.
Dr. Mariela Shirley served on the PhenX Substance Use and Addiction Working Group #2 – Risk Factors (https://www.phenx.org/node-tabid-726)
Dr. Mariela Shirley attended The Fourth Annual Federal Hispanic Career Advancement Summit, at the NIH in Bethesda, MD, September 20-21, 2011.
Dr. Robert Freeman participated at a consultation meeting for amfAR, The Foundation for AIDS Research, in Bethesda, MD on January 11, 2012.
Dr. Andras Orosz of the Division of Metabolism and Health Effects authored a chapter entitled "Alcohol, protein homeostasis and cancer" in the “Alcohol and Cancer” book written by DMHE members that was published in September, 2011.
Dr. Dale Hereld of DMHE served as an expert panel member and delivered a talk titled "Fetal Alcohol Spectrum Disorders: An NIAAA Update" at SAMHSA's FASD Center of Excellence Joint Meeting of the Expert Panel and American Indian/Alaska Native/Native Hawaiian Expert Panel, in Bethesda, MD, on December 8, 2011.
Dr. Lawrence Baizer of DNB and Dr. Kathy Jung of DMHE co-chaired a satellite session, organized by the Biomarkers Working Group, at the annual meeting of the American Association of Pharmaceutical Scientists in Washington, DC, on October 23, 2011. Entitled “Development and Applications of Biomarkers of Alcohol Abuse and Tissue Damage, Cancer and Neurodegeneration,” the session included presentations by Kent Vrana, Albert Fornace, Samir Hanash and Chad Ray.
Dr. Sam Zakhari presented “Epigenetics and the Immune System: Who Cares?” at the Alcohol and Immunology Research Interest Group meeting at Loyola University Medical Center, on November 18, 2011. He also presented “What Can NIH Do for You?” to Biomedical Science Graduate School students at Loyola University, as part of a Career Development Seminar on November 17, 2011.
Dr. Sam Zakhari gave a presentation on “Activities of the Division of Metabolism
and Health Effects” to the Colombian Demand Reduction Delegation, on September 30, 2011.
Dr. Sam Zakhari presented “Alcohol Metabolism: Interactions with Hepatic Sinusoids” at the 16th International Symposium on Cells of the Hepatic Sinusoid, on September 24, 2011.
Dr. Sam Zakhari co-organized the 6th International Symposium on ALPD and Cirrhosis: From Stem Cells to Global Health; A tribute to the late Professor Hiromasa Ishii, Japan, October 21, 2011, and gave a presentation on “Global Outreach via ISALPD/C.”
Dr. Sam Zakhari chaired a session on “Inflammation, stem cells, and cancer in Digestive Diseases” during The 2011 Society of Chinese Bioscientists in America (SCBA) Baltimore-DC Chapter and National Institute of Alcohol Abuse and Alcoholism (NIAAA) intramural division joint Scientific Symposium on Bioscience, November 22, 2011.
Dr. Sam Zakhari represented NIAAA on the Common Fund HRHR Implementation Group meetings to discuss various issues related to funding.
Dr. Gary Murray represented NIAAA by participating in the SBIR One-on-One discussions at the University Startup Conference, at the Washington, D.C. Convention Center, on January 19, 2012.
DMHE staff prepared a document on Alcoholic Hepatitis, and presented their recommendations to the Extramural Advisory Board during the meeting on February 7, 2012.
Dr. Vivian Faden briefed the HHS Adolescent Working Group on the NIAAA Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide.
D. Press Releases
The following press releases describe research supported by NIAAA:
9/20/2011: NIH study finds hospitalizations increase for alcohol and drug overdoses
Hospitalizations for alcohol and drug overdoses – alone or in combination – increased dramatically among 18- to 24-year-olds between 1999 and 2008, according to a study by researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. Led by Aaron M. White, Ph.D. and Ralph W. Hingson, Sc.D., of NIAAA’s division of epidemiology and prevention research, the study examined hospitalization data from the Nationwide Inpatient Sample, a project of the U.S. Agency for Healthcare Research and Quality designed to approximate a 20 percent sample of U.S. community hospitals. The findings appear in the September issue of the Journal of Studies on Alcohol and Drugs. Drs. White, Hingson, and their colleagues report that, over the 10-year study period, hospitalizations among 18-24–year-olds increased by 25 percent for alcohol overdoses; 56 percent for drug overdoses; and 76 percent for combined alcohol and drug overdoses.
10/03/2011: Social media may help identify college drinking problems
College students who post references to getting drunk, blacking out, or other aspects of dangerous drinking on social networking sites are more likely to have clinically significant alcohol problems than students who do not post such references, according to a study supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. Researchers led by first author Megan A. Moreno, M.D., at the University of Wisconsin-Madison and co-author Dimitri A. Christakis, M.D. at the University of Washington, Seattle, examined public Facebook profiles of more than 300 undergraduate students at those universities. The researchers divided the profiles into three categories: those that had no alcohol references; those that had alcohol references but no references to intoxication or problem drinking; and those that included references to "being drunk," "getting wasted," or other problem drinking behaviors. They also invited the profile owners to complete an online version of the Alcohol Use Disorders Identification Test, or AUDIT, a screening tool that clinicians use to measure problem drinking.
10/06/2011: NIH study finds doctors miss many alcohol screening opportunities
Physicians often fail to counsel their young adult patients about excessive alcohol use, according to a study led by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. NIAAA guidelines for low risk drinking call for men to drink no more than four drinks in a day and no more than 14 drinks per week. For women, the guidelines are three or fewer drinks per day and no more than seven drinks per week. Previous studies have shown that screening and brief interventions by health care providers – asking patients about alcohol use and advising them to reduce risky drinking -- can promote significant, lasting reductions in drinking levels and alcohol-related problems…In the current study, Ralph W. Hingson, Sc.D., director of NIAAA’s division of epidemiology and prevention research, and colleagues at Boston University School of Public Health and Boston Medical Center conducted a random survey of more than 4,000 people in the United States between the ages of 18 and 39. The researchers asked survey participants about their drinking habits and whether they had been seen by a doctor during the past year. Those who had seen a doctor were asked additional questions to determine whether the doctor had assessed their alcohol use and advised them about safe drinking practices during the visit. The researchers report that 16 percent of those surveyed were non-drinkers, 24 percent drank at or below daily or weekly limits, 47 percent exceeded daily or weekly limits, and 13 percent exceeded both. The findings are online in the Journal of General Internal Medicine.
10/13/2011: NIH releases clinician's guide for screening underage drinking
Based on just two questions from a newly released guide, health care professionals could spot children and teenagers at risk for alcohol-related problems. Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide is now available from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. Developed in collaboration with the American Academy of Pediatrics, clinical researchers, and health practitioners, the guide introduces a two-question screening tool and an innovative youth alcohol risk estimator to help clinicians overcome time constraints and other common barriers to youth alcohol screening. “We know that alcohol is by far the drug of choice among youth,” says NIAAA acting director Kenneth R. Warren, Ph.D. “Underage drinking is also a marker for other unhealthy behaviors and it often goes undetected. This new tool was designed to allow busy practitioners who manage the health and well-being of children and adolescents to conduct fast, effective alcohol screens and brief interventions.”
11/14/2011: NIAAA researcher wins prestigious neuroscience prize
Xin Jin, Ph.D., a postdoctoral fellow at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, received the Peter and Patricia Gruber International Research Award from the Society for Neuroscience today during the society’s annual meeting in Washington, D.C. The $25,000 prize is awarded annually to two young scientists whose research includes significant international collaboration and shows exceptional potential for advancing the field. Dr. Jin’s honor stems from his collaboration with Rui M. Costa, Ph.D., principal investigator of the Champalimaud Neuroscience Program at the Gulbenkian Institute in Portugal on a study that advanced knowledge of how the brain controls movement. The findings have promising implications for disorders where these signals break down, such as Parkinson’s and Huntington’s disease.
E. Multi-Media Products from NIAAA
NIAAA Spectrum -- Issue 8 of the Institute's online webzine, will be released in February, 2012
Alcohol Research & Health
Vol. 34, No. 2 -- Preventing Alcohol Abuse and Alcoholism - An Update -- was published online on December 7, 2011. The next issue of AR&H, on genetics, will be published in February, 2012.
Issue #82 -- Fetal Alcohol Disorders – was published online in January, 2012.
NIAAA’s Holiday Seasonal Outreach
As part of its seasonal outreach series, NIAAA distributed the fact sheet “New Year, Old Myths, New Fatalities” via PR Newswire in December 2011. The fact sheet was picked up by major Internet news outlets such as Yahoo!, The Boston Globe, and The Sacramento Bee, as well as numerous major television network (FOX, NBC, CBS, ABC) local affiliates nationwide. The releases had a total audience of more than100,000,000. Other groups, such as HealthDay and Join Together, developed and disseminated stories with information pulled from the fact sheet. Additionally, the fact sheet graphic appeared on PR Newswire’s Times Square and Las Vegas Fashion Show Mall billboards. Hard copies of the fact sheet were disseminated to area law enforcement and safe driving initiatives—such as Checkpoint Strikeforce—and state MADD offices.
F. News Media Interactions
Recent News Media Interviews
Dr. Sam Zakhari, director of the NIAAA Division of Metabolism and Health Effects, gave interviews to:
- Shira Litwack, Eat Exercise Live (internet radio talk show), on the health effects of alcohol.
- Gil Kaufman, MTV News website, on alcohol poisoning, in light of the death of singer Amy Winehouse.
- Melinda Beck, Wall Street Journal, on alcohol and cancer.
- Anna Maltby, Self Magazine, on reversing the long-term health problems caused by alcohol.
- Jill Adams, LA Times, on the health effects of moderate drinking / alcohol and breast cancer.
- Nicole Wise, Daily Health News, on holiday drinking.
- Rachel Sturtz, The Daily (iPad newspaper), on the pathology and treatment of hangovers.
- Letitia Stein, St. Petersburg Times, on alcohol risks and benefits.
- Lindsey Tanner, Associated Press, on the causes, prevention, and treatment of hangovers.
- Amy Saunders, Columbus Dispatch, on the causes, prevention, and treatment of hangovers.
- Matthew Hoffman, Bottom Line Health, on alcohol risks and benefits.
- Sam Benshoof, Fargo Forum, on the causes, prevention, and treatment of hangovers.
- Brittany Risher, Women's Health, on the causes, prevention, and treatment of hangovers.
- Andy Coghlan, New Scientist magazine, on new alcohol guidelines drafted by the UK House of Commons.
- John Briley, AARP.org, on health benefits of reducing alcohol consumption among older adults.
Dr. Markus Heilig, NIAAA Clinical Director, was interviewed by:
- Andy Coghlan, New Scientist magazine, about a study in the Journal of Neuroscience by NIAAA grantees regarding anti-alcohol effects of dihydromyricetin.
George Kunos, M.D., Ph.D., NIAAA Scientific Director, was interviewed by:
- Kristina Fiore, MedPage Today, about a study published in the British Journal of Pharmacology that was co-authored by Dr. Kenner Rice of the NIAAA and NIDA intramural programs. The study reported evidence that TLR4 signaling is involved in the acute behavioral actions of alcohol in mice.
Dr. Joseph Hibbeln, Acting Chief, NIAAA Section on Nutritional Neurosciences, gave interviews to:
- Gregg Zoroya, USA Today, about his recent paper on the link between low DHA levels and suicide risk among U.S. military personnel.
- Joanna Cosgrove, Nutraceuticals World, about his recent paper on the link between low DHA levels and suicide risk among U.S. military personnel.
- Caitlin Hagan, CNN Medical Unit, about his recent paper on the link between low DHA levels and suicide risk among U.S. military personnel.
- Monica Eng, Chicago Tribune, on the relationship of omega 3 fatty acid consumption to mental health and human behavior.
- Donald Vaughan, Military Officer Magazine, about his recent paper on the link between low DHA levels and suicide risk among U.S. military personnel.
- Nina Teicholz, Freelance Author, on the relationship of omega 3 fatty acid consumption to mental health and human behavior.
Dr. Robert Huebner, Acting Director, NIAAA Division of Treatment and Recovery Research, was interviewed by:
- Melissa Stoeltje, San Antonio Express-News, on treatment options for alcohol problems.
Dr. John Matochik of the Division of Neuroscience and Behavior, was interviewed by:
- Alison Knopf, Alcoholism & Drug Abuse Weekly, on the use of SPECT brain imaging in the treatment of alcohol and drug abuse.
Dr. Joanne Fertig, program officer, NIAAA Division of Treatment and Recovery Research, was interviewed by:
- Marie McCullough, Philadelphia Inquirer, on Chantix (varenicline) trials for alcohol problems.
Dr. Aaron White, health science administrator, NIAAA Division of Epidemiology and Prevention Research, was interviewed by:
- Caroline Beeler, WHYY FM, Philadelphia, on dangers of high alcohol content in 4-Loko and other high alcohol/energy drink combinations.
- Alison Knopf, Alcoholism & Drug Abuse Weekly, about NIAAA study on increase in hospitalizations for alcohol and drug overdoses.
- Terry Griffin, Open Minds Weekly News Wire (weekly report for behavioral health and social service industry), about NIAAA study on increase in hospitalizations for alcohol and drug overdoses.
- Lauren Cox, MyHealthNewsDaily.com, regarding the long-term cognitive effects of alcohol abuse.
- Leah Zerbe, Rodale.com (publisher of Prevention, Men's Health, and Women's Health magazines), on hangovers.
- William Marquez, BBC online, on the effectiveness of so-called hangover “cures.”
- Deborah Kotz, Boston Globe, on some of the unusual ways that teens purportedly consume alcohol – is it possible to get drunk using these methods and are they safe?
Dr. Ralph Hingson, Director, NIAAA Division of Epidemiology and Prevention Research, was interviewed by:
- Jenna Johnson, Washington Post, regarding alcohol-related mortality among college students.
- Deborah Brauser, Medscape Medical News, on Dr. Hingson’s recent paper regarding how doctors miss many alcohol screening opportunities.
- Gabrielle Hernandez, Tufts Daily, on a discounted "Happy Hour" drinks proposal in MA.
- Genevra Pittman, Reuters Health, on alcohol use in kids.
- Cathy Lewis, HearSay (WHRO-FM, Norfolk, Va NPR affiliate), on state alcohol policies.
Dr. Rosalind Breslow, health scientist administrator, NIAAA Division of Prevention and Epidemiology Research, was interviewed by:
- Tucker McGrath, Men’s Health, regarding alcohol and cancer in connection with Dr. Breslow’s recent Am J Epi paper titled “Prospective Study of Alcohol Consumption Quantity and Frequency and Cancer-Specific Mortality in the US Population.
- Melinda Beck, Wall Street Journal, regarding Dr. Breslow’s recent Am J Epi paper titled “Prospective Study of Alcohol Consumption Quantity and Frequency and Cancer-Specific Mortality in the US Population.
- Laurie Tarkan, ViV magazine (vivmag.com) regarding Dr. Breslow’s recent Am J Epi paper titled “Prospective Study of Alcohol Consumption Quantity and Frequency and Cancer-Specific Mortality in the US Population.”
Dr. Vivian Faden, director of the NIAAA Office of Science Policy and Communications (OSPC) and associate director of Behavioral Research, NIAAA, was interviewed by:
- Celia Vimont of Join Together (a daily news service re substance abuse prevention, treatment and recovery) regarding the new NIAAA alcohol screening guide for underage drinkers.
- Wally Akinso, NIH Radio, regarding the new NIAAA alcohol screening guide for underage drinkers.
Dr. Deidra Roach, of the NIAAA Division of Treatment and Recovery Research, was interviewed about alcohol and women by:
- freelance writer Kelli Walsh
G. NIAAA Program Announcement and Request for Applications Information
RFA-AA-12-010 Resource support for Consortiums for HIV/AIDS and Alcohol-Related Outcomes Research Trials (CHAART) U24
This funding opportunity (FOA) solicits Cooperative Agreement (U24) applications to continue to support the currently NIAAA-funded " Consortiums for HIV/AIDS and Alcohol-Related Research Translation” (CHARRT) or Alcohol and HIV/AIDS Centers (P01, P50, P60) to enhance their capacity to carry out multidisciplinary, transdisciplinary, and/or integrative behavioral and biological research. The CHARRT consortiums and Alcohol and AIDS Centers aim to accelerate specific areas of research related to the goals of improving HIV/AIDS treatment among infected individuals affected by alcohol use, and to prevent the transmission of HIV within U.S. and international populations. The U24 mechanism is used to support and provide resources to existing consortiums and centers.
RFA-AA-12-009 Interventions to Improve HIV/AIDS and Alcohol-Related Outcomes (U01)
This FOA solicits cooperative agreement grant applications (U01) to develop and strategically test coordinated interventions to reduce alcohol use and alcohol-related consequences in HIV-impacted populations. In addition, this research seeks to develop a new framework for sustainable implementation research among HIV+ alcohol users, with the ultimate goal of significantly improving health care systems. This initiative intends to build on existing cohorts of HIV+ patients, including those who have been diagnosed recently and are just entering treatment, and those who are well-established in HIV treatment.
RFA-AA-12-008 Evaluation of NIAAA’s Alcohol Screening Guide for Children and Adolescents (R01)
The purpose of this Funding Opportunity Announcement is to solicit applications to evaluate the new NIAAA alcohol screener for youth as described in "Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide." Although the questions were empirically developed, are based on a vast amount of data from national surveys as well as numerous prospective studies, and have high sensitivity and specificity in the sample studied, it is important that the precision of the screener be evaluated in practice.
Applications are being sought that will evaluate the two question screener in youth ages 9 to 18 both: 1) as a predictor of alcohol risk, alcohol use, and alcohol problems including AUDs; and 2) as an initial screen for other behavioral health problems, for example other drug use, smoking, or conduct disorder.
RFA-AA-12-007 (U01): Translational Research in Alcoholic Hepatitis
NIAAA invites cooperative agreement applications (U01) from single institutions or consortia of institutions to conduct research in the areas of Alcoholic Hepatitis (AH). The major goal of this research initiative is to expedite the translation of emerging findings that could advance the development of new or existing treatments for AH. A close collaboration between basic scientists and clinicians to further improve the understanding of the mechanisms underlying AH, and translate that knowledge into novel therapies is essential for this research activity. This initiative is specifically directed at AH and not at alcoholic fibrosis/cirrhosis and/or complications of portal hypertension.
PA-12-031 (R01), PA-12-030 (R21) and PA-12-029 (R03): Screening and Brief Alcohol Interventions in Underage and Young Adult Populations. The objective of these announcements is to encourage Research Project Grant, Exploratory/ Developmental Grant, and Small Grant Program research projects on screening and brief interventions to prevent and/or reduce alcohol use and alcohol-related harms.
PA-12-025(R01); PA-12-026(R21): Alcohol impairment of immune function, host defense and tissue homeostasis
NIAAA invites applications from researchers with broad ranges of expertise to study the consequences of alcohol consumption on immune function with the ultimate goal of alleviating infection and reversing alcohol-induced organ damage. Susceptibility to infection and organ damage are the two most common causes of alcohol-related morbidity and mortality. These consequences of alcohol abuse are closely associated with profound impairment of the host innate and adaptive immune systems. The mechanisms of these immune alterations and their link with alcohol-related medical problems are, in most cases, poorly understood. The goal of this announcement is to attract applications on basic and translational research: 1) to identify how alcohol alters immune function; 2) to establish functional links between immune alterations and alcohol related infections and organ damage; and 3) to develop means for mitigating immune impairment with the goal of alleviating alcohol-induced pathology.
NIAAA has participated in NIH initiatives on high throughput screening and chemical probe development: PAR-12-058, 059 Solicitation of Assays for High Throughput Screening (HTS) to Discover Chemical Probes (R01, R21); PAR-12-060 Solicitation of Validated Hits for the Discovery of in vivo Chemical Probes (R01). These initiatives aim to stimulate research in 1) discovery and development of novel, small molecules for their potential use in studying disease treatment relevant to the missions of the participating NIH Institutes, and 2) discovery and/or validation of novel, biological targets that will inform studies of disease mechanisms. Emphasis will be placed on assays that provide new insight into important disease targets and processes.
NOT-CA-12-007 Administrative Supplements to NIH-funded Program Projects/Center Grants: Research Relevant to the Family Smoking Prevention and Tobacco Control Act
NIAAA is participating in this Administrative Supplement Opportunity Announcement, which is open to eligible NIH awardees with active P01, P50, and P60 grants. Depending on the funding mechanism and the scope of the eligible "parent" award, the supplemental funding may be requested to augment research projects relevant to smoking and tobacco products and/or their constituents. These administrative supplements will be supported using funds from the Food and Drug Administration (FDA) Center for Tobacco Products (CTP) designated for tobacco regulatory research and mandated by the Family Smoking Prevention and Tobacco Control Act (FSPTCA), Public Law 111-31. Following FSPTCA, the NIH and the FDA have formed an interagency partnership to foster and facilitate research relevant to tobacco regulations. Within the framework of the Tobacco Control Act, the FDA and NIH share interest in supporting research and pilots to aid the development and evaluation of optimal tobacco product regulations. The administrative supplements program and other FDA-NIH initiatives are intended to provide a rapid mechanism for the FDA to promote research and generate findings needed to inform the development of regulations pertaining to the manufacture, distribution, and marketing of tobacco products. Consistent with the FDA CTP mission, this Notice seeks administrative supplements that expand, enhance, or facilitate research relevant to these issues.
H. NIAAA Research Programs
The following items represent examples of the breadth and quality of research conducted and supported by NIAAA.
Researchers Identify Potential Treatment Target for Co-occurring Nicotine and Alcohol Problems
Nicotine addiction and alcohol use disorders are common and often occur together. No single drug is currently available for the simultaneous treatment of both conditions, which share common genetic factors. Although the molecular mechanisms that underlie nicotine and alcohol comorbidity are unknown, previous research has shown that mice lacking one form of a molecule known as protein kinase C (PKC) show decreased alcohol reinforcement and reward as well as increased aversion to alcohol. In the current study, researchers report that mice lacking the same form of PKC also show diminished reinforcing and rewarding effects of nicotine compared to control animals. These findings suggest that inhibiting this form of PKC might be a useful strategy for treating comorbid nicotine and alcohol problems. (Lee AM and Messing RO, Proc Natl Acad Sci U.S.A. 108:16080-5, 2011)
Mifepristone Reduces Stress-Related Drinking in Rats
Chronic alcohol use leads to changes in the release and function of brain chemicals called glucocorticoids. These changes may serve to maintain harmful alcohol consumption and increase vulnerability to relapse during abstinence from drinking. Scientists examined whether a compound that blocks receptors for glucocorticoids could influence alcohol drinking in rats. They found that the compound, called mifepristone, did not affect baseline alcohol consumption. However, mifepristone treatment suppressed stress-induced reinstatement of alcohol-seeking in rats that had been deprived of alcohol. The findings indicate that mifepristone might prevent stress-induced relapse to alcohol use in humans. And, since it is already FDA-approved for other uses, mifepristone may be a candidate for clinical trials in the near future. (Simms JA et al. Neuropsychopharmacology. 2011 Nov 2. [Epub ahead of print])
Acute tolerance on the ascending and descending limbs of the BAC during drinking and driving.
This is the first study to investigate acute tolerance to alcohol during simulated driving and behavioral performance at comparable points on both the ascending and descending limbs of the blood alcohol curve. Measuring acute tolerance on the descending limb is important because it is during this period that decisions to drive a car may be made as the drinking episode may be ending. This study is significant in investigating the effects of acute tolerance on individual behavioral components. The researchers show that there is acute tolerance to motor impairment (i.e., less impairment on the grooved pegboard task), but no acute tolerance for behavioral inhibitory control as measured by the Go/No-Go task. Thus an individual may feel no motor impairments and therefore engage in impulsive risky driving while still under the influence of alcohol. Knowledge of the behavioral components that are affected by alcohol during both the ascending and descending limbs of the blood alcohol curve may inform both prevention and intervention safe driving programs. (Weafer J and Fillmore MT. Psychopharmacolgy, Epub ahead of print September 30, 2011)
Chronic Ethanol Feeding Accelerates Liver Cancer Progression in Mice in a Sex-Dependent Manner
Women are more likely to develop liver disease earlier than men, but cirrhosis is more common in men than women. The underlying basis for these gender differences has not been fully established. Therefore, a recent study examined the effects of ethanol on the promotion of hepatocellular carcinoma (HCC) initiated by the carcinogen diethylnitrosamine (DEN) in male and female mice. Researchers investigated the impact of ethanol on two separate stages of liver pathology -- formation of hepatic foci and, later, formation of HCC. They found marked gender-specific differences in the expression of various transcription factors that either suppress or support tumor growth following treatment with DEN plus ethanol. Most informative was the inverse change in SMAD3, a molecule that modulates expression of TGF. SMAD3 was elevated in males relative to females. In males, the more abundant TGF may lead to enhanced T regulatory response, thereby limiting immune surveillance and possibly enhancing fibrosis, and ultimately contributing to the greater incidence of HCC in male mice. (Brandon-Warner E, et al. Alcohol Clin Exp Res 2011 Oct 21. [Epub ahead of print])
Neuroadaptations in the Putamen are Associated with Long-term, Relapsing Alcohol Drinking in Primates
Alcoholism and alcohol use disorders are characterized by several months to decades of heavy and problematic drinking, interspersed with periods of abstinence and relapse to heavy drinking. Researchers modeled this alcohol-drinking phenotype in macaque monkeys to explore neuronal adaptations in the striatum, a brain region that controls habitual behaviors. They found that prolonged drinking with repeated abstinence narrowed the variability in daily intake, increased the amount of alcohol consumed in bouts, and led to blood ethanol concentrations more than twice the legal intoxication limit. After the final abstinence period of this extensive drinking protocol, they found a selective increase in dendritic spine density and enhanced glutamatergic transmission in the putamen, but not in the caudate nucleus. Intrinsic excitability of medium-sized spiny neurons was also enhanced in the putamen of alcohol-drinking monkeys in comparison with non-drinkers, and GABAeric transmission was selectively suppressed in the putamen of heavy drinkers. These morphological and physiological changes indicate a shift in the balance of inhibitory/excitatory transmission that biases the circuit toward an enduring increase in synaptic activation of putamen output as a consequence of prolonged heavy drinking and relapse. The resultant potential for increased putamen activation may underlie an alcohol-drinking phenotype of regulated drinking and sustained intoxication. (Cuzon Carlson VC, Seabold GK, Helms CM, Garg N, Odagiri M, Rau AR, Daunais J, Alvarez VA, Lovinger DM, Grant KA. Neuropsychopharmacology. 2011 Nov; 36(12): 2513-28.)
Mutation Reveals a Role for Synapse Number in the Regulation of Ethanol Sensitivity
Genetic factors are well-established contributors to the risk for alcohol use disorders (AUDs). Environmental factors also play important roles in AUD risk, and can interact in complex ways with genetic factors. In a recent study conducted in fruit flies, scientists identified a mutant gene, dubbed ‘arouser,’ in flies with increased sensitivity to the sedative effects of ethanol. A reduced sensitivity to the sedating effects of alcohol is a characteristic associated with alcohol use disorders (AUDs). They found that the arouser mutation regulates ethanol sensitivity in developing neurons by activating one major biochemical signaling pathway, and inhibiting another. The increased alcohol sensitivity in the arouser mutants was also associated with an increased number of synaptic terminals. Social isolation of arouser mutant flies reversed the altered alcohol-phenotype and synapse number. This study demonstrates that ‘genes are not our entire destiny’ because an environmental manipulation can significantly alter ethanol sensitivity on a genetically vulnerable background. (Eddison et al., (2011) Neuron 70:979-90)
Study Shows that Alcohol Exposure During Pregnancy Impairs Brain Blood Flow in the Developing Fetus
Alcohol consumption during pregnancy can lead to fetal growth retardation, mental retardation, and neurodevelopmental delay. The fetal brain initiates neurogenesis and vasculogenesis during the second trimester, and depends on maternal-fetal circulation for nutrition and growth signals. In this study, conducted with pregnant mice, researchers used high-resolution ultrasound imaging to assess the effect of single and repeated binge-like maternal alcohol exposures on maternal circulation and fetal umbilical, aortic, internal carotid, and middle cerebral arterial circulation. They found that binge-type maternal alcohol exposure during a period equivalent to the second trimester resulted in rapid and persistent loss of blood flow from the umbilical artery to the fetal brain, potentially compromising nutrition and the maternal/fetal endocrine environment during a critical period for neuron formation and angiogenesis in the maturing brain. A single episode of alcohol exposure significantly and rapidly reduced brain-directed arterial blood flow in the fetus, whereas the maternal system was largely unaffected. Remarkably, the effects of alcohol on fetal blood flow persisted for at least 24 hours. The findings indicate impairment of fetal blood flow by alcohol might play a significant role in the pathogenesis of fetal alcohol effects. (Bake S, et al. Alcohol Clin Exp Res, 2011 Dec 5. [Epub ahead of print])
Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol.
The hippocampus is a key brain region involved in both short- and long-term memory processes and may play critical roles in drug-associated learning and addiction. In a recent study, researchers found extensive hippocampal gene expression changes common to both cocaine-addicted and alcoholic individuals that may reflect neuronal adaptations common to both addictions. However, they also observed functional changes that were related only to long-term cocaine exposure, particularly the inhibition of mitochondrial inner membrane functions related to oxidative phosphorylation and energy metabolism, which has also been observed previously in neurodegenerative diseases. Cocaine- and alcohol-related histone H3K4me3 changes highly overlapped, but greater effects were detected under cocaine exposure. There was no direct correlation, however, between either cocaine- or alcohol-related histone H3k4me3 and gene expression changes at an individual gene level, indicating that transcriptional regulation as well as drug-related gene expression changes are outcomes of a complex gene-regulatory process that includes multifaceted histone modifications. (Zhou Z, Yuan Q, Mash DC, Goldman D. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6626-31. Epub 2011 Apr 4.)
Study Calls Attention to Muscle Pain in Alcohol-Induced Peripheral Neuropathy
Skin or cutaneous pain is commonly recognized in peripheral neuropathies, such as those caused by abusive alcohol consumption, but the presence of muscle pain has previously not received much attention. In the current study, researchers used an animal (rat) model to demonstrate that mechanical hyperalgesia in muscle paralleled that in the skin, but the onset of muscle pain was slower than for cutaneous pain. The experiments used antisense oligodeoxynucleotides to block protein kinase C epsilon (PKCε) which confirmed that both muscle and skin pain in alcohol-related peripheral neuropathy is dependent on the PKCε signaling cascade in pain receptors. This study provides the foundation for development of effective pharmacological treatments, and also serves to increase clinical awareness of the presence of muscle pain in the painful neuropathies, including those induced by alcohol abuse. (Alvarez et al. Ann Neurol 2011; 70:101-109)
Researchers Find Pain Hypersensitivity Associated With Heroin and Alcohol Dependence.
Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. In this study, investigators measured pain sensitivity in rats allowed short access or long access to heroin or cocaine self-administration, or in rats made dependent on alcohol. Heroin self-administering animals given long access became significantly more sensitive to pain whereas animals self-administering cocaine were unaltered. Similar to heroin, alcohol-dependent rats also developed hypersensitivity to pain after eight weeks of alcohol vapor exposure. The CRF1R antagonist MPZP significantly alleviated the hypersensitivity to pain observed in rats dependent on heroin or alcohol. The emergence of pain hypersensitivity with heroin and alcohol dependence may represent a drug-associated negative emotional state that drives dependence on these substances and suggests that recruitment of CRF-regulated nociceptive pathways is associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities. Edwards S et al. Neuropharmacology. 2011 Nov 23. [Epub ahead of print].)
Abnormal Cortical Thickness Alterations in FASD and Their Relationships with Facial Dysmorphology
Accumulating evidence from structural brain imaging studies on individuals with fetal alcohol spectrum disorder (FASD) has supported links between prenatal alcohol exposure and brain morphological deficits. Previous studies have documented volumetric reductions in a number of brain regions including the corpus callosum, cerebellum, basal ganglia, and hippocampus. In this current study, researchers examined the effects of alcohol exposure on cortical thickness and potential relationships with facial dysmorphology. They report cortical thickening of several frontal, temporal, and parietal lobe regions in three independent samples of children recruited from the United States and South Africa. Prominent differences were noted in the inferior frontal gyrus, a region involved in response inhibition, attention, social cognition and executive functioning. Furthermore, an inverse relationship between cortical thickness and palpebral fissure length (a diagnostic criterion for FAS) was reported, suggesting the use of regional increases in cortical thickness as a biomarker for disrupted brain development in individuals with prenatal alcohol exposure (Yang Y, et al., Cereb Cortex. 2011 Jul 28. [Epub ahead of print]).
Alcohol Disrupts Lipid Rafts’ Promotion of Neural Development
Fetal alcohol spectrum disorder is estimated to affect 1% of live births. The similarities between children with fetal alcohol syndrome and those with mutations in the gene encoding L1 cell adhesion molecule (L1) implicates L1 as a target of alcohol developmental neurotoxicity. Alcohol specifically inhibits the neurite outgrowth promoting function of L1 at pharmacologic concentrations. In the current study, researchers demonstrated that alcohol also promotes the accumulation of L1 molecules in cholesterol-rich domains of the plasma membrane known as lipid rafts in rat cerebellar granule neurons. They also showed that the lipid-raft-disrupting agent MBCD impaired L1-dependent neurite extension. The findings suggest that lipid rafts play a role in L1-mediated neurite extension and that alcohol may disrupt this process by altering L1's transit through or activation within lipid rafts. (Tang N, et al. J Neurochem 2011; vol. 119, no. 4:859-67)
Study Identifies Differences in Subjective and Neural Responses to Alcohol Between Heavy and Social Drinkers
Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals’ vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized. In this study, researchers compared functional magnetic resonance brain imaging and subjective responses to alcohol or placebo between HDs and social drinkers (SDs). During the imaging, they presented emotional cues to measure how emotion modulated the effects of alcohol on the brain's reward circuitry. They found that, at equivalent blood alcohol concentrations, HDs reported lower subjective alcohol effects than SDs. Alcohol significantly activated the nucleus accumbens in SDs, but not in HDs. Self-reported ratings of intoxication correlated with striatal activation, suggesting that activation may reflect subjective experience of intoxication. Fearful faces significantly activated the amygdala in the SDs only, and this activation was attenuated by alcohol. This study shows that HDs not only experience reduced subjective effects of alcohol, but also demonstrate a blunted response to alcohol in the brain's reward system. The findings indicate that reduced subjective and neural response to alcohol in HDs may be suggestive of either the development of tolerance to alcohol, or of pre-existing decreased sensitivity to alcohol's effects. (J. M. Gilman, V. A. Ramchandani, T. Crouss, and D. W. Hommer, Neuropsychopharmacology. Jan 2012; 37(2): 467-77.)
Childhood Trauma and FKBP5 Gene Variants May Interact to Increase Aggressive Behavior.
Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation. To determine whether there would be an interaction between genetic variation in FKBP5, a gene associated with depressive and anxiety disorders, and childhood trauma in predicting aggressive behavior, researchers analyzed FKBP5 variants among a population of male prisoners. The researchers found that individuals with a history of childhood trauma were likely to exhibit aggressive and violent behavior as adults, an effect that was also influenced by the presence of certain FKBP5 variants. They conclude that the data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior. (Bevilacqua L, Carli V, Sarchiapone M, George DK, Goldman D, Roy A, Enoch MA. Arch Gen Psychiatry. 2012 Jan;69(1):62-70.)
Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice.
Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, and that inflammation in turn aggregates steatosis. Researchers therefore hypothesized that the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models. They generated IL-10 knockout (IL-10(-/-) ) mice and several other strains of genetically modified mice. Compared with wild-type mice, IL-10(-/-) mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or high-fat diet feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10(-/-) mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10(-/-) mice. The researchers conclude that IL-10 knockout mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or high-fat diet. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver. (Miller AM, Wang H, Bertola A, Park O, Horiguchi N, Hwan Ki S, Yin S, Lafdil F, Gao B. Hepatology 2011; 54:846-856).
Alcoholic liver disease: pathogenesis and new therapeutic targets.
Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to fibrosis and cirrhosis. The latest surveillance report published by NIAAA showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Early work on the pathogenesis of the disease focused on ethanol metabolism-associated oxidative stress and glutathione depletion, abnormal methionine metabolism, malnutrition, and production of endotoxins that activate Kupffer cells. In this paper, researchers review findings from recent studies that have characterized specific intracellular signaling pathways, transcriptional factors, aspects of innate immunity, chemokines, epigenetic features, microRNAs, and stem cells that are associated with ALD. Despite research progress, no targeted therapies for ALD are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. There is an urgent need to develop new pathophysiology-oriented therapies. Recent translational studies of human samples and animal models have identified promising therapeutic targets. (Gao B, Bataller R. Gastroenterology. 2011 Nov;141(5):1572-85)
Study Sheds Light on Molecular Effects of Alcohol on Akt Changes.
Although PI3K/Akt signaling that regulates neuronal survival has been implicated in the harmful effects of alcohol on the central nervous system, the underlying molecular mechanisms have not been fully described. Akt-membrane interaction is a prerequisite step for Akt activation since it induces interdomain conformational changes to an open conformer that allows Akt phosphorylation by upstream kinases. In this study, researchers investigated the effect of alcohol on Akt activation by quantitatively probing Akt conformation using chemical cross-linking, (18)O labeling and mass spectrometry. They found that alcohol at pharmacologically relevant concentrations directly interacts with Akt and alters the local pleckstrin homology domain configuration near the PIP(3)-binding site. We also found that ethanol significantly impairs subsequent membrane-induced interdomain conformational changes needed for Akt activation. The observed alteration of Akt conformation caused by ethanol during the activation sequence provides a new molecular basis for the effects of ethanol on Akt signaling. The in vitro conformation-based approach employed in this study should also be useful in probing the molecular mechanisms for the action of ethanol or drugs on other signaling proteins, particularly for those undergoing dramatic conformational change during activation processes such as members of AGC kinase super family. (Huang BX, Kim HY. ACS Chem Biol. 2011 Dec 7. [Epub ahead of print])
Twin Studies Suggest that a Complex Genetic Architecture Influences Alcohol Consumption and Alcohol Problems.
Twin studies demonstrate that genes influence alcohol consumption and suggest that such studies may be useful in gene identification efforts. The extent to which these phenotypes will be informative in identifying susceptibility genes involved in alcohol dependence depends on the extent to which genetic influences are shared across measures of alcohol consumption and alcohol problems. Previous studies have demonstrated that alcohol consumption reported for the period of heaviest lifetime drinking shows a large degree of genetic overlap with alcohol dependence. However, many studies with genetic material assess current alcohol consumption, and there are many different aspects of consumption -- frequency of use, quantity of use, and frequency of intoxication, for example -- that can be assessed. In the current study, researchers used data from two large, independent, population-based twin samples, to examine the extent to which genetic influences are shared across many different measures of alcohol consumption and alcohol problems. They found that genetic correlations across current consumption measures and alcohol problems were high across both samples. However, both samples suggest a complex genetic architecture with many different genetic factors influencing various aspects of current consumption and alcohol problems. The findings provide important information for designing future research aimed at elucidating complex alcohol-related phenotypes. (Dick DM, Meyers JL, Rose RJ, Kaprio J, Kendler KS. Alcohol Clin Exp Res. 2011 Dec;35(12):2152-61. Epub 2011 Jun 20.)
ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance.
Nitroglycerin, which treats impaired cardiac function through vasodilation as it is converted to nitric oxide, is used worldwide for patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance result from the inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction. Researchers tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent myocardial infarction. In a rat model of myocardial infarction, 16 hours of prior, sustained nitroglycerin treatment resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the myocardial infarction. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after myocardial infarction in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. The findings suggest that activators of ALDH2 such as Alda-1 may help to protect patients with myocardial infarction from nitroglycerin-induced increase in cardiac injury while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin. While controlled clinical trials are needed to translate these findings to human patients, the findings suggest that the long-term use of nitroglycerin may need to be reconsidered in clinical settings. Alternatively, ALDH2 activators, such as Alda-1 may be used to complement nitroglycerin treatment regimen to ward off its negative effects, while preserving its therapeutic benefits. (Sun L, Ferreira JC, Mochly-Rosen D. Sci Transl Med. 2011 Nov 2, vol. 3, no. 107:107ra111)
Overexpression of Nrf2 Protects Cerebral Cortical Neurons from Alcohol-induced Apoptotic Death.
Alcohol can cause apoptotic death of neurons by depleting glutathione with an associated increase in oxidative stress. In this study, researchers examined the role of transcription factor Nrf2, which is activated by oxidative stress and governs the expression of a collection of antioxidant enzymes. Confirming previous findings, ethanol exposure was shown to lead to up-regulation of Nrf2 transcript, protein, activity levels, and target gene expression in both cerebral cortex and primary cortical neurons (PCN). Further studies with PCN revealed that this increase in Nfr2 activity was insufficient to prevent accumulation of reactive oxygen species (ROS) and markers of apoptosis and depletion of GSH resulting from alcohol exposure. Conversely, these adverse effects were amplified by knockdown of Nrf2 levels and largely eliminated by Nrf2 over-expression. These findings suggest that Nrf2 is a critical factor for neuron survival in the face of alcohol exposure and, thus, may serve as an effective target for interventions for preventing or mitigating the consequences of prenatal alcohol exposure. (Narasimhan M, et al. Mol Pharmacol 2011; vol. 80, no. 6:988-99)
The Alcohol Clinical Trials Initiative (ACTIVE): Purpose and goals for assessing important and salient issues for medications development for alcohol use disorders.
Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some ‘standards’ for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future. (Anton R., R. Z. Litten, D.E. Falk, J. M. Palumbo, R. T. Bartus, R. L. Robinson, J. R. Kranzler, T. R. Kosten, R. E. Meyer, C. P. O’Obrien, K. Mann, D. Meulien, and the ACTIVE Group. Neuropsychopharmacology 37:402-411, 2012.)
Researchers Find that Monocyte Chemoattractant Protein-1 Regulates Macrophage Activation, Pro-Inflammatory Responses, and Hepatic Steatosis in Alcoholic Liver Disease in Mice.
Inflammatory cell mediators produced in the liver during chronic alcohol exposure contribute to liver injury. Though pro-inflammatory cytokine production in the alcoholic liver is extensively investigated, the importance of chemokines, such as Monocyte Chemoattractant Protein-1 (MCP- 1), in alcoholic liver injury is still uncertain. MCP-1 or chemokine (C-C motif) ligand 2 (CCL2), an important CC-chemokine, recruits and activates monocytes/macrophages to the site of tissue injury and regulates adhesion molecules and pro-inflammatory cytokines tumor necrosis factor alpha (TNFa), IL-1b, and IL-6. In addition, recent studies have suggested a role for MCP-1 in metabolic diseases, such as diabetes and obesity-related insulin resistance and hepatic steatosis. In recent studies, the lack of MCP-1 has been found to be protective in some cases of liver injury, such as hepatic granuloma formation and obesity-induced fatty liver, while in other instances, such as concanavalin A–induced liver injury and lethal endotoxemia, the absence of MCP-1 worsens disease. In this study, researchers used MCP-1- deficient mice, to demonstrate, for the first time, that MCP-1 in the liver regulates macrophage activation, pro-inflammatory responses, and hepatic steatosis in alcoholic liver disease. These studies provide a link between inflammatory cell activation and pathways of fatty acid metabolism during alcoholic liver injury likely involved in the amplification and progression of disease. Therefore, it appears plausible that pharmacological approaches to block MCP-1 in the alcoholic liver may be beneficial to early alcoholic fatty liver injury and also abrogate inflammatory pathways contributing to propagation in ALD. (Mandrekar P et al. Hepatology 2011 Dec; vol. 54, no. 6:2185-97)