NIAAA Director’s Report on Institute Activities to the 136th Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism
Table of Contents
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, clinical and translational research at NIH.
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 651 RPGs in FY 2014, including 174 competing awards
On March 4, 2014, President Obama submitted to Congress his FY 2015 budget request for all Federal agencies – the FY 2015 President’s Budget. Included in this request is a proposed FY 2015 budget for the National Institutes of Health (NIH) of $30.4 billion. The NIAAA budget request for FY 2015 is $446.0 million which is $0.6 million or a 0.1 % increase over the FY 2014 Enacted level.
to the public.
| FY 2014
| FY 2015
|Research Project Grants||674||253,2017||682||253,769|
|Res. Centers in Minority Instit.||-||-||-||-|
|Cooperative Clinical Research||1||7,500||1||7,500|
|Biomedical Research Support||-||-|
|Minority Biomed. Research Support||1||340||1||340|
|Subtotal, Other Research||136||37,064||136||37,064|
|Total Research Grants||828||316,063||836||316,625|
|Research & Develop. Contracts||65||38,040||65||38,390|
|Res. Management & Support||130
UPDATE ON CRAN (COLLABORATIVE RESEARCH ON ADDITION AT THE NIH)
The most recent RFA, RFA-14-008/009: Using Social Media to Understand and Address Substance Use and Addiction received 116 applications. These will be reviewed in June and July and a funding plan is expected to be presented to CRAN leadership for approval by July 15th.
An important new CRAN initiative is underway. Known as the National Longitudinal Study on Neurodevelopmental Consequences of Substance Use, the project is currently supported by NIAAA, NIDA, NCI, and NICHD; NIMH is participating in planning while considering support. The initiative will involve a large-scale imaging and neuropsychological study (up to 10,000 children) to assess developmental effects of substance exposure including alcohol, marijuana, nicotine, and other drugs. The goal is to begin before exposure (~age 10) and follow subjects through young adulthood (~10 year follow-up). An expert panel meeting was held at NIH on May 27-28 to develop recommendations on the best study design and measures. Chaired by Michael Charness of the Boston VA, Harvard, and Boston Medical, the panel included Dr. Adolf Pfefferbaum, SRI International, a key investigator in NIAAA’s N-CANDA initiative, and other noted experts in neuroimaging of children, developmental pediatrics, and neuropsychological assessment. The next steps for this project include the issuing of a Request for Information (RFI) in the federal register to solicit public comments on study design, and further gathering of input from the scientific community at a satellite symposium of the Society for Neuroscience Meeting in November 2014. A Notice of Funding Opportunity will be issued by the participating IC’s in early FY2015. More information can be obtained by visiting the CRAN website at http://addictionresearch.nih.gov/
As Director of NIAAA, Dr. George Koob presented at several national and international meetings since the last Council meeting. These activities included the First Annual Conference on Translational Research; the Emerging Models for Integrated Healthcare Delivery Clinical Treatment Network Conference; the Gordon Research Conference on Alcohol and the Nervous System; the American Psychopathological Association Meeting; the Society for Neuro-Immune Pharmacology; the American Society of Addiction Medicine, the Asian Pacific Society for Alcohol Research, and the Society for Prevention Research Conference. Dr. Koob also co-hosted the 3rd International meeting on Alcohol and Stress in Volterra, Italy.
In addition, Dr. Koob delivered the Krop Lectureship in Pharmacology at Georgetown University and a seminar in the Biomedical Engineering Department at the State University of New York Stony Brook.
Aurelia Higginbotham joins the Office of the Director as a Travel Specialist. She previously worked at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) as an Extramural Support Assistant in the program area of the Musculoskeletal division. There she assisted a staff of one director, nine program officers and one analyst.
Laurie Rosenblatt joins the Ethics and Management Analysis Branch as a Management Analyst. She previously worked at the NIH Clinical Center, Office of Protocol Services, as a Program Specialist. Her previous work experience is in research and regulation management, as a Patient Coordinator and Clinical Trials Specialist. Her expertise is in the collection and maintenance of protocol related data as well as auditing techniques as they relate to publication and regulation adherence.
Dr. Gene-Jack Wang joins NIAAA as a Senior Medical Staff Clinician with the Laboratory of Neuroimaging. Before coming to NIAAA he was a Professor of Radiology at Stony Brook University in Stony Brook, NY and the Senior Scientist and Chairman of the Medical Department at Brookhaven National Laboratory in Upton, NY. His area of expertise is application of positron emission tomography (PET) and functional magnetic Resonance Imaging (fMRI) to the study of various brain disorders. His area of research is using PET and fMRI to study the neuro-psychiatric mechanisms and manifestations of alcoholism, drug addiction, obesity, and eating disorder in humans.
Monique Hill accepted a position at the National Institute of Neurological Disorders and Stroke (NINDS) as their Committee Management Specialist. In addition to similar duties held at NIAAA, she will be responsible for ensuring reviewers receive compensation, conducting Ethics Reviews for Special Government Employees (Council, PAC, and BSC members).
Dr. Page Chiapella and Dr. Cherry Lowman recently retired from the Division of Treatment and Recovery Research (DTRR), where they served as health scientist administrators for 23 years. Dr. Chiapella was instrumental in developing the DTRR portfolio on recovery, mutual help, and suicide. Dr. Lowman developed the foundation for the health services research portfolio and was considered an expert on the topic of relapse prevention. The Institute thanks them for their dedication to the clinical and health services research effort at NIAAA and wishes them well in their new endeavors.
Captain David T. George, M.D. (Ted) has retired from the PHS on March 31, 2014. He is looking forward to enjoying more time with his family especially with his, soon to be, 3 grandchildren. He will also continue to support NIAAA by his continued involvement with a collaborative NINDS protocol involving Deep Brain Stimulation of individuals with treatment refractory alcohol dependence.
Dr. Lorraine Gunzerath retired from federal service on February 28, 2014. Dr. Gunzerath left the private sector to join NIAAA in 2000 though she had earlier been a part of the NIH as a fellow in the National Cancer Institute’s intramural program. Dr. Gunzerath had served many significant roles within the Institute. Among these, she led the development of NIAAA’s first electronic grants data system (SMART), which served to maintain oversight of the scope and changing dynamics of the Institute’s research programs. Subsequently, following a request to the Institute from the White House for a comprehensive report on the health effects of moderate drinking, Dr. Gunzerath took the lead responsibility for this activity which included an expert state-of-the-science review and published Report. Dr. Gunzerath served as first author on the publication arising from this effort, and the Moderate Drinking Report was used in the development of the 2005 and 2010 Dietary Guidelines for America by a joint advisory group to the Departments of Agriculture and Health and Human Services. Dr. Gunzerath continued to maintain a strong interest in the positive and negative aspects of moderate alcohol use in the years that followed. Dr. Gunzerath also served NIAAA and the NIH playing a key staff role in the multi-year efforts that eventually led to the development of the substance use and addiction functional integration, known as the Collaborative Research on Addiction at NIH (CRAN).
New NIAAA Positions
Dr. Bridget Williams-Simmons has been appointed Chief of the Science Policy Branch (SPB). In 2007, Dr. Williams-Simmons joined NIAAA as a health scientist administrator in SPB where she has worked on a wide range of science policy topics. During that time she served as NIAAA’s American Recovery and Reinvestment Act (ARRA) coordinator as well as lead on a number of other trans-NIH projects. Recently, in addition to her NIAAA responsibilities, Dr. Williams-Simmons was on a part time detail to the NIH Office of Extramural Research where she worked on several high-profile NIH issues. Dr. Williams-Simmons came to NIAAA in 2006 during her internship in the Emerging Leaders Program of the Department of Health and Human Services. As part of that program she gained valuable experience in various roles throughout NIH and HHS, including at the Center for Scientific Review, the National Cancer Institute, the Substance Abuse and Mental Health Services Administration, and the Indian Health Service. Dr. Williams-Simmons received her Ph.D. from Tulane University in Biochemistry and her B.S. in Biochemistry from Xavier University of LA.
Dr. Patricia Powell has been appointed Associate Director for Scientific Initiatives in the Office of the NIAAA Director. Previously she was Chief of the Science Policy Branch, where she served since 2007. Dr. Powell was instrumental in working with the Governor’s Spouses Initiative Leadership to Keep Children Alcohol Free and was a Senior Scientific Editor for the Surgeon General’s 2007 Call to Action to Prevent and Reduce Underage Drinking. Prior to joining NIAAA, she was an American Association for the Advancement of Science (AAAS) fellow at the National Science Foundation focusing on how to provide information about cutting edge science to the public through science museums, television and radio programs, and IMAX films. Dr. Powell has twenty years of research experience in developmental genetics, and cellular and molecular biology. She received her Ph.D. from Washington University in Cellular and Molecular Biology and did post-doctoral studies at the Salk Institute, University of California at San Diego, and Washington University. She received her B.A. in Classics from Franklin and Marshall College.
NIAAA is pleased to welcome a group of new training fellows who have joined the NIAAA intramural program recently or will join in the coming weeks. The NIH Postbaccalaureate IRTA (Intramural Research Training Award) program provides recent college graduates who are planning to apply to graduate or professional (medical/dental/pharmacy) school an opportunity to spend one or two years performing full-time research at the NIH. The postdoctoral IRTA program and Visiting Fellow program gives recent doctoral degree recipients the opportunity to enhance their research skills at NIH. The technical IRTA program is designed to produce a cadre of highly trained research support personnel.
AMODIO, JONATHAN, POST-BACCALAUREATE IRTA (Intramural Research Training Award)
ARCURIO, LINDSAY, POST-DOC IRTA
AUGUSTIN, SHANA, POST-DOC IRTA
BLACKBURN, ASHLEY, TECHNICAL IRTA
BLAU, LAUREN, POST-BACCALAUREATE IRTA
COREY, KRISTIN, POST-BACCALAUREATE IRTA
DESHPANDE, SARITA, SUMMER STUDENT IRTA
DUTTA, NISHA, POST-BACCALAUREATE IRTA
FAROKHNIA, MEDHI, POST-DOCTORAL IRTA FELLOW
HA, SEUNG-KWON, VISITING FELLOW
HE, YONG, SUPPLEMENTAL PREDOC VISITING FELLOW
HELTON, SARAH, POST-BACCALAUREATE IRTA
HOLOVAC, KELLIE, SUMMER STUDENT IRTA
JUCZEWSKI, KONRAD, PRE-DOC VISITING PROG (Graduate Partnerships Program – GPP)
KANUPARTHI, PRASAD, SUMMER IRTA
MENEGAS, SAMANTHA, STUDENT IRTA
MILLER-CREWS, ISAAC, POST-BACCALAUREATE IRTA;
PARK, TAEYEOP, VISITING FELLOW
RAMIREZ, TERESA, POST-DOC IRTA
RAUFFENBART, CAROLINE, POST-BACCALAUREATE IRTA
ROHN, MATTHEW, POST-BACCALAUREATE IRTA
SASHA, BRIETZKE, POST-BACCALAUREATE IRTA
SHOKRI KOJORI, EHSAN, VISITING FELLOW
STEVENS, JOCELYN, POST-BACCALAUREATE IRTA
SUNDBY, KELSEY, POST-BACCALAUREATE IRTA
WIERS, CORINDE, VISITING FELLOW
YEPES, MAELYS, SUMMER IRTA
ZHOU, ZHOU, VISITING FELLOW
HONORS & AWARDS
NIAAA Honorary Lectures
On March 25, 2014, Dr. Edith Sullivan presented the 18th Annual Mark Keller Honorary Lecture. The title of her presentation was “Functional Compromise and Compensation in Alcoholism: Neuropsychology Meets Neuroimaging.” Dr. Sullivan is a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine. She was honored for outstanding research in the use of neuroimaging and neuropsychology to show how alcohol-related brain injuries contribute to specific cognitive and motor problems.
Dr. Bernice Porjesz delivered the 6th Annual Jack Mendelson Honorary Lecture on May 20, 2014. Her lecture was entitled “Neurophysiological Endophenotypes in the Search for Genes for Alcoholism.” Dr. Porjesz is Professor of Psychiatry and Behavioral Sciences and Director of the Henri Begleiter Neurodynamics Laboratory at SUNY Downstate Medical Center in Brooklyn, NY. She is a leading expert in research on alcoholism, neurophysiology and genetics.
NIH Director’s Awards
Dr. David Lovinger will receive an NIH Director’s Award for “discovering novel forms of synaptic plasticity, providing outstanding leadership in the neuroscience of addiction, and demonstrating exemplary skills as a mentor.”
Dr. Kenneth R. Warren has also been selected to receive an NIH Director’s Award for “outstanding and sustained service to the National Institutes of Health and commitment to alcohol and addictions research as the Acting Director of NIAAA.”
The Research Society on Alcoholism has selected NIAAA Deputy Director Dr. Warren to receive the RSA Lifetime Achievement Award. The award recognizes a person with a long, balanced career whose contributions to alcohol research, training, service and advocacy have had a lasting impact on the field. Dr. Warren is a distinguished scientific administrator and an authority on the effects of alcohol use during pregnancy. More than 30 years ago, he initiated NIAAA’s research program on fetal alcohol syndrome (FAS). For his work on the development of the first Surgeon General’s Advisory on Alcohol Use in Pregnancy, Warren received a Superior Service Award from the Public Health Service in 1982. Currently, Warren chairs the interagency coordinating committee on fetal alcohol spectrum disorders.
Dr. Andrew Holmes, Chief of the Laboratory of Behavioral and Genomic Neuroscience, was selected as the 2014 winner of the A. E. Bennett Award of the Society of Biological Psychiatry for basic research.
NEW REQUESTS FOR APPLICATIONS (RFAs) AND NOTICE OF FUNDING OPPORTUNITIES (NOFOs)
NIAAA issued a new NOFO on PAR-14-051, “Mechanisms of Behavior Change in the Treatment of Alcohol use Disorders (R01)” and companions PAR-14-052 (R03) and PAR-14-053 (R21). These NOFOs solicit applications that 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” of treatment and alcohol use treatment outcomes.
NIAAA issued a new NOFO on Alcohol-Induced Effects on Tissue Injury and Repair (PA 14-124 (R21),-123 (R01)). This NOFO solicits applications that will elucidate the molecular and cellular mechanisms of tissue injury and repair associated with alcohol use in humans. Excessive alcohol consumption has the potential to adversely affect multiple organ systems including the liver, brain, heart, pancreas, lung, kidney, endocrine and immune systems, as well as bone and skeletal muscle. In addition, there is accumulating evidence that long term alcohol consumption is associated with reduced host capacity for recovery and repair following trauma. The NOFO also encourages the study of alcohol’s effect on stem cells, embryonic development, and regeneration, studies on molecular and cellular actions of moderate alcohol consumption. A better understanding of these underlying mechanisms may provide new avenues for developing more effective and novel approaches for prognosis, diagnosis, intervention, and treatment of alcohol-induced organ damage. Scientific contact: William Dunty.
NIAAA reissued the following notice of funding opportunities (NOFO):
PA 14-198 (R01) Unconventional Roles of Ethanol Metabolizing Enzymes, Metabolites, and Cofactors in Health and Disease. This NOFO solicits applications that focus on integrated, innovative research on the novel and unconventional contributions of ethanol metabolizing pathways, their metabolites, cofactors, and interactions with synergizing biological pathways in the development of alcohol- induced diseases and end organ injuries. It is anticipated that this NOFO will generate data that may lead to breakthroughs in our understanding of identifying key cellular and molecular components in the initiation, progression and maintenance of the diverse medical disorders caused by excessive, long term alcohol consumption. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient population debilitated by the vast array of alcohol-induced pathologies and enable clinicians to improve disease outcomes and, consequently, public health. Scientific contact: Andras Orosz
PA 14-188 (R21),-189 (R03),-190 Epidemiology and Prevention in Alcohol Research. This Notice of Funding Opportunity (NOFO) encourages the submission of investigator-initiated research grant applications to support research investigating the epidemiology of alcohol use, alcohol-related harms, and alcohol use disorders and the prevention of underage drinking, alcohol-related harms, and alcohol use disorders. Scientific contact: Marcia Scott
PA-14-138 (R21),-139 (R01) on Neuroimmune Mechanisms of Alcohol Related Disorders (R21, R01). Through these Notice of Funding Opportunities (NOFOs), NIAAA aims to stimulate research to study the neuroimmune mechanisms underlying brain functional and behavioral changes associated with alcohol use disorders. Recent studies reveal that neuroimmune factors play an important role in modulating synaptic function, neurodevelopment, and neuroendocrine function. These neuromodulatory properties of immune factors in the CNS provide a new frame work to understand neuroimmune mechanisms underlying brain functional and behavioral changes associated with alcohol dependence. These NOFOs seek studies to address the role of neuroimmune modulation in response to and in the neuroadaptation of the brain to acute and chronic alcohol exposure, and alcohol dependence and withdrawal. Scientific contact: Changhai Cui.
New Medications Development Focus in the DTRR Program Announcements
In March of this year, DTRR issued a Notice that clarified the scope of the notice of funding opportunities entitled Alcohol Use Disorders; Treatment Services; and Recovery Research (R01; R21; R03). These NOFO’s are overseen by our Division of Treatment and Recovery Research. The language in these NOFO’s as described in the announcements, remains unchanged, but the section on “Medications Development for the Treatment of Alcohol Use disorders and Alcohol-Induced Tissue Damage” was changed to reflect a new focus on developing novel medications for alcohol use disorders. Specifically, the new section states: Applications that propose standard efficacy trials of widely-studied and well-characterized medications such as naltrexone, topiramate, acamprosate, varenicline, ondansetron, gabapentin, baclofen, and disufiram in alcohol dependent subjects will not be considered.
NIAAA COMMUNICATIONS & MEDIA COVERAGE
Super Bowl Outreach
For a new seasonal project in late January 2014, NIAAA promoted new Super Bowl static and animated PSAs through social media and the NBC Times Square billboard. Capitalizing on football images easily associated with the “Big Game,” the PSAs stressed the risks of binge drinking and driving after game-watching parties. People.com ran all static ads online at no cost to NIAAA for the week leading up to the Super Bowl, an estimated donated value of more than $13,500, and prompting nearly 1,000 click-throughs to the NIAAA website. People.com circulated the three ads periodically, maximizing the impact of advertising during one of the most expensive advertising periods of the year.
Twitter Chat on Treatment Options
As part of the season In recognition of Alcohol Awareness Month, NIAAA held a Twitter chat on treatment options for alcohol problems on April 29 at 3:00 p.m. ET (#NIAAAchat), which was co-hosted by the National Council on Alcoholism and Drug Dependence (@NCADDnational). Dr. Dan Falk, Division of Treatment and Recovery Research, served as the chat’s scientific expert. Messages from the chat were widely retweeted, with a potential reach of 962,000 accounts and 4.9 million impressions. An archived version of the chat is available here: www.storify.com/NIAAAnews/treatment-options-for-alcohol-problems.
Billboards and Public Transit PSA’s
Beginning in April 2014, NIAAA secured donated ad space for 80 PSAs in the New York City and Washington, DC areas. This included 40 posters in the New York Port Authority bus terminal, 10 posters in the Washington, DC Metro Rail system, and 30 highway billboards. The PSAs sought to raise awareness about the number of children in homes with a parent with an alcohol use disorder. Overall, the ads represented a donated media value of $84,140, with an estimated 16,931,107 gross impressions per month.
New Fact Sheet
OSPC produced the fact sheet, “Alcohol Facts and Statistics,” that includes information on common statistics related to alcohol use. The fact sheet, posted online in April, is available here: www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics
In NIAAA co-sponsored the international meeting Alcoholism and Stress: A Framework for Future Treatment Strategies, held on May 6-9, 2014 in Volterra, Italy. This conference examined the role of stress in alcoholism and development of treatment for alcohol dependence. It was a unique gathering of alcohol researchers from North America, Europe and Asia and facilitated exchange of findings of basic and clinical research as well as comparison of strategies for development of new medications targeted to treatment of alcoholism. The presentations reviewed current concepts of the role of the stress neurocircuits in addiction, the use of animal models to study stress and addiction, and the results of clinical trials of new medications for treatment of alcohol dependence. The drug development round table and session discussions identified the priorities and most productive direction of future research. Drs. George Koob, Ken Warren, Antonio Noronha, Lindsey Grandison and Joanne Fertig served as discussant leaders, panel presenters or session chairs.
The first Gordon Research Conference on Alcohol & the Nervous System was held on February 16-21, 2014, at the Hotel Galvez, Galveston, TX. Drs. David Lovinger, Changhai Cui (chairs), and Dorit Ron (vice chair), organized the conference, which highlighted the most recent advances in research on the neurobiology of alcohol actions, and related neuroscientific studies. The meeting focused on cutting edge research addressing various aspects of the alcohol effects that contribute to excessive drinking and alcohol dependence, including structural and functional plasticity, basal ganglia neurocircuitry, stress and reward systems, neural development, signaling cross talk, genetics and epigenetics, and translational research. Dr. George Koob gave the opening keynote lecture discussing a neurocircuitry view of alcohol and addiction research. Dr. Antonio Noronha chaired the session on Alcohol and the Brain Stress System.
Brain Awareness Week NIH and the National Museum of Health and Medicine at Walter Reed Army Medical Center hosted the Museum’s 15th annual Brain Awareness Week on March 12 and 13. Brain Awareness Week, organized by the Dana Alliance for Brain Initiative, is an annual international partnership of government agencies, scientific organizations, university and volunteer groups dedicated to advancing education about the brain. Various NIH institutes with neuroscience –related programs presented a series of hands-on demonstrations and exhibits. On March 12, NIAAA staff (Drs. Ivana Grakalic, Diana Urbanas, Regunathan Soundar and Anita Bechtholt) presented the “Cool Spot Carnival” that started with a presentation on alcohol and adolescent brain development. Students learned about the effect of alcohol on teen/tween brains and the lifelong consequences of underage drinking. Children also had the opportunity to try their hand scoring in a football-toss game while wearing “fatal vision goggles” to simulate being under the influence of alcohol.
Take Your Child to Work Day NIH celebrated its 20th annual Take Your Child to Work Day on April 24. Through educational and fun activities, children ages 5-15 experienced the world of biomedical research at NIH as well as critical services and resources needed to support it. NIAAA’s “Cool Spot Carnival” hosted by Dr. Ivana Grakalic, Dr. Diana Urbanas, and Jo-Ann Kriebel started with a presentation on alcohol and adolescent brain development. Students also played a football-toss game while wearing “Fatal Vision” goggles to simulate being under the influence of alcohol. Children were also able to tour Dr. Fumihito Ono’s zebra fish lab and the Fishers Lane Animal Lab facilities.
NIAAA also reached out to the next generation of scientists and engineers with its activities at the USA Science and Engineering Festival, April 25-27. Approximately 325,000 attendees visited the USA Science and Engineering festival at the Washington, DC convention center. NIH hosted a pavilion that included activities from many ICs, including NIAAA’s Cool Spot Carnival.
The Institute also presented a booth at the NIH Minority Health Awareness Day Expo.
PRESS RELEASES (FEBRUARY – MAY 2014)
A single alcohol binge can cause bacteria to leak from the gut and increase levels of bacterial toxins in the blood, according to a study funded by the National Institutes of Health (NIH). Increased levels of these bacterial toxins, called endotoxins, were shown to affect the immune system, with the body producing more immune cells involved in fever, inflammation, and tissue destruction.
Muscle weakness from long-term alcoholism may stem from an inability of mitochondria, the powerhouses of cells, to self-repair, according to a study funded by the National Institutes of Health.
April 07, 2014
April is Alcohol Awareness Month, a time to learn about the health and social problems caused by drinking too much. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) encourages the public to dedicate this month to understanding how excessive drinking can affect health, to evaluating their own drinking habits, and to discovering the latest developments in treatments for alcohol use disorders.
RECENT NEWS MEDIA INTERVIEWS
Dr. Koob gave numerous interviews to representatives of national and international news media on a number of timely topics related to NIAAA’s research and its impact on treatment and prevention of alcohol abuse and alcohol use disorders. These include interviews with The New York Times, CNN, Newsweek, U.S. News & World Report, among others.
NIAAA division directors and other NIAAA experts were also frequent sources of information for reporters from a broad range of domestic and international news organizations.
SELECT NIAAA STAFF ACTIVITIES
Dr. Bob Freeman, as the NIAAA Scientific Contact on trans-NIH PA-13-363 (“Research on the Health Determinants and Consequences of Violence and its Prevention, Particularly Firearm Violence,” released in Fall 2013), participated in the Federal Partner Meeting on Injury Prevention. This meeting was organized by the CDC Foundation and held on February 19-20, 2014, in Washington, DC. This meeting comprised representatives from the Departments of Education, Health and Human Services, and Justice, who met to discuss current efforts and future opportunities associated with firearm violence prevention research. Dr. Freeman also gave talks describing the NIAAA violence prevention research program to the American Association of State Colleges and Universities on February 20, 2014, in Washington, DC, and the HHS Interpersonal Violence and Substance Abuse Scientific Interest Group on April 7, 2014, at the Neuroscience Center. In addition, Dr. Freeman organized an HIV/AIDS prevention workshop titled “NIAAA Workshop to Consider Next Steps in HIV Preventive Intervention Development,” which convened on February 27-28, 2014, at NIH. The meeting was co-funded by NIAAA and the NIH Office of Disease.
Dr. Peggy Murray, Director of the Global Alcohol Research Program, chaired an Institute of Medicine Global Violence Prevention Forum workshop on Violence and Mental Illness on February 26 – 27, in Washington, DC. Dr. Murray also gave a talk on the state of the science in screening and brief intervention research at the NIH at the 3rd Asian Pacific Society for Alcohol and Addiction Research (APSAAR), held in Shanghai China, April 24-25th. Dr. Peggy Murray participated in a panel discussion on the use of the concept of “a standard drink” in the development of the Dietary Guidelines at the annual meeting of the Beer Institute in Washington, DC, on May 13th.
Dr. Aaron White gave two presentations on underage drinking the New Jersey Prevention Network conference (March 7, 2014) and two talks at the Midwest Alcohol Policy Summit in Ohio (April 3, 2014).
Dr. George Kunos gave a plenary lecture titled “Targeting the Peripheral Endocannabinoid/CB1 Receptor System (ECS) for the Treatment of Type-2 Diabetes (T2DM) and its complications” at the Keystone Symposium on Lipid Signalling Pathways, in Dublin, Ireland, March 19-24. He was an invited lecturer at the Experimental Biology 2014 Symposium on G-Protein-Coupled Receptors as Therapeutic Targets, in San Diego, on April 28. His talk was titled “Peripheral CB1 Receptors as Emerging Therapeutic Targets.”
Dr. Gary Murray of the Division of Metabolism and Health Effects represented NIAAA at the Keystone Symposium on “Lipid Pathways in Biology and Disease” in Dublin, Ireland from March 19-24, 2014.
Dr. Kathy Jung of the Division of Metabolism and Health Effects represented NIH and the trans-NIH ME/CFS Working Group at the 11th Biennial Conference of the International Association for Chronic Fatigue Syndrome/Myaligic Encephalomyelitis (IACFS/ME) in San Francisco, CA, on March 21-13, 2014.
Dr. Qi-Ying Liu gave a talk entitled “Alcohol Use Disorders and Epilepsy” at the ICARE: Interagency Collaborative to Advance Research in Epilepsy annual meeting, March 24, 2014. ICARE is a forum for sharing information about ongoing and planned epilepsy research activities, highlighting advances and discussing needs and opportunities, and promoting increased collaboration toward common research goals.
Dr. P.J. Brooks of the Division of Metabolism and Health Effects gave a presentation entitled “Cancer-related research interests of the National Institute on Alcohol Abuse and Alcoholism” at the American Association for Cancer Research, April 7, 2014, in San Diego, CA.
Gregory Bloss gave a brief presentation to the National Bureau of Economic Research’s Health Economics section on April 11, 2014, on economic research into the determinants and consequences of alcohol-related behaviors.
Dr. Ralph Hingson presented two talks at the Second Meeting of the Global Network of the World Health Organization (WHO) National Counterparts for Implementation of Global Strategy to Reduce the Harmful Use of Alcohol, held in Geneva, Switzerland, in May 2014. His talks addressed minimum legal drinking age and reducing problematic alcohol use through knowledge dissemination. One hundred thirty countries were in attendance. Dr. Hingson is on the WHO Steering Committee to Implement the Global Strategy. Dr. Hingson also presented on “New Research Since the Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking” at the Pan American Health Organization’s (PAHO) Second Meeting of the Pan American Network on Alcohol and Public Health (PANNAPH), held in Cartagena, Colombia, on April 10, 2014.
Dr. Rosalind Breslow judged graduate student posters in nutrition for the University of Maryland's Department of Nutrition and Food Science Research Day on May 2, 2014. The meeting was held in Beltsville, MD, at the National Agricultural Library.
Dr. Robert Huebner provided an update on NIAAA's clinical research activities to the Council on Addiction Psychiatry, a subcommittee of the American Psychiatric Association, on May 6, 2014, in New York City.
Dr. Deidra Roach provided NIAAA materials for a special exhibit on the NIH campus during National Women's Health Week (NWHWk) on Wednesday, May 14, 2014. The event was coordinated by the NIH Office of Women's Health Research.
Dr. Marcia Scott was a panel presenter in an Office of Behavioral and Social Sciences Research (OBSSR)-sponsored meeting entitled, “Workshop on Challenges in Replication of GxE Research in the Behavioral and Social Sciences,” held on the NIH campus on May 22-23, 2014. A broad focus of this first in a series of GxE meetings is to inform NIH program and review staff, and the broader research community on key challenges to finding GxE in behavioral and social sciences research studies that cut across content and IC mission. More specifically, the goal of this workshop is to highlight the emergence of unique issues and alternate methods of replication for resolution of these issues, including requirements of replication, unique samples, validation using animal models, and data harmonization across studies. Dr. Scott presented the NIAAA violence prevention research program to the American Association of State Colleges and Universities (2/20/14; Washington, DC) and the HHS Interpersonal Violence and Substance Abuse Scientific Interest Group (4/7/14, at the Neuroscience Center).
Dr. David Lovinger recently presented symposia at the University of Massachusetts School of Medicine in March, the Albert Einstein College of Medicine in April, the Vanderbilt University School of Medicine in May. He also presented at the Pierre Morell Research Day Symposium at the University of North Carolina Chapel Hill.
In June, Dr. Bin Gao presented a talk on the “Immunological mechanisms of alcoholic liver disease” at the 2nd International Symposium for Liver Inflammation and Cancer in Hefei, China; the International Immune-Mediated Digestive Diseases Forum in Beijing, China; and Single Topic Conference of Taiwan Association for the Study of the Liver in Taiwan.
Dr. Andrew Holmes has been an invited speaker at several events and institutions include the Haifa Forum for Brain and Behavior, Louisiana State University, the University of Calgary, the University of Western Ontario, and the International College of Neuropsychopharmacology.
Dr. David Goldman spoke at the following symposiums from February to May 2014: Gordon Research Conference in Galveston, TX (Feb.); Bioethics Colloquium in Bethesda, MD (Feb.); and the Society of Biological Psychiatry in New York, NY (May)
Antonio Noronha, Changhai Cui, Adron Harris, and John Crabbe have edited the book on “Neurobiology of Alcohol Dependence” (ISBN: 978-0-12-405941-2, Elsevier, 2014). This book presents a comprehensive overview on our current understanding of the neurobiological mechanisms underlying alcohol dependence at the molecular, cellular, circuitry, and behavioral levels. It highlights the profound impact of alcohol on multiple neurocircuits related to reward, stress, habit formation, and executive function, provides critical reviews on the implication of the neuroplasticity of these systems in alcohol dependence, and bridges genetic factors to behavioral phenotypes, emphasizing the importance of both genes and epigenetics contributing to alcohol dependence and alcohol related traits.
- The Research Society on Alcoholism (RSA) will hold its 37th annual scientific meeting June 21-25 in Bellevue, WA. Many NIAAA employees will attend the conference and its satellite sessions.
- On June 21, the Division of Treatment and Recovery Research will cosponsor the 10th Annual RSA Satellite Session on Research on Mechanisms of Behavior Change entitled, “The New Scientific Agenda: The Continuum of Mechanism Development.”
- On November 14, NIAAA is sponsoring a satellite symposium on “PTSD, the Amygdala and Alcohol Use Disorders” prior to the annual Society for Neuroscience meeting. There is a high incidence of alcohol abuse among those suffering from post-traumatic stress disorder (PTSD). The symposium will address the current state of research on PTSD and alcohol use, the neurobiology of PTSD, genetic and epigenetic risks, biomarkers, evolving animal models of PTSD and alcohol intake, and possible treatments for co-occurring PTSD and alcohol abuse.
NIAAA RESEARCH HIGHLIGHTS
Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum
Significance: This finding advances our understanding of the role of neuroplasticity – the change in a neural pathway associated with learning a behavior – in the molecular actions of intoxicating/addictive substances. Future studies will examine how alcohol interacts with this type of neuroplasticity.
As prescription opioid analgesic abuse rates rise, so does the need to understand the long-term effects of opioid exposure on brain function. Thedorsal striatum is an important site for drug-induced neuronal plasticity. We found that exogenously applied and endogenously released opioidsinduced long-term depression (OP-LTD) of excitatory inputs to the dorsal striatum in mice and rats. Mu and delta OP-LTD, although both being presynaptically expressed, were dissociable in that they summated, differentially occluded endocannabinoid-LTD and inhibited different striatal inputs. Kappa OP-LTD showed a unique subregional expression in striatum. A single in vivo exposure to the opioid analgesic oxycodone disrupted mu OP-LTD and endocannabinoid-LTD, but not delta or kappa OP-LTD. These data reveal previously unknown opioid-mediated forms of long-term striatal plasticity that are differentially affected by opioid analgesic exposure and are likely important mediators of striatum-dependent learning and behavior. (Atwood BK, Kupferschmidt DA, Lovinger DM. Nat Neurosci. 2014 Apr;17(4):540-8).
Deep brain optical measurements of cell type-specific neural activity in behaving mice
Significance: This finding describes an improved experimental method that allows researchers to use fiber optic techniques to measure specific deep brain activities in laboratory animals performing complex behavioral tasks.
Recent advances in genetically encoded fluorescent sensors enable the monitoring of cellular events from genetically defined groups of neurons in vivo. In this protocol, we describe how to use a time-correlated single-photon counting (TCSPC)-based fiber optics system to measure the intensity, emission spectra and lifetime of fluorescent biosensors expressed in deep brain structures in freely moving mice. When combined with Cre-dependent selective expression of genetically encoded Ca(2+) indicators (GECIs), this system can be used to measure the average neural activity from a specific population of cells in mice performing complex behavioral tasks. As an example, we used viral expression of GCaMPs in striatal projection neurons (SPNs) and recorded the fluorescence changes associated with calcium spikes from mice performing a lever-pressing operant task. The whole procedure, consisting of virus injection, behavior training and optical recording, takes 3-4 weeks to complete. With minor adaptations, this protocol can also be applied to recording cellular events from other cell types in deep brain regions, such as dopaminergic neurons in the ventral tegmental area. The simultaneously recorded fluorescence signals and behavior events can be used to explore the relationship between the neural activity of specific brain circuits and behavior. (Cui G, Jun SB, Jin X, Luo G, Pham MD, Lovinger DM, Vogel SS, Costa RM. Nat Protoc. 2014 Jun;9(6):1213-28).
Intravenous Ghrelin Administration Increases Alcohol Craving in Alcohol-Dependent Heavy Drinkers: A Preliminary Investigation
Significance: These findings provide preliminary evidence that ghrelin, a hormone that regulates hunger, may also play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacologic target for treatment.
BACKGROUND: There is a need to identify novel pharmacologic targets to treat alcoholism. Animal and human studies suggest a role for ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. METHODS: This was a double-blind, placebo-controlled human laboratory proof-of-concept study. Nontreatment-seeking, alcohol-dependent, heavy-drinking individuals were randomized to receive intravenous ghrelin 1 mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called urge) for alcohol, assessed by the Alcohol Visual Analogue Scale. RESULTS: Out of 103 screenings, 45 individuals received the study drug. Repeated measures of analysis of covariance revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg versus placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p = ns). No significant differences in side effects were found (p = ns). CONCLUSIONS: Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol-dependent heavy-drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacologic target for treatment. (Leggio L, Zywiak WH, Fricchione SR, Edwards SM, de la Monte SM, Swift RM, Kenna GA. Biol Psychiatry. 2014 Mar 25. [Epub ahead of print]).
Division of Epidemiology and Prevention Research
State variation in underreporting of alcohol involvement on death certificates: motor vehicle traffic crash fatalities as an example
Significance: Based on the results of this study, researchers conclude that the role of alcohol in injury death appears to be vastly underreported.
OBJECTIVE: We used motor vehicle traffic (MVT) crash fatalities as an example to examine the extent of underreporting of alcohol involvement on death certificates and state variations.
METHOD: We compared MVT-related death certificates identified from national mortality data (Multiple Cause of Death [MCoD] data) with deaths in national traffic census data from the Fatality Analysis Reporting System (FARS). Because MCoD data were not individually linked to FARS data, the comparisons were at the aggregate level. Reporting ratio of alcohol involvement on death certificates was thus computed as the prevalence of any mention of alcohol-related conditions among MVT deaths in MCoD, divided by the prevalence of decedents with blood alcohol concentration (BAC) test results (not imputed) of .08% or greater in FARS. Through bivariate analysis and multiple regression, we explored state characteristics correlated with state reporting ratios. RESULTS: Both MCoD and FARS identified about 450,000 MVT deaths in 1999-2009. Reporting ratio was only 0.16 for all traffic deaths and 0.18 for driver deaths nationally, reflecting that death certificates captured only a small percentage of MVT deaths involving BAC of .08% or more. Reporting ratio did not improve over time, even though FARS indicated that the prevalence of BAC of at least .08% in MVT deaths increased from 19.9% in 1999 to 24.2% in 2009. State reporting ratios varied widely, from 0.02 (Nevada and New Jersey) to 0.81 (Delaware). CONCLUSIONS:
The comparison of MCoD with FARS revealed a large discrepancy in reporting alcohol involvement in MVT deaths and considerable state variation in the magnitude of underreporting. We suspect similar underreporting and state variations in alcohol involvement in other types of injury deaths. (Castle IJ, Yi HY, Hingson RW, White AM. J Stud Alcohol Drugs. 2014 Mar;75(2):299-312).
Randomized controlled trial of a web-delivered personalized normative feedback intervention to reduce alcohol-related risky sexual behavior among college students
Significance: Findings demonstrate that personalized normative feedback specific to drinking in sexual situations reduced alcohol-related risky sexual behavior. The study highlights the potential utility of a brief intervention that can be delivered via the Internet to reduce high-risk drinking and alcohol-related risky sexual behavior among college students.
Objective: The purpose of this study was to evaluate the efficacy of personalized normative feedback (PNF) on college student alcohol-related risky sexual behavior (RSB). Method: In a randomized controlled trial, 480 (57.6% female) sexually active college students were stratified by gender and level of drinking and randomly assigned to an alcohol-only intervention, an alcohol-related RSB-only intervention, a combined alcohol and alcohol-related RSB intervention, or control. All assessment and intervention procedures were Web-based. Results: Results indicated a significant reduction in drinking outcomes for the alcohol only and the combined alcohol and alcohol-related RSB interventions relative to control. Findings further demonstrated a significant reduction in alcohol-related RSB outcomes for the alcohol-related RSB only and the combined alcohol and alcohol-related RSB interventions relative to control. There were no significant intervention effects on alcohol-related negative consequences. These findings demonstrate that the combined alcohol and alcohol-related RSB intervention was the only intervention successful at reducing both drinking and alcohol-related RSB outcomes relative to control. There were no significant differences when comparing the combined alcohol and alcohol-related RSB intervention to the alcohol-only intervention or the alcohol-related RSB-only intervention. Finally, results suggested that the intervention effects on high-risk behaviors were mediated by reductions in descriptive normative perceptions. Conclusions: These findings demonstrate that PNF specific to drinking in sexual situations was needed to reduce alcohol-related RSB. Furthermore, this study highlights the potential utility of a brief intervention that can be delivered via the Internet to reduce high-risk drinking and alcohol-related RSB among college students. (Lewis MA, Patrick ME, Litt DM, Atkins DC, Kim T, Blayney JA, Norris J, George WH, Larimer ME. J Consult Clin Psychol. 2014 Jun;82(3):429-40).
Association between riding with an impaired driver and driving while impaired
Significance: This study found that past experience riding with an alcohol impaired driver increased the likelihood that a teen driver would receive a DWI once they were licensed.
OBJECTIVE: To examine the association between driving while alcohol/drug impaired (DWI) and the timing and amount of exposure to others' alcohol/drug-impaired driving (riding while impaired [RWI]) and driving licensure timing among teenage drivers.
METHODS: The data were from waves 1, 2, and 3 (W1, W2, and W3, respectively) of the NEXT Generation Study, with longitudinal assessment of a nationally representative sample of 10th graders starting in 2009-2010. Multivariate logistic regression was used for the analyses.
RESULTS: Teenagers exposed to RWI at W1 (adjusted odds ratio [AOR] = 21.12, P < .001), W2 (AOR = 19.97, P < .001), and W3 (AOR = 30.52, P < .001) were substantially more likely to DWI compared with those reporting never RWI. Those who reported RWI at 1 wave (AOR = 10.89, P < .001), 2 waves (AOR = 34.34, P < .001), and all 3 waves (AOR = 127.43, P < .001) were more likely to DWI compared with those who never RWI. Teenagers who reported driving licensure at W1 were more likely to DWI compared with those who were licensed at W3 (AOR = 1.83, P < .05).
CONCLUSIONS: The experience of riding in a vehicle with an impaired driver increased the likelihood of future DWI among teenagers after licensure. There was a strong, positive dose-response association between RWI and DWI. Early licensure was an independent risk factor for DWI. The findings suggest that RWI and early licensure could be important prevention targets. (Li K, Simons-Morton BG, Vaca FE, Hingson R. Pediatrics. 2014 Apr;133(4):620-6).
Impact of interventions targeting unhealthy alcohol use in Kenya on HIV transmission and AIDS-related deaths.
Significance: An alcohol intervention with the effectiveness observed in a published randomized controlled trial has the potential to reduce infections over 20 years by nearly 5% and avert nearly 18,000 deaths related to HIV.
BACKGROUND: HIV remains a major cause of preventable morbidity and mortality in Kenya. The effects of behaviors that accompany unhealthy alcohol consumption are a pervasive risk factor for HIV transmission and progression. Our objective was to estimate the portion of HIV infections attributable to unhealthy alcohol use and to evaluate the impact of hypothetical interventions directed at unhealthy alcohol use on HIV infections and deaths. METHODS: We estimated outcomes over a time horizon of 20 years using a computer simulation of the Kenyan population. This computer simulation integrates a compartmental model of HIV transmission with a mechanistic model of HIV progression that was previously validated in sub-Saharan Africa. Integration of the transmission and progression models allows simultaneous consideration of alcohol's effects on HIV transmission and progression (e.g., lowering antiretroviral adherence may increase transmission risk by elevating viral load, and may simultaneously increase progression by increasing the likelihood of AIDS). The simulation considers important aspects of heterogeneous sexual mixing patterns, including assortativeness of partners by age and activity level, age-discordant relationships, and high activity subgroups. Outcomes included number of new HIV infections, number of AIDS deaths, and infectivity (number of new infections per infected person per year). RESULTS: Our model estimated that the effects of behaviors accompanying unhealthy alcohol consumption are responsible for 13.0% of new HIV infections in Kenya. An alcohol intervention with effectiveness similar to that observed in a published randomized controlled trial of a cognitive-behavioral therapy-based intervention in Kenya (45% reduction in unhealthy alcohol consumption) could prevent nearly half of these infections, reducing their number by 69,858 and reducing AIDS deaths by 17,824 over 20 years. Estimates were sensitive to assumptions with respect to the magnitude of alcohol's underlying effects on condom use, antiretroviral therapy adherence, and sexually transmitted infection prevalence. CONCLUSIONS: A substantial number of new HIV infections in Kenya are attributable to unhealthy alcohol use. HIV remains a major cause of preventable morbidity and mortality in Kenya. The effects of behaviors that accompany unhealthy alcohol consumption are a pervasive risk factor for HIV transmission and progression. Our objective was to estimate the portion of HIV infections attributable to unhealthy alcohol use and to evaluate the impact of hypothetical interventions directed at unhealthy alcohol use on HIV infections and deaths. A substantial number of new HIV infections in Kenya are attributable to unhealthy alcohol use. (Braithwaite RS, Nucifora KA, Kessler J, Toohey C, Mentor SM, Uhler LM, Roberts MS, Bryant K. Alcohol Clin Exp Res. 2014 Apr;38(4):1059-67).
Division of Metabolism and Health Effects
Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals
Significance: This report addresses the consequences of binge alcohol drinking in men and women. Previous literature has established that a single binge is capable of generating a response similar to that frequently reported as a consequence of chronic alcohol abuse. Notable in this new study, the authors investigated the effects of binge alcohol in men and women and demonstrated that the effect is greater in women than in men. Specifically, these authors have demonstrated for the first time that a single acute binge alcohol drinking has the potential to increase not only serum endotoxin but also 16S rDNA levels, a biomarker for bacterial translocation into the blood, coupled to an increase in inflammatory cytokine levels that disturb innate immune responses and that this effect is greater in men than in women. This differential effect might have implication on alcohol’s effect on overall women’s health and opens a new avenue for future alcohol research.
Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic alcohol use results in increased gut permeability and increased serum endotoxin levels that contribute to many of the biological effects of chronic alcohol, including alcoholic liver disease. In this study, we evaluated the effects of acute binge drinking in healthy adults on serum endotoxin levels. We found that acute alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut. Compared to men, women had higher blood alcohol and circulating endotoxin levels. In addition, alcohol binge caused a prolonged increase in acute phase protein levels in the systemic circulation. The biological significance of the in vivo endotoxin elevation was underscored by increased levels of inflammatory cytokines, TNFα and IL-6, and chemokine, MCP-1, measured in total blood after in vitro lipopolysaccharide stimulation. Our findings indicate that even a single alcohol binge results in increased serum endotoxin levels likely due to translocation of gut bacterial products and disturbs innate immune responses that can contribute to the deleterious effects of binge drinking. (Bala S, Marcos M, Gattu A, Catalano D, Szabo G. PLoS One. 2014 May 14;9(5):e96864).
Dietary cholesterol protects against alcohol-induced cerebral artery constriction
Significance: One of the major health complications of binge drinking is an increased risk for cerebral ischemia, stroke, and death from ischemic stroke. Although alcohol is known to be able to induce cerebral artery constriction by inhibition of calcium/voltage-gated potassium channels of large conductance (BK) in vascular smooth muscle, physiological modulators of AICAC remain largely unknown. Here, the authors studied the effect of dietary cholesterol intake in a rat model and demonstrated a protective effect of cholesterol buildup in cerebral arteries against AICAC. Identification of molecular mechanisms that underlie cholesterol-driven protection against AICAC may unveil therapeutic countermeasures to alcohol-driven cerebrovascular pathology by targeting EtOH sensing sites on BK channels or counteracting EtOH’s effects in biological membranes.
BACKGROUND: Binge drinking represents the major form of excessive alcohol (ethanol [EtOH]) consumption in the United States. Episodic (such as binge) drinking results in blood alcohol levels (BAL) of 18 to 80 mM and leads to alcohol-induced cerebral artery constriction (AICAC). AICAC was shown to arise from EtOH-induced inhibition of large-conductance, calcium/voltage-gated potassium (BK) channels in the vascular smooth muscle. Factors that modulate BK channel-mediated AICAC remain largely unknown. METHODS: Male Sprague Dawley rats were placed on high-cholesterol (2% of cholesterol) diet for 18 to 23 weeks. Their littermates were placed on control iso-caloric diet. AICAC was evaluated both in vivo and in vitro, by means of pial arteriole diameter monitoring through a closed cranial window and diameter measurements of isolated, pressurized cerebral arteries. Cholesterol level in the cerebral artery tissue was manipulated by methyl-β-cyclodextrin to reverse dietary-induced accumulation of cholesterol. BK channel surface presence on the plasma membrane of cerebral artery myocytes was evaluated by immunofluorescence staining. BK channel function in pressurized cerebral artery was assessed using selective BK channel blocker paxilline. RESULTS: Within 5 minutes of 50 mM EtOH injection into carotid artery in vivo, arteriole diameter decreased by 20% in control group. Pial arteriole constriction was significantly reduced in rats on high-cholesterol diet, resulting in only 10% reduction in diameter. BAL in both groups, however, remained the same. Significant reduction in AICAC in group on high-cholesterol diet compared to control was also observed after middle cerebral artery dissection and in vitro pressurization at 60 mmHg, this reduction remaining after endothelium removal. Cholesterol level in de-endothelialized cerebral arteries was significantly increased in rats on high-cholesterol diet. Removal of excessive cholesterol content restored AICAC to the level observed in cerebral arteries of rats on normal diet. Immunofluorescence staining of BK channel-forming and accessory, smooth muscle-specific β1 subunit in freshly isolated cerebral artery myocyte showed that high-cholesterol diet did not down-regulate surface presence of BK protein. However, paxilline-induced cerebral artery constriction was diminished in arteries from rats on high-cholesterol diet. CONCLUSIONS: Our data indicate that dietary cholesterol protects against AICAC. This protection is caused by cholesterol buildup in the arterial tissue and diminished function (but not surface presence) of EtOH target-BK channel. (Bukiya A, Dopico AM, Leffler CW, Fedinec A. Alcohol Clin Exp Res. 38:1216-26 2014).
Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes
Significance: Excessive alcohol consumption is a major cause of pancreatitis. Pancreatic stellate cells (PSC) undergo a phenotypic and functional transition to activated myofibroblasts which produce and deposit collagen at high levels by a process regulated by connective tissue growth factor (CCN2). Expression of CCN2 is highly up-regulated in activated PSC and is associated with enhanced expression of microRNA-21 (miR-21). This positive feedback loop between CCN2 and miR-21 was identified that resulted in enhancement of their respective expression as well as that of collagen α1(I).
Pancreatitis is an inflammatory condition of the pancreas which, in its chronic form, involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer, and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). In response to noxious agents such as alcohol-excessive consumption of which is a major cause of pancreatitis in the West-normally quiescent PSC undergo a phenotypic and functional transition to activated myofibroblasts which produce and deposit collagen at high levels. This process is regulated by connective tissue growth factor (CCN2), expression of which is highly up-regulated in activated PSC. We show that CCN2 production by activated PSC is associated with enhanced expression of microRNA-21 (miR-21) which was detected at high levels in activated PSC in a murine model of alcoholic chronic pancreatitis. A positive feedback loop between CCN2 and miR-21 was identified that resulted in enhancement of their respective expression as well as that of collagen α1(I). Both miR-21 and CCN2 mRNA were present in PSC-derived exosomes, which were characterized as 50-150 nm CD9-positive nano-vesicles. Exosomes from CCN2-GFP- or miR-21-GFP-transfected PSC were taken up by other PSC cultures, as shown by direct fluorescence or qRT-PCR for GFP. Collectively these studies establish miR-21 and CCN2 as participants in a positive feedback loop during PSC activation and as components of the molecular payload in PSC-derived exosomes that can be delivered to other PSC. Thus interactions between cellular or exosomal miR-21 and CCN2 represent novel aspects of fibrogenic regulation in PSC. Summary Chronic injury in the pancreas is associated with fibrotic pathology which is driven in large part by CCN2-dependent collagen production in pancreatic stellate cells. This study shows that CCN2 up-regulation in PSC is associated with increased expression of miR-21 which, in turn, is able to stimulate CCN2 expression further via a positive feedback loop. Additionally miR-21 and CCN2 were identified in PSC-derived exosomes which effected their delivery to other PSC. The cellular and exosomal miR-21-CCN2 axis is a novel component in PSC fibrogenic signaling. (Charrier A1, Chen R, Chen L, Kemper S, Hattori T, Takigawa M, Brigstock DR. J Cell Commun Signal. 2014 Jan 26. [Epub ahead of print]).
Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling
Significance: Skeletal muscle wasting is a serious problem in the aging and is exacerbated by alcohol use. This paper describes mitochondrial fusion in skeletal muscle for the first time, and identifies an important gene Mfn1, the abundance of which is decreased 50 percent in rats on a regular alcohol diet-while other fusion proteins were unchanged. This decrease was coupled with a massive decrease in mitochondrial fusion, thus blocking this vital repair mechanism that may be behind development of muscle weakness. Identification of this important pathway and the proteins involved in the process opens up the possibility of developing a drug to treat it.
Genetic targeting experiments indicate a fundamental role for mitochondrial fusion proteins in mammalian physiology. However, owing to the multiple functions of fusion proteins, their related phenotypes are not necessarily caused by altered mitochondrial fusion. Perhaps the biggest mystery is presented by skeletal muscle, where mostly globular-shaped mitochondria are densely packed into the narrow intermyofilamental space, limiting the interorganellar interactions. We show here that mitochondria form local networks and regularly undergo fusion events to share matrix content in skeletal muscle fibers. However, fusion events are less frequent and more stable in the fibers than in nondifferentiated myoblasts. Complementation among muscle mitochondria was suppressed by both in vivo genetic perturbations and chronic alcohol consumption that cause myopathy. An Mfn1-dependent pathway is revealed whereby fusion inhibition weakens the metabolic reserve of mitochondria to cause dysregulation of calcium oscillations during prolonged stimulation. Thus, fusion dynamically connects skeletal muscle mitochondria and its prolonged loss jeopardizes bioenergetics and excitation-contraction coupling, providing a potential pathomechanism contributing to myopathies. (Eisner V, Lenaers G, Hajnóczky G. J Cell Biol. 205:179-95 2014).
Rescue of holoprosencephaly in fetal alcohol-exposed Cdon mutant mice by reduced gene dosage of Ptch1
Significance: This study extends previous findings that impairment of the Sonic hedgehog (SHH) signaling pathway by prenatal alcohol promotes holoprosencephaly (HPE), the deficient development of midline brain, face and palate structures, which is seen in Fetal Alcohol Syndrome (FAS). Using a mouse model of prenatal alcohol-induced HPE, the present study shows that increasing SSH signaling greatly diminished the frequency of HPE, thus demonstrating a central role of impaired SSH signaling in HPE and suggesting that genetic variants of the SHH pathway in human populations may exist that either promote or prevent HPE in alcohol-exposed fetuses
Holoprosencephaly (HPE) is a commonly occurring developmental defect in which midline patterning of the forebrain and midface is disrupted. Sonic hedgehog (SHH) signaling is required during multiple stages of rostroventral midline development, and heterozygous mutations in SHH pathway components are associated with HPE. However, clinical presentation of HPE is highly variable, and carriers of heterozygous mutations often lack apparent defects. It is therefore thought that such mutations must interact with more common modifiers, genetic and/or environmental. We have modeled this scenario in mice. Cdon mutant mice have a largely subthreshold defect in SHH signaling, rendering them sensitive to a wide spectrum of HPE phenotypes by additional hits that are themselves insufficient to produce HPE, including transient in utero exposure to ethanol. These variable HPE phenotypes may arise in embryos that fail to reach a threshold level of SHH signaling at a specific developmental stage. To provide evidence for this possibility, here we tested the effect of removing one copy of the negative regulator Ptch1 from Cdon(-/-) embryos and compared their response to ethanol with that of Cdon(-/-);Ptch1(+/+) embryos. Ptch1 heterozygosity decreased the penetrance of HPE in this system by >75%. The major effect of reduced Ptch1 gene dosage was on penetrance, as those Cdon(-/-);Ptch1(+/-) embryos that displayed HPE did not show major differences in phenotype from Cdon(-/-);Ptch1(+/+) embryos with ethanol-induced HPE. Our findings are consistent with the notion that even in an etiologically complex model of HPE, the level of SHH pathway activity is rate-limiting. Furthermore, the clinical outcome of an individual carrying a SHH pathway mutation will likely reflect the sum effect of both deleterious and protective modifier alleles and their interaction with non-genetic risk factors like fetal alcohol exposure. (Hong M, Krauss RS. PLoS One 8(11):e79269).
Mechanisms of action of acetaldehyde in the up-regulation of the human 2(I) collagen gene in hepatic stellate cells: key roles of Ski, SMAD3, SMAD4, and SMAD7
Significance: The present findings unveil additional critical steps in the acetaldehyde-mediated fibrogenic process and thus suggest possible new targets for antifibrogenic therapy.
Alcohol-induced liver fibrosis is a multifactorial event characterized by increased collagen production as a result of upregulation of 2(I) collagen (COL1A2) gene. Acetaldehyde, the first metabolite of ethanol, is fibrogenic and induces expression of both COL1A1 and COL1A2 genes by a mechanism dependent on the generation of H2O2. Acetaldehyde induces expression and activation of TGF-b1 and of its type II receptor. However, the early events triggered by acetaldehyde occurring within the first 6 to 12 hours after acetaldehyde administration are not dependent on TGF-b1 and protein synthesis. To unravel key molecular mechanisms involved in acetaldehyde-mediated up-regulation of type I collagen, the authors have investigated the key roles played by this ethanol metabolite in up-regulation of type I collagen genes in human and mouse hepatic stellate cells (HSCs). Acetaldehyde induced up-regulation of COL1A2 by 3.5-fold, with concomitant increases in the mRNA (threefold) and protein (4.2- and 3.5-fold) levels of SMAD3 and SMAD4, respectively. It also caused a 60% decrease in SMAD7 expression. More importantly, acetaldehyde effectively promotes the translocation of the other transcription repressor, Ski, a member of the Ski/Sno oncogene family, from the nucleus to the cytoplasmic compartment to undergo proteasomal degradation via the ubiquitin pathway. These findings suggest that transcriptional up-regulation of COL1A2 by acetaldehyde occurs via two distinct mechanisms. The first occurs very rapidly, is transient, and involves the elimination of repressors of COL1A2 (such as Ski and SMAD7) and the phosphorylation of SMAD3. The second mechanism is more sustained and corresponds to the expression of TGF-b1 and consequent up-regulation of SMAD3 and SMAD4, a process that starts after 6 to 12 hours of exposure to acetaldehyde. Based on these findings the authors suggest that Ski plays a major role in the fibrogenic action of acetaldehyde by sequestering the SMAD4eSki complex from the nucleus to the cytoplasm, leading to the proteasomal degradation of Ski via the ubiquitin pathway and consequent activation of SMAD4. (Reyes-Gordillo K, Shah R, Arellanes-Robledo J, Hernández-Nazara Z, Rincón-Sánchez AR, Inagaki Y, Rojkind M, Lakshman MR. Am J Pathol 184, 1458-67, 2014).
Alcohol-induced autophagy contributes to loss in skeletal muscle mass
Significance: By examining the expression of autophagy markers and real-time PCR to study autophagy induction in human skeletal muscle biopsies from alcoholic cirrhotics and controls, and in mouse tissues these authors were able to establish a causative link between muscle autophagy induced by ethanol exposure and sarcopenia.
Patients with alcoholic cirrhosis and hepatitis have severe muscle loss. Since ethanol impairs skeletal muscle protein synthesis but does not increase ubiquitin proteasome-mediated proteolysis, we investigated whether alcohol-induced autophagy contributes to muscle loss. Autophagy induction was studied in: A) Human skeletal muscle biopsies from alcoholic cirrhotics and controls, B) Gastrocnemius muscle from ethanol and pair-fed mice, and C) Ethanol-exposed murine C2C12 myotubes, by examining the expression of autophagy markers assessed by immunoblotting and real-time PCR. Expression of autophagy genes and markers were increased in skeletal muscle from humans and ethanol-fed mice, and in myotubes following ethanol exposure. Importantly, pulse-chase experiments showed suppression of myotube proteolysis upon ethanol-treatment with the autophagy inhibitor, 3-methyladenine (3MA) and not by MG132, a proteasome inhibitor. Correspondingly, ethanol-treated C2C12 myotubes stably expressing GFP-LC3B showed increased autophagy flux as measured by accumulation of GFP-LC3B vesicles with confocal microscopy. The ethanol-induced increase in LC3B lipidation was reversed upon knockdown of Atg7, a critical autophagy gene and was associated with reversal of the ethanol-induced decrease in myotube diameter. Consistently, CT image analysis of muscle area in alcoholic cirrhotics was significantly reduced compared with control subjects. In order to determine whether ethanol per se or its metabolic product, acetaldehyde, stimulates autophagy, C2C12 myotubes were treated with ethanol in the presence of the alcohol dehydrogenase inhibitor (4-methylpyrazole) or the acetaldehyde dehydrogenase inhibitor (cyanamide). LC3B lipidation increased with acetaldehyde treatment and increased further with the addition of cyanamide. We conclude that muscle autophagy is increased by ethanol exposure and contributes to sarcopenia. (Thapaliya S, Runkana A, McMullen MR, Nagy LE, McDonald C, Naga Prasad SV, Dasarathy S Autophagy. 10:677-90, 2014).
Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy
Significance: Steatosis resulting from alcohol consumption is a precursor to more serious liver diseases such as hepatitis and cirrhosis. In this work, the authors show that cannabidiol, a non-psychoactive cannabinoid, protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of oxidative stress, and inhibition of autophagy. This study provides the mechanistic foundation for translational studies to assess the potential use of cannabidiol in the prevention of alcohol related steatosis.
Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether Cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy. (Yang L, Rozenfeld R, Wu D, Devi LA, Zhang Z, Cederbaum A. Free Radical Biology and Medicine 68, 260–267).
Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men
Significance: The study suggests that the abnormalities in red blood cells observed in alcoholics are caused by high exposure to acetaldehyde, a toxic byproduct of alcohol breakdown, as well as by nutritional deficiencies. These blood abnormalities may be prevented by supplementing the diet with folate.
BACKGROUND: Oxidation of ethanol by alcohol dehydrogenase (ADH) generates acetaldehyde (AcH), which is converted to acetate by aldehyde dehydrogenase-2 (ALDH2). Roughly 40% of East Asians are ALDH2-deficient due to an inactive enzyme encoded by the ALDH2*2 allele. ALDH2-deficient individuals have a dramatically elevated risk of esophageal cancer from alcohol consumption. METHODS: We investigated the relationship between ALDH2*2, ADH1B*2 (encoding a highly active ADH) and erythrocyte abnormalities, in a population of Japanese alcoholic men (N = 1,238). RESULTS: Macrocytosis (mean corpuscular volume [MCV] ≥100 fl) and macrocytic anemia (MCV ≥100 fl and hemoglobin <13.5 g/dl) were found in 62.4 and 24.1% of the subjects, respectively. Age-adjusted daily alcohol consumption did not differ according to ADH1B and ALDH2 genotypes. However, macrocytosis and macrocytic anemia were strongly associated with the ALDH2*1/*2 genotype multivariate odds ratios (ORs; 95% confidence interval [CI] = 2.85 [1.95 to 4.18] and 3.68 [2.64 to 5.15], respectively, versus ALDH2*1/*1). In comparison with the ADH1B*1/*1 and ALDH2*1/*1 genotype combination, the ADH1B*1/*1 and ALDH2*1/*2 genotype combination and the ADH1B*2 allele and ALDH2*1/*2 genotype combination increased stepwise the ORs (95% CI) for macrocytosis (1.65 [0.92 to 2.94] and 4.07 [2.33 to 7.11], respectively, p for difference in OR = 0.015) and macrocytic anemia (2.80 [1.52 to 5.15] and 5.32 [3.29 to 8.62], respectively, p for difference in OR = 0.045). Genotype effects were more prominent on the risks of the more advanced erythrocyte abnormalities. Older age, cigarette smoking, and low body mass index independently increased the risks of the erythrocyte abnormalities. Consumption of beer, which contains folate, decreased the risks, whereas consumption of alcoholic beverages lacking folate did not. CONCLUSIONS: These results suggest that the erythrocyte abnormalities in alcoholics are attributable to high AcH exposure as well as to nutritional deficiencies and may be prevented by folate. (Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K. Alcohol Clin Exp Res. 38:1237-46, 2014).
Division of Neuroscience and Behavior
Altered sedative effects of ethanol in mice with α1 glycine receptor subunits that are insensitive to Gβγ modulation
Significance: This study demonstrates that knock-in mice with a phenotypically silent mutation in the glycine receptor show shorter times in loss of righting reflex in response to sedative dose of ethanol, suggesting lower ethanol sensitivity. These data provide the first evidence to link a molecular site in the glycine receptor with the sedative effects produced by intoxicating doses of ethanol.
Alcohol abuse and alcoholism are major health problems and one of the leading preventable causes of death. Before achieving better treatments for alcoholism, it is necessary to understand the critical actions of alcohol on membrane proteins that regulate fundamental functions in the central nervous system. After generating a genetically modified knock-in (KI) mouse having a glycine receptor (GlyR) with phenotypical silent mutations at KK385/386AA, we studied its cellular and in vivo ethanol sensitivity. Analyses with Western blot and immunocytochemistry indicated that the expression of α1 GlyRs in nervous tissues and spinal cord neurons (SCN) were similar between WT and KI mice. The analysis of synaptic currents recorded from KI mice showed that the glycinergic synaptic transmission had normal properties, but the sensitivity to ethanol was significantly reduced. Furthermore, the glycine evoked current in SCN from KI was resistant to ethanol and G-protein activation by GTP-γ-S. In behavioral studies, KI mice did not display the foot clasping behavior upon lifting by the tail and lacked an enhanced startle reflex response that are characteristic of other glycine KI mouse lines with markedly impaired glycine receptor function. The most notable characteristic of the KI mice was their significant lower sensitivity to ethanol (-40%), expressed by shorter times in loss of righting reflex (LORR) in response to a sedative dose of ethanol (3.5 g/Kg). These data provide the first evidence to link a molecular site in the GlyR with the sedative effects produced by intoxicating doses of ethanol. (Aguayo LG, Castro P, Mariqueo T, Muñoz B, Xiong W, Zhang L, Lovinger DM, Homanics GE. Neuropsychopharmacology. 2014 May 7 [Epub ahead of print]).
Prenatal alcohol exposure modifies glucocorticoid receptor subcellular distribution in the medial prefrontal cortex and impairs frontal cortex-dependent learning
Significance: This study demonstrates that mice prenatally exposed to alcohol show deficits in glucocorticoid receptor trafficking in the medial prefrontal cortex, which may contribute to the reduced flexibility in reversal learning. It reveals the important role of glucocorticoid receptors in the impairment of the frontal cortical-dependent behavior associated with prenatal alcohol exposure.
Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice. (Allan AM, Goggin SL, Caldwell KK. PLoS One. 2014 Apr 22;9(4):e96200.)
Drinking alcohol has sex-dependent effects on pair bond formation in prairie voles
Significance: Voluntary alcohol consumption inhibited partner preference formation in socially monogamous male prairie voles, but facilitated partner preference in females. The effects of alcohol on social bonding were mediated by neural mechanisms regulating pair bond formation (especially neuropeptide Y and corticotropin-releasing factor) and not alcohol's effects on mating, locomotor, or aggressive behaviors. These findings provide the first evidence to our knowledge that alcohol has a direct impact on the neural systems involved in social bonding in a sex-specific manner, providing an opportunity to explore the mechanisms by which alcohol affects social relationships.
Alcohol use and abuse profoundly influences a variety of behaviors, including social interactions. In some cases, it erodes social relationships; in others, it facilitates sociality. Here, we show that voluntary alcohol consumption can inhibit male partner preference (PP) formation (a laboratory proxy for pair bonding) in socially monogamous prairie voles (Microtus ochrogaster). Conversely, female PP is not inhibited, and may be facilitated by alcohol. Behavior and neurochemical analysis suggests that the effects of alcohol on social bonding are mediated by neural mechanisms regulating pair bond formation and not alcohol's effects on mating, locomotor, or aggressive behaviors. Several neuropeptide systems involved in the regulation of social behavior (especially neuropeptide Y and corticotropin-releasing factor) are modulated by alcohol drinking during cohabitation. These findings provide the first evidence to our knowledge that alcohol has a direct impact on the neural systems involved in social bonding in a sex-specific manner, providing an opportunity to explore the mechanisms by which alcohol affects social relationships. (Anacker AM, et al. Proc Natl Acad Sci U S A. 111(16):6052-7).
Restraint stress alters nociceptin/orphanin fq and crf systems in the rat central amygdala: significance for anxiety-like behaviors
Significance: This study shows that stress leads to an increased NOP-mediated neuronal activity in the CeA. Alcohol withdrawal, a condition associated with dysregulation of the stress system and increased CRF tone in the CeA, has also been found to induce increased function of N/OFQ. These findings suggest a critical role of the N/OFQ system in opposing the recruitment of the CeA CRF system associated with stress-related stimuli, including alcohol withdrawal.
Corticotropin releasing factor (CRF) is the primary mediator of stress responses, and nociceptin/orphanin FQ (N/OFQ) plays an important role in the modulation of these stress responses. Thus, in this multidisciplinary study, the authors explored the relationship between the N/OFQ and the CRF systems in response to stress. Using in situ hybridization (ISH), they assessed the effect of body restraint stress on the gene expression of CRF and N/OFQ-related genes in various subdivisions of the amygdala, a critical brain structure involved in the modulation of stress response and anxiety-like behaviors. They found a selective upregulation of the NOP and downregulation of the CRF1 receptor transcripts in the CeA and in the BLA after body restraint. Thus, they performed intracellular electrophysiological recordings of GABAA-mediated IPSPs in the central nucleus of the amygdala (CeA) to explore functional interactions between CRF and N/OFQ systems in this brain region. Acute application of CRF significantly increased IPSPs in the CeA, and this enhancement was blocked by N/OFQ. Importantly, in stress-restraint rats, baseline CeA GABAergic responses were elevated and N/OFQ exerted a larger inhibition of IPSPs compared with unrestraint rats. The NOP antagonist [Nphe1]-nociceptin(1–13)NH2 increased the IPSP amplitudes in restraint rats but not in unrestraint rats, suggesting a functional recruitment of the N/OFQ system after acute stress. Finally, they evaluated the anxiety-like response in rats subjected to restraint stress and nonrestraint rats after N/OFQ microinjection into the CeA. Intra-CeA injections of N/OFQ significantly and selectively reduced anxiety-like behavior in restraint rats in the elevated plus maze. These combined results demonstrate that acute stress increases N/OFQ systems in the CeA and that N/OFQ has anti-stress properties (Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, Oleata CS, Heilig M, Roberto M. Journal of Neuroscience. 2014 Jan 8; 34(2):363-372).
Functional magnetic resonance imaging (fmri) responses to alcohol pictures predicts subsequent transition to heavy drinking in college students
Significance: College students who transitioned to heavy use a year later showed at baseline a higher blood oxygen level-dependent (BOLD) response (as measured by functional magnetic resonance imaging) to alcohol-related pictures in several brain areas compared to those college students who remained either continuously moderate or heavy drinkers. The activation of brain areas to alcohol cues (i.e., pictures) which served as a single factor in the regression model predicted subsequent transition to heavy drinking better than other factors such as a family history of alcoholism or level of impulsivity.
BACKGROUND AND AIMS: Young adults show the highest rates of escalating drinking, yet the neural risk mechanisms remain unclear. Heavy drinkers show variant functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to alcohol cues, which may presage increasing drinking. In this longitudinal study, we ascertained whether BOLD response to alcohol pictures predicted subsequent heavy drinking among college students. METHODS: Participants were 43 18-21-year-olds in the United States who underwent BOLD scanning and completed monthly substance use surveys over the following year. Participants were categorized according to baseline and follow-up drinking into 13 continuously moderate drinkers, 16 continuously heavy drinkers and 14 transitioners who drank moderately at baseline but heavily by follow-up. During fMRI scanning at baseline, participants viewed alcohol and matched non-alcohol beverage images. RESULTS: We observed group differences in alcohol cue-elicited BOLD response in bilateral caudate, orbitofrontal cortex, medial frontal cortex/anterior cingulate and left insula (clusters > 2619 ml, voxelwise F(2,40) > 3.23, P < 0.05, whole-brain corrected P < 0.05), where transitioners hyperactivated compared with moderate and heavy drinkers (all Tukey P < 0.05). Exploratory factor analysis revealed a single brain network differentiating those who subsequently increased drinking. Exploratory regressions showed that, compared with other risk factors (e.g., alcoholism family history, impulsivity), BOLD response best predicted escalating drinking amount and alcohol-related problems. CONCLUSIONS: Neural response to pictures of alcohol is substantially enhanced among United States college students who subsequently escalate drinking. Greater cue-reactivity is associated with larger increases in drinking and alcohol-related problems, regardless of other baseline factors. Thus, neural cue-reactivity could uniquely facilitate identifying individuals at greatest risk for future problematic drinking (Dager AD, Anderson BM, Rosen R, Khadka S, Sawyer B, Jiantonio-Kelly RE, Austad CS, Raskin SA, Tennen H, Wood RM, Fallahi CR, Pearlson GD. Addiction 2014; 109:585-595).
Chronic alcohol disrupts dopamine receptor activity and the cognitive function of the medial prefrontal cortex
Significance: This study links the impairment of dopamine D2/D4 receptor mediated signaling to ethanol-induced cognitive deficit. It demonstrates that chronic intermittent ethanol exposure significantly disrupted D2/D4 receptor modulation of the neuronal activity in the medial prefrontal cortex (mPFC) and reduced behavioral flexibility.
Dopamine (DA) receptors in the medial prefrontal cortex (mPFC) exert powerful effects on cognition by modulating the balance between excitatory and inhibitory neurotransmission. The present study examined the impact of chronic intermittent ethanol (CIE) exposure on cognitive function and DA receptor-mediated neurotransmission in the rat mPFC. Consistent with alterations in executive function in alcoholics, CIE-exposed rats exhibited deficits in behavioral flexibility in an operant set-shifting task. Since alterations in dopaminergic neurotransmission in the mPFC have been implicated in a number of behavioral disorders including addiction, studies were then performed in the adult acute slice preparation to examine changes in DA receptor function in the mPFC following CIE exposure. In slices obtained from control rats, DA receptor stimulation was observed to exert complex actions on neuronal firing and synaptic neurotransmission that were not only dependent upon the particular receptor subtype but also whether it was a pyramidal cell or a fast-spiking interneuron. In contrast to slices from control rats, there was a near complete loss of the modulatory actions of D2/D4 receptors on cell firing and neurotransmission in slices obtained immediately, 1 and 4 weeks after the last day of CIE exposure. This loss did not appear to be associated with changes in receptor expression. In contrast, CIE exposure did not alter D1 receptor function or mGluR1 modulation of firing. These studies are consistent with the suggestion that chronic alcohol exposure disrupts cognitive function at least in part through disruption of D2 and D4 receptor signaling in mPFC. (Trantham-Davidson H, Burnett EJ, Gass JT, Lopez MF, Mulholland PJ, Centanni SW, Floresco SB, Chandler LJ. Journal of Neuroscience. 2014, 34 (10):3706-18).
Reduced ethanol consumption by alcohol-preferring (p) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell
Significance: This study highlights the potential of deep brain stimulation (DBS) as a treatment intervention. The study demonstrated two points:1) pharmacological inactivation of the bilateral nucleus accumbens shell (AcbSh) reduces ethanol( EtOH) operant responding in the alcohol preferring (P)rat after chronic EtOH use has been established; and 2) unilateral DBS of the AcbSh is effective at reducing daily EtOH consumption in alcoholic animals.
OBJECTIVE: There is increasing interest in deep brain stimulation (DBS) for the treatment of addiction. Initial testing must be conducted in animals, and the alcohol-preferring (P) rat meets the criteria for an animal model of alcoholism. This study is composed of 2 experiments designed to examine the effects of 1) pharmacological inactivation and 2) DBS of the nucleus accumbens shell (AcbSh) on the consumption of alcohol by P rats. METHODS: In the first experiment, the effects of reversible inactivation of the AcbSh were investigated by administering intracranial injections of γ-aminobutyric acid (GABA) agonists. Bilateral microinjections of drug were administered to the AcbSh in P rats (8-10 rats/group), after which the animals were placed in operant chambers containing 2 levers--one used to administer water and the other to administer 15% EtOH--to examine the acquisition and maintenance of oral EtOH self-administration. In the second experiment, a DBS electrode was placed in each P rat's left AcbSh. The animals then received 100 or 200 μA (3-4 rats/group) of DBS to examine the effect on daily consumption of oral EtOH in a free-access paradigm. RESULTS: In the first experiment, pharmacological silencing of the AcbSh with GABA agonists did not decrease the acquisition of EtOH drinking behavior but did reduce EtOH consumption by 55% in chronically drinking rats. Similarly, in the second experiment, 200 μA of DBS consistently reduced EtOH intake by 47% in chronically drinking rats. The amount of EtOH consumption returned to baseline levels following termination of therapy in both experiments. CONCLUSIONS: Pharmacological silencing and DBS of the AcbSh reduced EtOH intake after chronic EtOH use had been established in rodents. The AcbSh is a neuroanatomical substrate for the reinforcing effects of alcohol and may be a target for surgical intervention in cases of alcoholism. (Wilden JA, Qing KY, Hauser SR, McBride WJ, Irazoqui PP, Rodd ZA J Neurosurg. 2014 Apr;120(4):997-1005).
Division of Treatment and Recovery Research
Cumulative proportion of responders analysis (CPRA) as a tool to assess treatment outcome in alcohol clinical trials
Significance: This study presented a novel application of an analytical technique—cumulative proportion of responders analysis—to determine which dichotomous endpoints, derived from continuous drinking measures, have the greatest treatment effects in alcohol clinical trials.
OBJECTIVE: Several definitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one definition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRAhas been used to examine the efficacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the efficacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment. METHOD: All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their efficacy. RESULTS: Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. CONCLUSIONS: CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatmentsuccess given various definitions of a positive response. (Falk DE, Litten RZ, Anton RF, Kranzler HR, Johnson BA, ACTIVE Workgroup. J Stud Alcohol Drugs. 2014 Mar;75(2):335-46).
Risks of alcohol use disorders related to drinking patterns and a history of treatment for or concern about heavy drinking
Significance: The results of this study provide quantitative guidance for primary care practitioners who wish to make population-based recommendations to patients who might benefit by reducing both overall intake and amounts per occasion in an effort to lower their risks of developing AUDs.
OBJECTIVE: The purpose of this study was to examine the relations between drinking (mean quantity and heavy drinking patterns) and alcohol use disorders (AUDs) in the U.S. general population. METHOD: Data from three telephone National Alcohol Surveys (in 2000, 2005, and 2010) were pooled, with separate analyses for men and women restricted to current drinkers (ns = 5,922 men, 6,270 women). Predictors were 12-month volume (mean drinks per day), rates of heavy drinking (5+/4+ drinks in a day for men/women), and very heavy drinking (8+, 12+, and 24+ drinks in a day). Outcomes were negative alcohol-related consequences constituting abuse (1+ of 4 DSM-IV-based domains assessed by 13 items) and alcohol dependence (symptoms in 3+ of 7 DSM-IV-based domains), together taken to indicate an AUD. Segmentation analyses were used to model risks of problem outcomes from drinking patterns separately by gender. RESULTS: In the general population, men and women who consumed ≤1 drink/day on average with no heavy drinking days did not incur substantial risks of an AUD (<10%). Men who drank from 1 to 2 drinks/day on average but never 5+ incurred a 16% risk of reporting an AUD (3.5% alcohol dependence). At higher volumes, men and women who indicated higher rates of drinking larger amounts per day and/or involving 8+ and 12+ drinks/day (and even 24+ drinks/day for men) showed much higher risks of experiencing AUDs. CONCLUSIONS: The findings provide quantitative guidance for primary care practitioners who wish to make population-based recommendations to patients who might benefit by reducing both overall intake and amounts per occasion in an effort to lower their risks of developing AUDs. (Greenfield TK, Bond J, Ye Y, Kerr WC, Nayak MB, Kaskutas LA, Anton RF, Litten RZ, Kranzler HR. 2014. J Stud Alcohol Drugs. 2014 Mar;75(2):319-27).
A smartphone application to support recovery from alcoholism: a randomized clinical trial
Significance: Results of the study indicated that, compared to treatment as usual, a multi-featured smartphone application helped patients to reduce alcohol consumption following residential treatment for alcohol use disorders.
IMPORTANCE Patients leaving residential treatment for alcohol use disorders are not typically offered evidence-based continuing care, although research suggests that continuing care is associated with better outcomes. A smartphone-based application could provide effective continuing care. OBJECTIVE To determine whether patients leaving residential treatment for alcohol use disorders with a smartphone application to support recovery have fewer risky drinking days than control patients. DESIGN, SETTING, AND PARTICIPANTS An unmasked randomized clinical trial involving 3 residential programs operated by 1 nonprofit treatment organization in the Midwestern United States and 2 residential programs operated by 1 nonprofit organization in the Northeastern United States. In total, 349 patients who met the criteria for DSM-IV alcohol dependence when they entered residential treatment were randomized to treatment as usual (n = 179) or treatment as usual plus a smartphone (n = 170) with the Addiction-Comprehensive Health Enhancement Support System (A-CHESS), an application designed to improve continuing care for alcohol use disorders. INTERVENTIONS Treatment as usual varied across programs; none offered patients coordinated continuing care after discharge. A-CHESS provides monitoring, information, communication, and support services to patients, including ways for patients and counselors to stay in contact. The intervention and follow-up period lasted 8 and 4 months, respectively. MAIN OUTCOMES AND MEASURES Risky drinking days-the number of days during which a patient's drinking in a 2-hour period exceeded 4 standard drinks for men and 3 standard drinks for women, with standard drink defined as one that contains roughly 14 g of pure alcohol (12 oz of regular beer, 5 oz of wine, or 1.5 oz of distilled spirits). Patients were asked to report their risky drinking days in the previous 30 days on surveys taken 4, 8, and 12 months after discharge from residential treatment. RESULTS For the 8 months of the intervention and 4 months of follow-up, patients in the A-CHESS group reported significantly fewer risky drinking days than did patients in the control group, with a mean of 1.39 vs 2.75 days (mean difference, 1.37; 95% CI, 0.46-2.27; P = .003). CONCLUSIONS AND RELEVANCE The findings suggest that a multifeatured smartphone application may have significant benefit to patients in continuing care for alcohol use disorders. (Gustafson DH, McTavish FM, Chih MY, Atwood AK, Johnson RA, Boyle MG, Levy MS, Driscoll H, Chisholm SM, Dillenburg L, Isham A, Shah D. 2014. JAMA Psychiatry 71:566-72).
Research opportunities for medications to treat alcohol dependence: addressing stakeholders' needs
Significance: This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking. These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers.
During the past decade, significant advances have been made in the development of medications to treat alcohol dependence. Four medications have been approved by the U.S. Food and Drug Administration for treating alcohol dependence-naltrexone, injectable naltrexone, acamprosate, and disulfiram-and several others show promise. The fact remains, however, that because of the heterogeneity of alcohol dependence, these medications will not work for all people, in all circumstances. Moreover, clinicians are not routinely prescribing these medications for alcohol treatment. This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking. These issues are framed from the perspective of the various stakeholders involved, including clinicians, patients, regulatory agencies, the pharmaceutical industry, and third-party payers. Addressing these issues will not only help to improve treatment but, as further described, will also open up many new research opportunities for alcohol investigators in the coming decade. (Litten RZ, Falk D, Ryan M, Fertig J. Alcohol Clin Exp Res. 2014 Jan;38(1):27-32).
Five-year healthcare utilization and costs among lower-risk drinkers following alcohol treatment
Significance: This study found that, following outpatient alcohol treatment, abstinent patients and low-risk drinkers had similar healthcare utilization and costs over a 5-year followup in a large, private, nonprofit integrated healthcare delivery system.
BACKGROUND: Lower-risk drinking is increasingly being examined as a treatment outcome for some patients following addiction treatment. However, few studies have examined the relationship between drinking status (lower-risk drinking in particular) and healthcare utilization and cost, which has important policy implications. METHODS: Participants were adults with alcohol dependence and/or abuse diagnoses who received outpatient alcohol and other drug treatment in a private, nonprofit integrated healthcare delivery system and had a follow-up interview 6 months after treatment entry (N = 995). Associations between past 30-day drinking status at 6 months (abstinence, lower-risk drinking defined as nonabstinence and no days of 5+ drinking, and heavy drinking defined as 1 or more days of 5+ drinking) and repeated measures of at least 1 emergency department (ED), inpatient or primary care visit, and their costs over 5 years were examined using mixed-effects models. We modeled an interaction between time and drinking status to examine trends in utilization and costs over time by drinking group. RESULTS: Heavy drinkers and lower-risk drinkers were not significantly different from the abstainers in their cost or utilization at time 0 (i.e., 6 months postintake). Heavy drinkers had increasing odds of inpatient (p < 0.01) and ED (p < 0.05) utilization over 5 years compared with abstainers. Lower-risk drinkers and abstainers did not significantly differ in their service use in any category over time. No differences were found in changes in primary care use among the 3 groups over time. The cost analyses paralleled the utilization results. Heavy drinkers had increasing ED (p < 0.05) and inpatient (p < 0.001) costs compared with the abstainers; primary care costs did not significantly differ. Lower-risk drinkers did not have significantly different medical costs compared with those who were abstinent over 5 years. However, post hoc analyses found lower-risk drinkers and heavy drinkers to not significantly differ in their ED use or costs over time. CONCLUSIONS: Performance measures for treatment settings that consider treatment outcomes may need to take into account both abstinence and reduction to nonheavy drinking. Future research should examine whether results are replicated in harm reduction treatment, or whether such outcomes are found only in abstinence-based treatment. (Kline-Simon AH, Weisner CM, Parthasarathy S, Falk DE, Litten RZ, Mertens JR. Alcohol Clin Exp Res. 2014 Feb;38(2):579-86).
Alcohol medications development: advantages and caveats of government/academia collaborating with the pharmaceutical industry
Significance: This commentary examines how the medication development process can be expedited via collaborations between government, academia, and pharmaceutical and biotechnology companies.
The process of developing pharmacological treatments for alcohol use disorder is notoriously complex and challenging. The path to market is long, costly, and inefficient. One way of expediting and reducing the drug development process is through collaborations-building partnerships among government, academia, pharmaceutical and biotechnology companies, healthcare organizations and advocacy groups, and the patients (end consumers) themselves. By forging collaborations, particularly with pharmaceutical companies, the alcohol treatment field stands to reap benefits in generating new medications for use in mainstream treatment settings. At the same time, there are certain caveats that should be considered, particularly by academic researchers, before entering into such partnerships. This commentary examines the advantages and caveats of government and academia collaborations with pharmaceutical companies. (Litten RZ, Ryan M, Falk D, Fertig J. Alcohol Clin Exp Res. 2014 May;38(5):1196-9).