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NIAAA Director's Report on Institute Activities to the 133rd Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism
Table of Contents
Advancing Treatment for Alcohol Dependence
Earlier in June, we announced an exciting research finding in the treatment field -- varenicline, a smoking-cessation drug marketed under the brand name Chantix, has shown promise as a viable treatment option for alcohol dependence in a large-scale trial. Varenicline’s effects were comparable to those seen in studies of naltrexone and acamprosate, two of the medications already approved by the U.S. Food and Drug Administration for the treatment of alcohol dependence.
With nearly 18 million people in the United States with an alcohol use disorder and an annual total economic cost of $224 billion, there is a clear need for more interventions to treat alcohol use disorders. At NIAAA, we are striving to expand and improve treatment options for people with alcohol dependence and to make more people aware of the options that are currently available.
As part of these efforts, NIAAA founded the Clinical Investigations Group (NCIG) in 2007 to test the safety and effectiveness of promising drugs and to bridge the gap between preclinical studies and Phase III clinical trials involving larger groups of participants. In addition to the recent varenicline trial, NCIG has examined two other pharmaceuticals: Quetiapine, a drug used in treating psychiatric disorders, and levetiracetam XR (Keppra XR®), an antiseizure drug.
In addition to pharmaceutical approaches, NIAAA continues to investigate an array of behavioral treatment options including cognitive behavioral therapy, brief interventions, and motivational enhancement therapy. There is no single treatment approach that works for all people in all situations. Treatment response is highly individual and ultimately, choosing to get treatment may be more important than the approach used. It is vital that we convey the message that there are a variety of treatment options in multiple settings.
The more we learn about helping people who struggle with alcohol use disorders, the more we recognize that individually tailored treatments hold great promise. You have likely heard about the advances in personalized medicine for treating cancer and other diseases; there is clear applicability for a personalized approach to treating alcohol dependence as well. Through our research, we continue to examine what factors (including genetics) predict a person’s response to treatment, with the end goal of being able to match an individual to a treatment approach based on their unique characteristics.
We continue to make strides in expanding our repertoire of effective treatment strategies for alcohol use disorders, as well as developing easy-to-use screening tools for clinicians to identify those in need of treatment. The ultimate goal of our efforts is to ensure that those who need treatment get it and that they get the most effective treatment available for them.
Ken R. Warren
The NIAAA received a budget allocation of $433.0 million that reflects a $26.1 million decrease from the FY 2012 Enacted level under the Consolidated and Further Continuing Appropriations Act, 2013 (P.L. 113-6), signed by President Obama on March 26, 2013, and the sequestration provisions of the Balanced Budget and Emergency Deficit Control Act, as amended, 2 U.S.C. § 901a for FY 2013. The Type 5 awards will be issued at 93% of the FY 2013 commitment level (including RPGs, SBIRs/STTRs, Centers, Ks and Other Research Grants). This policy does not apply to projects supported by Ruth L. Kirschstein-National Research Service Award (NRSA) Individual Fellowships & Institutional Training Grants. All legislative mandates that were in effect in FY 2012 remain in effect in FY 2013, including the salary limitation set at Executive Level II of the Federal Pay Scale ($179,700), which was effective with grant awards with an initial Issue Date on or after December 23, 2011.
President Obama submitted to Congress the FY 2014 budget request on April 10, 2013 for all Federal agencies. The FY 2014 NIAAA budget request of $463.8 million reflects an increase of $5.2 million from the FY 2012 Actual of $458.7 million.
Update on Functional Integration (Collaborative Research on Addiction at NIH)
Much has happened in the months since it was announced that NIH would support a functional integration of substance use, abuse, and addiction-related research. First, a change in terminology – our collaborative efforts will no longer be referred to as a “functional integration” but rather by the acronym CRAN for Collaborative Research on Addiction at NIH or CRAN.
The Steering Committee has planned three RFAs for FY 2014. They are: Administrative Supplements to Promote Collaborative Research on Addiction at NIH (CRAN): Comorbidity-Related Research; Competitive Revision Applications to Promote Functional Integration for Collaborative Research on Addiction at NIH (CRAN); and Using Social Media to Understand and Address Substance Use and Addiction (both R01 and R21 announcements).
We are also in the process of developing a website that will list FOAs, resources, relevant advances in the field, etc., with a target launch date of September 2013. This site will be modeled after the Neuroscience Blueprint site as well as those of other NIH-collaborative ventures. Lastly, NIAAA and NIDA have scheduled their first joint Council meeting for February 5, 2014 in Wilson Hall.
BUDGET FOR THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM (DOLLARS IN THOUSANDS)
Kenneth Warren, Ph.D., Calendar of Activities
February 2013 – June 2013
|Title of Activity||Date||Director’s Role|
3rd International Conference on Applications of Neuroimaging to Alcoholism (ICANA-3)
ICANA-3 and Center Directors Meeting
|February 16, 2013||Speaker|
|IOM Forum on Neuroscience and Nervous System Disorders Workshop: Accelerating Therapeutic Development for Nervous System Disorders towards First-in-Human Trials||
March 5, 2013;
April 8-9, 2013
|Site Visit to NIH-funded PASS (Prenatal Alcohol and SIDS and Stillbirth) project and presentation to staff and faculty titled, “FASD: Past, Present and Future” Stellenbosch University, Cape Town, South Africa||April 10-12, 2013||Speaker|
Training Workshop on Fetal Alcohol Spectrum Disorders (FASD) and Planning Meeting for Implementing the International Collaborative Research Project on Child Development and Prenatal Risk Factors with a Focus on FASD in the African Region, Windhoek, Namibia
|April 15-19, 2013||Speaker|
|Presentation to University of Namibia School of Medicine faculty and students on history of and opportunities in alcohol and FASD research, Windhoek, Namibia||April 17, 2013||Speaker|
|NIAAA Alcohol Research Center Directors Summit Meeting||April 29-30, 2013||Speaker|
|PASS (Prenatal Alcohol in SIDS and Stillbirth) Network Steering Committee||May 2-3, 2013||Participant|
|Jack Mendelson, M.D., Honorary Lecture||May 21, 2013||Host|
3rd International SAF France Symposium
Fetal Alcohol Spectrum Disorder (FASD): Prevention, Diagnosis and Intervention
|May 29-31, 2013||Speaker|
|NIAAA National Advisory Council||June 13, 2013||Chair|
|36th Annual Research Society on Alcoholism (RSA) Scientific Meeting||June 22-26, 2013||Speaker|
In April 2013, Dr. Beverly Ruffin joined NIAAA and Division of Epidemiology and Prevention Research (DEPR) as a Health Scientist Administrator. Dr. Ruffin recently completed her Ph.D. in Social Welfare at Florida International University, and her dissertation was titled “The Longitudinal Influence of Physical Activity on Adolescent Alcohol Use.” Her research interests include health promotion and disease prevention, social determinants of health, and community-based participatory research involving at-risk and underserved communities.
In 2012, Dr. Ruffin completed the National Institutes of Health’s Ruth L. Kirschstein National Research Service Pre-Doctoral Fellowship. She has co-authored publications dealing with alcohol use among Latinos and the relationship of pubertal stage, age, and drinking in adolescent boys and girls. Dr. Ruffin will be administering grants in the following areas: 1) Pre-college underage drinking and 2) Outlets, neighborhoods, and contexts of drinking.
Dr. Brett Hagman has joined the Division of Treatment and Recovery Research (DTRR) staff. Prior to joining NIAAA, Dr. Hagman was a Research Assistant Professor in the Department of Mental Health Law and Policy at the University of South Florida (USF). Dr. Hagman was also a post-doctoral fellow at the Center of Alcohol Studies (CAS) at Rutgers-The State University of New Jersey in which he was recipient of a National Research Service Award fellowship from the National Institute on Alcohol Abuse and Alcoholism to pursue advanced research training in alcohol use treatment outcome protocols. He received his doctorate in Public Health from a joint program at Rutgers, the State University of New Jersey and the University of Medicine and Dentistry of New Jersey (UMDNJ).
He received his masters’ degree in Clinical Psychology (program track: Substance Abuse Treatment in Psychology) from the University of North Carolina-Wilmington. Dr. Hagman’s research focuses on the assessment and measurement of alcohol use and related negative consequences in emerging adults. An additional area of inquiry includes identifying the active ingredients (i.e., Mechanisms of Behavior Change) that underlie how psychosocial treatments for individuals with alcohol problems actually work. At present, Dr. Hagman has authored or co-authored numerous articles in top-tiered addiction journals. He has also secured extramural funding as PI or Co-PI on several state and federal grants/contracts.
Mr. Macy McRae, III, recently joined NIAAA as a Senior Administrative Officer. He previously worked as an Administrative Officer at the National Institutes of Mental Health (NIMH) for 4 ½ years and has been at NIH for 11 years in total.
Ms. Julie Simonds was appointed Extramural Support Assistant and joined DTRR in July 2012. She comes to NIAAA from the Department of Treasury and worked for the Internal Revenue Service. She will be supporting the Division of Treatment and Recovery Research within NIAAA.
Dr. Beata Buzas, Scientific Review Officer (SRO) - NIAAA Conference Grant Liaison Officer in the Extramural Project Review Branch/Office of Extramural Activities (EPRB/OEA) received the 2012 NIH Director’s Award as part of the RPC Scientific Review Officer Technical Competencies Team; and Dr. Richard Rippe, SRO-NIAAA Referral Officer (EPRB/OEA) received the 2013 NIH Director’s Award as part of the Enhancing Peer Review Survey Consultant Group.
The NIH Directors Awards were given to Dr. Buzas and Dr. Rippe in recognition of exceptional vision, teamwork, and collaboration in identifying Scientific Review Officer Core Technical Competencies, and enhancing Peer Review Survey Consultants’ evaluations, respectively.
Dr. Marcia Scott received a 2012 NCI Director’s Merit Award for outstanding coordination, leadership and dedication to success of the NIH Genes Environment and Health Initiative (GEI), as a member of the GEI Exposure Biology Program (EBP) Subcommittee and as project scientist for the GEI Exposure Biology Network on Exposures to Psychosocial Stress and Addictive Substances (NEPSAS).
Dr. Steve Vogel, Senior Investigator, Chief, Section on Cellular Biophotonics, Division of Intramural Clinical and Biological Research, recently received tenure by unanimous vote of the NIH Central Tenure Committee (CTC).
Dr. Bob Freeman is the NIAAA contact on the reissued PA 13-191/2 (R01/R21): “Structural Interventions, Alcohol Use, and Risk of HIV/AIDS,” published on April 11, 2013. This FOA encourages R01 research grant applications from institutions/organizations that propose to investigate the effectiveness of structural interventions aimed at reducing the risk of HIV/AIDS transmission by changing the environment of alcohol use.
Dr. P.J. Brooks is the NIAAA contact on PA-13-197 (R21): “The Role of Extracellular RNA in Mediating the Health Effects of Alcohol,” published on April 15, 2013. The purpose of this FOA is to provide support for innovative research into the role of extracellular RNA (exRNA) in the development of alcohol-related diseases and end-organ injuries.
Program Announcements PA-13-193 (R21) and PA-13-194 (R01) “Mechanisms of Alcohol and Nicotine Co-Addiction” were reissued to promote research to study neurobiological and behavioral mechanisms of dependence and how alcohol and nicotine use interact through these mechanisms to promote dependence. Dr. Ivana Grakalic is the program contact.
NIAAA is participating in initiatives PAR-13-134, 135 (X01, R03): “High Throughput Screening (HTS) to Discover Chemical Probes.” These Funding Opportunity Announcements (FOA) aim to promote and support discovery and development of new chemical probes as research tools for use by the research community to advance the understanding of biological functions and disease mechanisms. The FOAs will encourage partnership between assay submitters and a funded High Throughput Screening (HTS)/chemical probe discovery facility to conduct the joint research.
Dr. Kendall Bryant is the NIAAA contact on RFA-AA-13-003 (R01) and RFA-AA-13-004 (R21): “Research on Comparative Effectiveness and Implementation of HIV/AIDS and Alcohol Interventions.” The purpose of this solicitation is to encourage research on 1) on comparative effectiveness research focused on understanding factors related to patient engagement in appropriate alcohol and HIV care and retention in treatment; and 2) modeling and testing alternative approaches to the implementation of effective interventions to reduce HIV disease transmission and progression among users of alcohol, abused substances and tobacco. NIDA is a participating institute in this RFA.
New Multi-Media Products
NIAAA Graduation Fact Sheet – As part of its Seasonal Outreach Series, NIAAA recently distributed its fact sheet, Parents: Help Your Teens Party Right at Graduation, via PR Newswire. Seasonal fact sheets contain relevant statistics, practical science-based commentary, and NIAAA website information. The graduation fact sheet focuses on the adolescent brain and the physiological effects of excessive drinking. It also discusses alcohol poisoning and provides a link to the NIAAA college website. While complete results are still being calculated, to date the release has been picked up by more than 600 news outlets, including Yahoo!, The Boston Globe, The Sacramento Bee, and The Miami Herald. Numerous online, television, and radio sites also linked to the information, for a combined potential audience of approximately 60,000,000.
Graduation and Summer Safety Billboard Partnership Project – In addition to the fact sheet distribution, NIAAA has partnered with the Prevention Works in Somerset County Coalition/Somerset County Local Management Board (SCLMB) in Maryland to develop and launch a digital highway billboard to remind parents and teens of the risks of underage drinking after graduation. At the partner’s request, the billboard includes a number to the Maryland State Police to report incidents of underage drinking.
NIAAA/Somerset County (MD) Prevention Coalition Graduation Billboard
Following the graduation project, NIAAA will continue its work with SCLMB, and with other local coalitions in the mid-Atlantic region, to design billboards related to risky drinking in the summer months. In these co-branded arrangements, NIAAA typically provides message content and graphics, and the local partner pays the placement costs. For 2013, NIAAA will supplement these partnership placements with additional low-cost outdoor messaging (with links to appropriate NIAAA products) in mid-Atlantic shore communities during June and July. Last year, web traffic to these resources increased significantly while the messages were on display.
Alcohol Alert, No. 85 (“The Link Between Stress and Alcohol”) was posted on the NIAAA Web site in May and printed copies are now available: http://pubs.niaaa.nih.gov/publications/AA85/AA85.htm
A new fact sheet, “Alcohol Overdose: The Dangers of Drinking Too Much,” was posted online in February: http://pubs.niaaa.nih.gov/publications/AlcoholOverdoseFactsheet/Overdosefact.htm
In the Production Pipeline (noteworthy publications currently underway)
A full revision of the popular pamphlet, Harmful Interactions: Mixing Alcohol With Medicines, is underway. The text and layout were revised and currently are under review by NIAAA Program Staff.
A series of spin-off fact sheets spotlighting information from the brochure Beyond Hangovers is underway. Those fact sheets include an Overview and individual sheets featuring information on the Liver, Heart, Brain, Pancreas, Immune System, and Cancer.
Three issues of Alcohol Research: Current Reviews are underway. Topics include “Translating Research into Practice,” “The Use of Animal Models in Translational Research,” and “Defining Special Populations for Alcohol Use and Its Consequences.”
NIAAA is also updating the underage drinking prevention poster for kids. The posters show a vending machine featuring all the cool things kids could be doing instead of drinking alcohol.
The Clinician’s Guide is being revised to ensure it adheres to the new DSM criteria. Other revisions include updating the references and all statistics.
Noteworthy Multi-Media Statistics
As of April, there were 15,656 subscribers to the Alcohol Alert; 15,354 to Alcohol Research: Current Reviews; 11,892 to the NIAAA Newsletter; 10,247 to receive general information; and 9,806 to the Spectrum.
The RethinkingDrinking.com Web site recently crossed the 1 million visitor mark. The site has seen an increase in traffic this year, with an average of 1,000 visitors daily -- up from 600 visitors this time last year.
Anti-smoking medication shows promise for treating alcohol dependence (June 3, 2013)
A smoking-cessation medication may be a viable option for the treatment of alcohol dependence, according to a recent study. The study found that varenicline (marketed under the name Chantix), approved in 2006 to help people stop smoking, significantly reduced alcohol consumption and craving among people who are alcohol-dependent. The findings were published online in the Journal of Addiction Medicine.
Brain patterns may help predict relapse risk for alcoholism (May 1, 2013)
New research shows that distinct patterns of brain activity are linked to greater rates of relapse among alcohol dependent patients in early recovery. This research may give clues about which people in recovery from alcoholism are most likely to return to drinking.
NIH researchers identify pathway that may protect against cocaine addiction (April 15, 2013)
A new study gives insight into changes in the reward circuitry of the brain that may provide resistance against cocaine addiction. Scientists found that strengthening signaling along a neural pathway that runs through the nucleus accumbens – a region of the brain involved in motivation, pleasure, and addiction – can reduce cocaine-seeking behavior in mice.
NIAAA Recognizes Alcohol Awareness Month (April 1, 2013)
April was Alcohol Awareness Month — a time to raise awareness about the health and social problems caused by excessive drinking. Alcohol Awareness Month also offers people the opportunity to evaluate their own drinking and determine if they need to change their habits.
NIH develops improved mouse model of alcoholic liver disease (February 28, 2013)
Scientists may be better able to study how heavy drinking damages the liver using a new mouse model of alcohol drinking and disease developed by NIAAA researchers. The model incorporates chronic and binge drinking patterns to more closely approximate alcoholic liver disease in humans than any existing method. A report of the new model appears in the March issue of the journal Nature Protocols.
Scientists identify molecular events that underlie FASD (February 20, 2013)
Scientists have identified a molecular signaling pathway that plays an important role in the development of fetal alcohol spectrum disorders (FASD). The new research in cells and mice points to candidate genes for FASD susceptibility and may open new avenues for developing drugs to prevent alcohol damage to the fetal brain. A report of the study is online in the journal Proceedings of the National Academy of Sciences.
NIAAA honors nonprofit leader with Senator Harold Hughes Memorial Award (February 7, 2013)
Marianne “Mimi” Fleury, president and co-founder of the Community of Concern of North Bethesda, Md., received the Senator Harold Hughes Memorial Award from NIAAA. NIAAA Acting Director Kenneth R. Warren, Ph.D., announced her selection during the 132nd meeting of the National Advisory Council on Alcohol Abuse and Alcoholism.
Recent News Media Interviews
Dr. Greg Bloss, Economist, NIAAA Division of Epidemiology and Prevention Research, was interviewed by Brett Graff of the Miami Herald on the economic costs of alcohol abuse (3/11/13).
Dr. Rosalind Breslow, Program Officer, NIAAA Division of Epidemiology and Prevention Research, spoke with the following reporters on the topic of drinking and nutrition:
- Kerry Grens of Reuters Health (3/29/13)
- Kenny Thapoung of Women's Health magazine (4/11/13)
- Barbara Loecher of Diane, an online health magazine for women (5/6/13)
Dr. PJ Brooks, Program Officer, NIAAA Division of Metabolism and Health Effects, was interviewed by Jocelyn Fong of Scienceline.org, a project out of NYU’s science, health, and environmental reporting program. Dr. Brooks spoke about the flushing response to alcohol in East Asians (3/7/13). Dr. Brooks also spoke with:
- Tony Edwards, a freelance science writer in U.K., on the subject of alcohol and breast cancer (4/23/13).
- Ginny Graves of Health magazine, regarding alcohol and breast cancer (5/17/13).
Dr. Vivian Faden, Director of the NIAAA Office of Science Policy and Communications and Associate Director for Behavioral Research at NIAAA, was interviewed on college and underage drinking by Natalia Martinez Duncan of Coalitions, the newsletter of the Community Anti-Drug Coalitions of America (CADCA) (3/18/13).
Dr. Bin Gao, Acting Chief, NIAAA Laboratory of Liver Diseases, was interviewed by Marianne Hayes of the Metro newspaper (New York), on the NIAAA mouse model for alcoholic liver disease (3/1/13).
Dr. Markus Heilig, NIAAA Clinical Director, Chief of NIAAA Laboratory of Clinical and Translational Studies, discussed his work as an addiction scientist for a feature on Sveriges Television (SVT), Sweden’s national public service television company, Vetenskapens värld (The World of Science) program (3/12/13).
Dr. Joseph Hibbeln, Acting Chief of Section on Nutritional Neurochemistry, NIAAA Laboratory of Membrane Biochemistry and Biophysics, spoke with Ed Gray of Kikim Media, on the subject of omega-3 fatty acids (4/25/13).
Dr. Ralph Hingson, Director, Division of Epidemiology and Prevention Research, and Dr. Aaron White, Program Director, Underage and College Drinking Prevention Research, spoke with Matthew Carroll of the Boston Globe, regarding an increase in alcohol poisoning deaths in Massachusetts (3/13/13). Dr. Hingson also interviewed with:
- Max Glaskin of Vision Zero International, a vehicle safety magazine, about better ways of detecting of drivers impaired by alcohol to improve road safety (3/15/13).
- Michael Kranish of the Boston Globe, regarding lowering the legal limit for blood alcohol content (4/5/13).
- Alison Goldman of Women’s Health magazine, on the NTSB recommendation to lower legal BAC for drivers from 0.08 to 0.05 (5/21/13).
Dr. Robert Huebner, Director, NIAAA Division of Treatment and Recovery Research, spoke with Deborah Brauser of Medscape Medical News, regarding USPSTF Alcohol Screening Recommendations (5/14/13).
Dr. Raye Litten, Associate Director, NIAAA Division of Treatment and Recovery Research, was interviewed by Susan Young of MIT Technology Review, regarding an alcoholism vaccine being developed in Chile (2/5/13). Dr. Litten also spoke with:
- Stephanie Martina Ott, Columbia journalism student, on the topic of alcohol relapse (3/7/13).
- Alison Knopf of Alcoholism & Drug Abuse Weekly on the topic of alcoholism treatment “failure” (5/22/13).
Dr. Gary Murray, Acting Director, NIAAA Division of Metabolism and Health Effects, interviewed with Kevin Rector of the Baltimore Sun, regarding interpreting BAC levels (4/4/2013). He also spoke with:
- Emily Nelson of the Medill News Network, on the impact of alcohol on the aging population (4/18/13).
Dr. Christopher Ramsden, Clinical Investigator, NIAAA Laboratory of Membrane Biochemistry and Biophysics, was interviewed by Time magazine reporter Alice Park on his omega-6 fatty acid paper in BMJ (2/5/13). He was also interviewed on the same topic by the following reporters:
- Alan Mozes of HealthDay (2/5/13)
- Charlotte LoBuono of The Doctor Will See You Now (2/5/13)
- Jaimie Dalessio of Everyday Health (2/5/13)
- Kathleen Dohenney of WebMD (2/5/13)
- Marijka Hurko, Producer, CBC TV News (Toronto) (2/5/13)
- Gretchen Reynolds of New York Times magazine (2/7/13)
- Lesley Ciarula Taylor of The Toronto Star (2/7/13)
- Lars Dahlager of Politiken (Danish newspaper) (2/7/13)
- Ginny Robards of Super Human Radio (2/8/13)
Dr. Deidra Roach, Program Officer, Division of Treatment and Recovery Research, interviewed with Gretchen Voss of Cosmopolitan magazine for an article on women and drinking (3/11/13).
Dr. Richard Veech, Chief, NIAAA Laboratory of Metabolic Control, interviewed with Lorie Johnson, a medical reporter with the Christian Broadcasting Network (CBN News), on the use of ketone esters for the treatment of Alzheimer’s disease (4/30/13).
Dr. Aaron White, NIAAA Division of Epidemiology and Prevention Research, spoke with Elizabeth Foy Larsen of Scholastic Choices magazine (distributed in schools across the United States), on the topic of alcohol poisoning in middle and high school students (5/17/13). Dr. White also spoke with:
Fran Kritz of TakePart.com (website aimed at millenials) on the topic of college and underage drinking (5/20/13).
NOTABLE NIAAA STAFF ACTIVITIES (ARRANGED BY DATE)
Dr. Marcia Scott was the Planning Committee Chair for the workshop titled Challenges and Opportunities in GxE Research: Creating Consensus Recommendations for Guidelines on GxE Research. This workshop convened in January 2013 at NIAAA. Along with NIAAA grantees Danielle Dick and Kenneth Sher, Drs. Dionne Godette and Mariela Shirley were Planning Committee Members. The overall purpose of this workshop was to identify recommended best practices that can inform the formulation guidelines for conducting gene-environment interaction (GxE) studies.
On January 8, 2013, Dr. Ralph Hingson presented with Dr. Elizabeth Robertson, Senior Advisor for Prevention Research at the National Institute on Drug Abuse, about “The Future of Substance Abuse and Addiction (SUAA) Prevention Research” at the National Institutes of Health (NIH) Prevention Research Coordinating Committee (PRCC) Meeting in Rockville, MD. The purpose of the talk was to increase understanding of SUAA prevention research at NIH.
On February 5, 2013, Dr. Ralph Hingson presented his talk “New Research Since the Surgeon General’s Call to Action to Prevent and Reduce Underage Drinking” at the Community Anti-Drug Coalitions of America’s (CADCA) 23rd National Leadership Forum. This presentation outlined new research on trends in and consequences of underage drinking and interventions to prevent and reduce underage drinking that have emerged since the Surgeon General’s 2007 Call to Action. The presentation also discussed how CADCA coalitions can use this information to address this important public health issue.
On February 20-21, 2013, Dr. Judy Arroyo conducted outreach at the first annual region conference of Hispanic Serving Institutions (HSIs) in Anaheim California. In addition to presenting the group with funding and training opportunities at NIAAA, Dr. Arroyo also previewed the upcoming Common Fund Initiative to Enhance the Diversity of the Biomedical Workforce (see http://commonfund.nih.gov/diversity) for more information on these infrastructure and mentoring activities.
On February 26, 2013, Dr. Robert Freeman presented his webinar “Understanding and Preventing Alcohol-Related Violence in Adolescent Dating Couples,” sponsored by the Family Violence Prevention and Services Program of the Administration on Children, Youth and Families, in partnership with the National Resource Center on Domestic Violence and the Federal Interagency Workgroup on Teen Dating Violence. This webinar also featured NIAAA grantee Dr. Emily Rothman. In 2009, NIAAA partnered with NIDA and NICHD to produce a PA calling for research in teen dating violence (PA-09-169), and Dr. Rothman was the first recipient of a NIAAA grant under that announcement. Dr. Freeman’s presentation gave a brief overview of the topic.
Dr. Raye Litten presented “Pharmacotherapy of Alcohol Dependence: New Findings,” at the NIDA Clinical Trials Network (CTN) Meeting in Bethesda, Maryland, in March 2013.
On March 7, 2013, Drs. Ken Warren, Vivian Faden and Aaron White presented a webinar as part of the ICCPUD series of underage drinking webinars, titled “Brain Research and Underage Screening – Getting Informed, Preparing to Act.” Dr. Ken Warren provided a brief introduction to the problem of underage drinking, while Dr. Aaron White discussed alcohol’s effects on the developing brain and presented information on the prevalence and biology of blackouts and alcohol poisoning. Dr. Vivian Faden discussed the contextual factors surrounding youth drinking and the importance of screening youth for alcohol use, risk for use, and alcohol-related problems.
On March 13, 2013, Dr. Lynn Morin organized the third lecture in the seminar series “Addressing Health Disparities through Neuroscience: Views by Two,” a collaboration with NIDA, NICHD, NIMH and NINDS. NIAAA provided support for two speakers who address the degree to which evidence-based practices are generalizable to health disparities populations. Dr. Guillermo Bernal presented the NIH neuroscience community with an overview of cultural adaptations of evidenced-based treatments. Dr. Patricia Molina, who is a NIAAA Council member, presented a specific example of her work translating basic science derived knowledge to the clinical setting impacting chronic alcohol and HIV disease progression.
In April 2013, Dr. Mariela Shirley participated in the conference Advancing Transdisciplinary Translation for Prevention of High-Risk Behaviors: Critical Thinking to Overcome Individual and Institutional Barriers Conference in Washington, DC. The purpose of these meetings was to establish priorities, an infrastructure, and research agenda for developing a large-scale transdisciplinary and translational program of research to inform prevention of risk behaviors such as drug abuse and addiction, gambling, and aggression.
On April 3, 2013, Dr. Ralph Hingson moderated a session at Alcohol Policy (AP) 16 in Washington, DC, called “Enforcing Impaired-Driving Prevention Policy: Easier Said than Done?” This session discussed ways to improve road safety through impaired driving prevention.
Dr. Changhai Cui of the Division of Neuroscience and Behavior (DNB) co-chaired with Dr. Fulton Crews a symposium on “Neuroimmune Activation by Alcohol, Drugs and/or AIDS Contributes to Addiction Neurobiology” at the annual conference of the Society on NeuroImmune Pharmacology, April 3-6, 2013, San Juan, PR. This symposium highlighted latest research advances on the implication of neuroimmune activation as a key element of alcohol and drug dependence. Dr. Cui gave introductory remarks to the symposium. Speakers include Drs. Fulton Crews, Dipak Sarkar, Adron Harris, Mark Hutchinson, and Sietse Jonkman. Dr. Cui was also a panelist for the Think Tank Discussion held at the same conference.
Dr. Dale Hereld of the Division of Metabolism and Health Effects gave a presentation to agency representatives and members of the public at the April 4, 2013, meeting of the Interagency Coordinating Committee on Fetal Alcohol Spectrum Disorders (ICCFASD), providing an overview of NIAAA's FASD grant portfolio and related activities.
Dr. P.J. Brooks of the Division of Metabolism and Health Effects presented “Cancer-related research interests of the National Institute on Alcohol Abuse and Alcoholism (NIAAA)” at the American Association for Cancer Research (AACR) meeting on April 9, 2013, in Washington DC.
Dr. Antonio Noronha co-organized and co-chaired a translational symposium with Dr. Mason entitled “Alcohol: Potential Treatments” at the 4th Meeting of the International Drug Abuse Research Society meeting on Recent Advances in Drug Addiction, April 15-19 in Mexico City, Mexico. His introductory presentation highlighted some of NIAAA’s basic and clinical efforts at developing effective medications for the treatment of alcoholism.
On April 17, 2013, Dr. Ralph Hingson presented his talk “Rethinking Drinking” to the Pan American Health Organization (PAHO) in Washington, DC. This presentation was part of a panel in observance of Alcohol Awareness Month in the United States. The panel also promoted collaboration among its international membership to promote a higher level of awareness about alcohol-related problems and aimed to expand and improve knowledge of these concerns within all PAHO program areas.
The Division of Treatment and Recovery Research led in sponsoring and organizing a two-part symposium, “AA and Twelve-Step Recovery: New Findings for the Clinician,” at the American Society of Addiction Medicine (ASAM) Medical and Scientific Conference held in Chicago in April. Organizers included Dr. Bob Huebner, Dr. Marc Galanter, and Dr. Joan Zweben, who presented along with four other outstanding researchers. The symposium was not only well-attended but highly interactive. The sessions discussed and debated numerous issues including: effectiveness and how well it is documented; challenges (such as accessibility to data collection, as well as integration into more traditional patient care) arising from some groups’ governing principles indicating that they do not affiliate with outside organizations or professionals; and how physicians/therapists can best help patients find appropriate groups to maximize potential effectiveness, especially for adolescent and dually-diagnosed patients.
Dr. Mariela Shirley was the Lead for the Planning Committee for the workshop titled Building the Next Generation of Integrative Approaches for Understanding Comorbid Alcohol, Drug Abuse, and Attention Disorders. This workshop was in May 2013 and was a joint NIAAA and NIDA workshop. NIDA colleagues Karen Sirocco and Cheryl Boyce served on the Planning Committee. Other committee members at NIAAA were Drs. Dionne Godette and Marcia Scott. The overall purpose of this workshop is to engage major researchers in discussions with a goal toward developing novel approaches to understanding, preventing, and treating comorbid attention and substance use disorders.
Dr. Gary Murray of the Division of Metabolism and Health Effects represented the NIAAA at the National Primate Research Centers Roundtable on May 1, 2013, in Bethesda, MD.
Dr. Roz Breslow served as a judge for the University of Maryland annual Nutrition and Food Science Graduate Student Poster Competition at the National Agriculture Library in Beltsville, MD, on May 3, 2013. She also provided dietary counseling to consumers at the National Nutrition Month and National Registered Dietitian Day at NIH’s Natcher Auditorium on March 13, 2013.
Dr. P.J. Brooks presented “Alcohol and cancer: What do we know, what do we need to know and how can we find out” at the 2nd Alcohol and Cancer Conference in Breckenridge, CO, held May 11-15, 2013. Dr. Gary Murray also participated in the conference, which was organized and chaired by NIAAA researcher Dr. Vasilis Vasiliou. The conference was supported, in part, through an NIAAA R13 grant.
Dr. Antonio Noronha co-organized and co-chaired a symposium with Dr. Ponomarev on “Epigenetics of Brain Disorders” at the 15th Annual Meeting of the International Behavioral and Neural Genetics Society Meeting in Leuven, Belgium, held May 20-24, 2013. His introduction centered around the recent epigenetic findings on alcohol-related research and potential new compounds for treatment.
Drs. Ellen Witt, Dan Falk, and Robert Huebner organized a symposium on “Implicit Cognitions as Modifiable Targets in Behavioral Interventions” at the annual meeting of the Association of Psychological Science, May 25, 2013, Washington, D.C. This symposium presented research (both animal and human) on implicit cognitions and alcohol use disorders as well as anxiety-related disorders. The translation of findings from basic cognitive science to improving the efficacy of clinical interventions was discussed. Speakers include Henry Yin, Mark Fillmore, Bethany Teachman, and Reinout Weirs, with a discussion by Ken Sher.
Dr. Antonio Noronha presented at the session entitled “Plenary Session: NIH Open Forum with Leadership of NIMH, NIDA and NIAAA” at the 53rd Annual NCDEU Meeting held May 27-31 in Hollywood, Florida. Dr. Noronha’s presentation addressed NIAAA’s Preclinical Medications Development Program as well as NIAAA’s Clinical Investigation Group (NCIG) Program for Phase 2 Proof of Concept Clinical Trials.
On May 30, 2013, Dr. Marcia Scott participated in a roundtable discussion of “Domestic and International Strategies for Prevention Research On Young Adult High Risk Behaviors in Drinking Establishments,” at the Society for Prevention Research conference in San Francisco, CA. The panel addressed how to develop effective community partnerships to facilitate venue-based research and designing research that works in “real world” establishments.
Dr. Antonio Noronha was the keynote speaker at the Alcohol and Drug Abuse Center of Excellence (ADACE) at the LSU Health Sciences Center in New Orleans, LA, on May 31, 2013. His presentation entitled “Neuroscience & Behavioral Research at NIAAA: Research Priorities and Future Directions” also highlighted some of the themes and collaborative efforts that could be applied to questions regarding similarities and differences between alcohol use disorders (AUDs) and substance use disorders (SUDs), and other psychiatric disorders.
- Dr. Andras Orosz of the Division of Metabolism and Health Effects chaired and organized the inaugural symposium for the Proteostasis Scientific Interest Group “Proteostasis in Health and Disease,” on June 3, 2013. The symposium brought together national experts to address the health consequences of protein misfolding and aggregation that are known or suggested to be implicated in many devastating human disorders including neurodegenerative diseases, type 2 diabetes, cancer, alcoholic liver disease, cardiomyopathy, cystic fibrosis, cataract, prion disease, immune problems, metabolic deficiencies, aging and other chronic maladies.
NEW & UPCOMING PUBLICATIONS
Drs. Ken Warren, Peggy Murray, Ralph Hingson, Aaron White, PJ Brooks, and David Goldman have chapters in an upcoming book from Oxford University Press: Alcohol: Science, Policy, and Public Health. Lowenfels A., Boyle P. (Eds.).
Take Your Child to Work Day
NIH celebrated its 18th annual Take Your Child to Work Day on April 25. Through educational and fun activities, children ages 5-15 experienced the world of biomedical research at NIH. NIAAA hosted a number of hands-activities and demonstrations, coordinated by Jo-Ann Kriebel with assistance from Drs. Ivana Grakalic, Soundar Regunathan, and Matthew Reilly.
In Dr. Fumihito Ono’s Zebrafish lab, children got a hands-on look at how the small Zebrafish plays such a large role in alcohol research. Dr. Dennis Twombly of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) led the students through his popular “Drunken Brain” exhibit and slideshow. Dr. Andrea Barnes and DICBR staff led tours of the NIAAA animal care facility, and Diana Urbanas and Dr. Anita Bechtholt-Gompf led children through an obstacle course using the fatal vision goggles that simulate alcohol’s effects. Jo-Ann Kriebel and Greg Roa of OPSC led the popular “Cool Spot Carnival” activity, where children try to toss a football while wearing the goggles, and also get messages on peer pressure and other topics from the Cool Spot website for young teens. For younger siblings, Jessica Ryan hosted a fun and engaging activity about Earth Day.
New this year, renowned fruit fly researcher Dr. Ulrike Heberlein and her colleague, Dr. Galit Shohat-Ophir, led an interactive presentation that demonstrated how the fruit fly Drosophila can serve as a model organism to study the neural and molecular mechanisms underlying alcohol and drug abuse and addiction. Following her presentation, students were invited to do two hands-on experiments. In the first experiment, students made the fruit flies “drunk” by exposing them to alcohol vapors which resulted in impaired motor behavior. In the second, students observed fruit flies consuming alcohol in a special drinking apparatus.
Brain Awareness Week
NIH and the National Museum of Health and Medicine in Silver Spring, MD hosted the Museum’s 14th annual Brain Awareness Week on March 13 and 14. 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 14, NIAAA staff (Drs. Anita Bechthold-Gompf, Ivana Grakalic, Soundar Regunathan, and Diana Urbanas) 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.
On May 21, 2013, Dr. Bankole Johnson delivered the 2013 Jack Mendelson Honorary Lecture on “Personalizing the Treatment of Alcoholism.” Dr. Johnson is a pioneer in the development of medications to treat alcohol dependence. His research has transformed our understanding of how functional and structural abnormalities at the molecular level in the brain can promote addiction.
Johnson discovered that ondansetron, a serotonin antagonist often used to curb nausea and vomiting caused by chemotherapy, is particularly effective at helping early-onset alcoholics reduce their drinking. In another study, he determined that the anti-seizure drug topiramate can also help treat alcohol addiction.
A native of Nigeria, Johnson pursued his medical degree at the University of Glasgow in Scotland and trained in psychiatry at the Royal London, Maudsley and Bethlem Royal Hospitals in England. In 2004, he was named the Alumni professor and chairman of the department of psychiatry and neurobehavioral sciences at the University of Virginia, where he is also a professor in the department of neuroscience and the department of medicine.
NIAAA established the lecture series as a tribute to Dr. Jack Mendelson, who made remarkable contributions to the field of clinical alcohol research. Each spring, the series features a lecture by an outstanding alcohol investigator whose lifetime of clinical research has substantially advanced our understanding of alcohol susceptibility, alcohol’s effects on the brain and other organs and the prevention and treatment of alcohol use disorders.
The 36th annual Research Society on Alcoholism (RSA) scientific meeting will be held June 22-26, 2013, in Orlando, FL. Many NIAAA employees are expected to travel to the event to chair/participate in symposia or present posters.
- NIAAA will soon be releasing a guide to treatment for alcohol dependence for the public. The guide will include information about the evidence supporting different types of treatments and how to select a treatment that can work based on individual needs.
NIAAA RESEARCH HIGHLIGHTS (FEBRUARY 2013 – JUNE 2013)
Mouse model of chronic and binge ethanol feeding (the NIAAA model)
Scientists may be better able to study how heavy drinking damages the liver using a new mouse model of alcohol drinking and disease developed by researchers from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health. The model incorporates chronic and binge drinking patterns to more closely approximate alcoholic liver disease in humans than any existing method.
Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury is ad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4-6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-d ad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.
Chronic Plus Binge Ethanol Feeding Synergistically Induces Neutrophil Infiltration and Liver Injury in Mice: A Critical Role for E-selectin
The findings from this study help to explain how chronic plus binge ethanol feeding act in combination to induce liver injury in mice. The results suggest that chronic-binge ethanol feeding upregulates the expression of proinflammatory cytokines, followed by the induction of E-selectin, a protein involved in cell adhesion. Elevated E-selectin plays an important role in hepatic neutrophil infiltration and injury in mice induced by chronic-binge feeding, and may also be involved in the early stages of human alcoholic liver disease
We have previously demonstrated that chronic plus binge ethanol feeding acts synergistically to induce liver injury in mice; however, the mechanisms underlying this phenomenon remain unclear. In the current study, we show that chronic plus binge ethanol feeding synergistically upregulated the hepatic expression of IL-1β and TNF-α and induced neutrophil accumulation in the liver compared to chronic or binge feeding alone. The in vivo depletion of neutrophils through the administration of an anti-Ly6G antibody markedly reduced chronic-binge ethanol feeding-induced liver injury. Real-time PCR analyses revealed that hepatic E-selectin expression was upregulated 10-fold, whereas the expression of other neutrophil infiltration-related adhesion molecules (such as P-selectin, ICAM-1, and VCAM-1) was slightly upregulated or downregulated in this chronic-binge model. The genetic deletion of E-selectin prevented chronic-binge ethanol-induced hepatic neutrophil infiltration and the elevation of serum transaminases without affecting ethanol-induced steatosis. In addition, E-selectin-deficient mice showed reduced hepatic expression of several proinflammatory cytokines, chemokines, and adhesion molecules compared to wild-type mice after chronic-binge ethanol feeding. Finally, the expression of E-selectin was highly upregulated in human alcoholic fatty livers but not in alcoholic cirrhosis. Conclusions: Chronic-binge ethanol feeding upregulates the expression of proinflammatory cytokines, followed by the induction of E-selectin. Elevated E-selectin plays an important role in hepatic neutrophil infiltration and injury in mice induced by chronic-binge feeding, and may also contribute to the pathogenesis of early stages of human alcoholic liver disease. (Bertola A, Park O, Gao B. Hepatology. 2013 Mar 26 [Epub ahead of print])
A study by researchers at the National Institutes of Health gives insight into changes in the reward circuitry of the brain that may provide resistance against cocaine addiction. Scientists found that strengthening signaling along a neural pathway that runs through the nucleus accumbens – a region of the brain involved in motivation, pleasure, and addiction – can reduce cocaine-seeking behavior in mice.
A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals. (Bock R, Shin JH, Kaplan AR, Dobi A, Markey E, Kramer PF, Gremel CM, Christensen CH, Adrover MF, Alvarez VA. Nat Neurosci. 2013 May;16(5):632-8)
Voluntary movements involve the coordinated activation of two brain pathways that connect parts of deep brain structures called the basal ganglia, according to a new study in mice conducted by NIAAA researchers. The new findings challenge the classical view of basal ganglia function, which proposes that so-called direct and indirect pathways originating in a brain region called the striatum have opposing effects on movement. Newer models, however, suggest that co-activation of these pathways is necessary to synchronize basal ganglia circuits during movement. By improving understanding of how the basal ganglia control movements, these findings could aid in the development of treatments for disorders in which these circuits are disrupted, such as Parkinson’s disease, Huntington’s disease and addiction.
The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum--the so-called direct and indirect pathways--have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders. (Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM. Nature. 2013 Feb 14;494(7436):238-42)
Assessing drinking status in liver transplant patients with alcoholic liver disease
The article details several recently developed biochemical measures that can provide information about alcohol use in patients who are candidates for/recipients of liver transplants.
The accurate assessment of drinking by patients with alcoholic liver disease is important both before and after liver transplantation. Unfortunately, self-reports by these individuals often underestimate their actual alcohol consumption. Several recently developed biochemical measures can provide additional information on a patient's use of alcohol. This article describes ethyl glucuronide, ethyl sulfate, phosphatidyl ethanol, and carbohydrate-deficient transferrin as biomarkers of drinking and summarizes research dealing with their application in patients with alcohol use disorders who are candidates for or recipients of liver transplantation. The article also offers suggestions for enhancing the reliability of self-report measures of drinking status. (Allen JP, Wurst FM, Thon N, Litten RZ. Liver Transpl. 2013 Apr;19(4):369-76)
Resting-state synchrony in short-term versus long-term abstinent alcoholics
This finding suggests a possible compensatory mechanism of increasing synchrony of the executive control network and decreasing synchrony of the reward network that could develop over time with abstinence from alcohol to promote continued abstinence.
BACKGROUND: We previously reported that when compared with controls, long-term abstinent alcoholics (LTAA) have increased resting-state synchrony (RSS) of the inhibitory control network and reduced synchrony of the appetitive drive network, and hypothesized that these levels of synchrony are adaptive and support the behavioral changes required to maintain abstinence. In this study, we investigate whether these RSS patterns can be identified in short-term abstinent alcoholics (STAA). METHODS: Resting-state functional magnetic resonance imaging data were collected from 27 STAA, 23 LTAA, and 23 nonsubstance abusing controls (NSAC). We examined baseline RSS using seed-based measures. RESULTS: We found ordered RSS effects from NSAC to STAA and then to LTAA within both the appetitive drive and executive control networks: increasing RSS of the executive control network and decreasing RSS of the reward processing network. Finally, we found significant correlations between strength of RSS in these networks and (i) cognitive flexibility, and (ii) current antisocial behavior. CONCLUSIONS: Findings are consistent with an adaptive progression of RSS from short- to long-term abstinence, so that, compared with normal controls, the synchrony (i) within the reward network progressively decreases, and (ii) within the executive control network progressively increases. (Camchong J, Stenger VA, Fein G. Alcohol Clin Exp Res. 2013 May;37(5):794-803)
Heterogeneity in Growth and Desistance of Alcohol Use for Men in Their 20s: Prediction from Early Risk Factors and Association with Treatment
Findings from this study indicate that men raised in lower SES neighborhoods are likely to have a high chronic volume of alcohol use and moderate chronic alcohol problems but low or desisting engagement in heavy episodic drinking (HED) in their 20s. Desistance was more likely in men who had received treatment for alcohol use and, thus, who may have experienced relatively severe consequences of their drinking. Overall, the findings indicate the importance of examining heterogeneity of differential indicators of alcohol use in the 20s and the associations between risk factors and alcohol trajectory classes, to understand patterns of adult drinking behavior.
BACKGROUND: The course of men's alcohol use from ages 18 to 19 through 28 to 29 years was examined using growth mixture modeling (GMM) to determine alcohol trajectories for 3 conceptualizations of alcohol use: volume of use, heavy episodic drinking (HED), and drinking-related problems. Trajectory classes were validated against the young men's alcohol treatment history, and childhood/adolescent predictors of trajectory membership were examined. METHODS: Participants were 205 men from the Oregon Youth Study, an ongoing longitudinal study of predominantly White men recruited from higher crime neighborhoods who were assessed annually during their 20s. The multivariate association between 3 prospectively assessed risk factors-parental alcohol use, child antisocial behavior, and age at first drunken experience-and the latent classes extracted from the GMM were examined for each alcohol indicator. RESULTS: A 3-class-solution model best fit the data for each alcohol indicator. The classes for both HED and problematic drinking for the men were significantly associated with history of treatment for alcohol use. Overall, the findings indicated a relatively large class with persistently high volume of alcohol use across the 20s and a greater prevalence of desistance for HED and alcohol problems. Age at first intoxication was the best predictor of latent class membership, and men in the initially high-then-desisting alcohol classes had a high level of early risk. Concordance of trajectory class membership across alcohol indicators was moderate overall but particularly strong for higher problem groups, as almost all men in the increasing HED trajectory were also in the highest volume and alcohol problems trajectory classes. Levels of treatment were high for the higher and desisting HED and alcohol problems classes. CONCLUSIONS: Many of the men showed chronic alcohol use across the decade of the 20s and had problems resulting from their high usage. Whereas most of the men showed low and/or desisting HED across this period, desistance was less common for volume of use and for alcohol problems. (Capaldi DM, Feingold A, Kim HK, Yoerger K, Washburn IJ. Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1:E347-55)
Sulforaphane protects against ethanol-induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2-mediated antioxidant response
Neural crest cells (NCC) give rise to a variety of tissues during embryogenesis and their sensitivity to prenatal alcohol exposure is thought to contribute FASD. Generation of reactive oxygen species resulting from alcohol exposure has been implicated in the apoptotic death of NCC as well as neurons in the developing brain. This report demonstrates that sulforaphane, a compound present in cruciferous vegetables such as broccoli, confers protection of NCC against alcohol-induced apoptosis in vitro. Sulforaphane is known to activate Nrf2, a transcription factor which directs the expression of a host of antioxidant genes, including those encoding superoxide dismutase and catalase. Given the relative safety of this vegetable product and its demonstrated effectiveness in protecting NCC, sulforaphane has the potential to prevent or mitigate the effects of prenatal alcohol exposure.
Background and Purpose: Nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor that up-regulates a diverse array of antioxidant genes and protects cells from oxidative damage. This study is designed to determine whether D-L-sulforaphane (SFN) can protect neural crest cells (NCCs), an ethanol-sensitive cell population implicated in fetal alcohol spectrum disorders, against ethanol-induced apoptosis and whether protective effects of SFN are mediated by the induction of Nrf2-mediated antioxidant response. Experimental Approach: Control, SFN-treated or Nrf2-siRNA transfected NCCs were exposed to ethanol. Nrf2 activation, the expression and activities of Nrf2 downstream antioxidant proteins, reactive oxygen species generation and apoptosis were determined in control and ethanol-exposed NCCs. Key Results: Exposure of NCCs to SFN alone significantly increased Nrf2 activation and the expression of Nrf2 downstream antioxidants as well as the activities of the antioxidant enzymes. Treatment of NCCs with SFN along with ethanol significantly decreased ethanol-induced oxidative stress and apoptosis. In contrast, knockdown of Nrf2 by siRNA significantly increased the sensitivity of NCCs to ethanol-induced oxidative stress and apoptosis. Suppression of Nrf2 signalling in NCCs also significantly diminished SFN-mediated antioxidant response and abolished the protective effects of SFN on ethanol-induced oxidative stress and apoptosis. Conclusions and Implications: These results demonstrated that Nrf2-mediated antioxidant response plays an important role in the susceptibility of NCCs to ethanol-induced oxidative stress and apoptosis and that the protection of SFN against ethanol-induced oxidative stress and apoptosis in NCCs is mediated by the induction of Nrf2 signaling. (Chen X, Liu J, Chen SY. Br J Pharmacol. 2013 May;169(2):437-48)
Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule
Neural cell adhesion molecule L1 mediates neuronal migration and axon guidance during brain development and is thought to be an important target for ethanol's teratogenic effects. The current report demonstrates that this ethanol-sensitive disruption of L1-L1 interactions depends on phosphorylation of a specific serine residue, S1248, in the cytoplasmic domain of L1 by the kinase ERK2. ERK2 activity levels in embryos of two related mouse strains were shown be correlated with their sensitivity to ethanol's teratogenic effects. This indicates that intracellular phosphorylation of L1 by ERK2 renders interactions between L1 extracellular domains sensitive to ethanol. Thus, variations in ERK2 or other genes and conditions that influence its activity are likely to contribute to FASD pathogenesis.
There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity. (Dou X, Wilkemeyer MF, Menkari CE, Parnell SE, Sulik KK, Charness ME. Proc Natl Acad Sci USA. 2013 April 2;110(14):5683-8)
Sexual Orientation Differences in the Relationship Between Victimization and Hazardous Drinking Among Women in the National Alcohol Survey
The study found strong relationships between hazardous drinking and reports of childhood, adult, and lifetime victimization. Women who identified as lesbian or bisexual, and those who identified as heterosexual but reported same-sex partners, generally had higher odds of hazardous drinking, even when demographic characteristics, childhood victimization, and adult victimization were included in the multivariate model. Thus, it may be concluded that higher rates of victimization contribute to higher odds of hazardous drinking among sexual minority women but that there are likely additional factors, unmeasured in the current study, that mediate the relationship between sexual orientation and hazardous drinking.
This study examined relationships between past experiences of victimization (sexual abuse and physical abuse in childhood, sexual abuse and physical abuse in adulthood, and lifetime victimization) and hazardous drinking among sexual minority women compared to exclusively heterosexual women. Data were from 11,169 women responding to sexual identity and sexual behavior questions from three National Alcohol Survey waves: 2000 (n = 3,880), 2005 (n = 3,464), and 2010 (n = 3,825). A hazardous drinking index was constructed from five dichotomous variables (5+ drinking in the past year, drinking two or more drinks daily, drinking to intoxication in the past year, two or more lifetime dependence symptoms, and two or more lifetime drinking-related negative consequences). Exclusively heterosexual women were compared with three groups of sexual minority women: lesbian, bisexual, and women who identified as heterosexual but reported same-sex partners. Each of the sexual minority groups reported significantly higher rates of lifetime victimization (59.1% lesbians, 76% bisexuals, and 64.4% heterosexual women reporting same-sex partners) than exclusively heterosexual women (42.3%). Odds for hazardous drinking among sexual minority women were attenuated when measures of victimization were included in the regression models. Sexual minority groups had significantly higher odds of hazardous drinking, even after controlling for demographic and victimization variables: lesbian (ORadj = 2.0, CI = 1.1-3.9, p < .01; bisexual (ORadj = 1.8, CI = 1.0-3.3, p < .05; heterosexual with same-sex partners (ORadj = 2.7; CI = 1.7-4.3, p < .001). Higher rates of victimization likely contribute to, but do not fully explain, higher rates of hazardous drinking among sexual minority women. (Drabble L, Trocki KF, Hughes TL, Korcha RA, Lown AE. Psychol Addict Behav. 2013 Feb 25. [Epub ahead of print])
Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury
Hepatic Stellate Cells (HSC) are considered to be the main fibrogenic cell type in adult liver that, upon injury, trans-differentiate into myofibroblasts and express excessive amount of extracellular matrix proteins. In this study the authors examine the innovative hypothesis that mesothelial cells (MCs) could give rise to both HSCs and myofibroblasts following injury in the adult liver. Using isolated MCs from adult liver in vitro they demonstrate that these cells acquire mesenchymal cell phenotype through TGF signaling. In vivo conditional cell lineage tracing in Wt1CreERT2 mice revealed that MCs can give a rise to both HSC and myofibroblasts depending on the injury signals in liver. Understanding the mechanism of mesothelial-mesenchymal transitions may provide new therapeutic modalities to prevent or ameliorate the heavy burden of liver fibrosis of alcoholic patients and the subsequent development of cirrhosis and cancer.
In many organs, myofibroblasts play a major role in the scarring process in response to injury. In liver fibrogenesis, hepatic stellate cells (HSCs) are thought to transdifferentiate into myofibroblasts, but the origins of both HSCs and myofibroblasts remain elusive. In the developing liver, lung, and intestine, mesothelial cells (MCs) differentiate into specific mesenchymal cell types; however, the contribution of this differentiation to organ injury is unknown. In the present study, using mouse models, conditional cell lineage analysis has demonstrated that MCs expressing Wilms tumor 1 give rise to HSCs and myofibroblasts during liver fibrogenesis. Primary MCs, isolated from adult mouse liver using antibodies against glycoprotein M6a, undergo myofibroblastic transdifferentiation. Antagonism of TGF-β signaling suppresses transition of MCs to mesenchymal cells both in vitro and in vivo. These results indicate that MCs undergo mesothelial-mesenchymal transition and participate in liver injury via differentiation to HSCs and myofibroblasts. (Li Y, Wang J, Asahina K. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2324-9)
A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence
A smoking-cessation medication may be a viable option for the treatment of alcohol dependence, according to a study by scientists at the National Institutes of Health. The study found that varenicline (marketed under the name Chantix), approved in 2006 to help people stop smoking, significantly reduced alcohol consumption and craving among people who are alcohol-dependent.
OBJECTIVES: To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial α4β2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. METHODS: Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. RESULTS: The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. CONCLUSIONS: Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence. (Litten RZ, Ryan ML, Fertig JB, Falk DE, Johnson B, Dunn KE, Green AI, Pettinati HM, Ciraulo DA, Sarid-Segal O, Kampman K, Brunette MF, Strain EC, Tiouririne NA, Ransom J, Scott C, Stout R. J Addict Med. 2013 May 30. [Epub ahead of print])
Rescue of Infralimbic mGluR2 Deficit Restores Control Over Drug-Seeking Behavior in Alcohol Dependence
This study provides a detailed characterization of the role of the mGluR2 receptor in alcohol dependence using converging evidence from humans and rodents. Specifically, alcohol dependent rats showed a pronounced decrease in mGluR2 expression in the infralimbic cortex leading to enhanced ethanol consumption. This phenotype was rescued by viral-mediated mGluR2 delivery to the infralimbic cortex. Finally, human alcoholic brain showed decreased mGluR2 expression confirming the rodent results.
A key deficit in alcohol dependence is disrupted prefrontal function leading to excessive alcohol seeking, but the molecular events underlying the emergence of addictive responses remain unknown. Here we show by convergent transcriptome analysis that the pyramidal neurons of the infralimbic cortex are particularly vulnerable for the long-term effects of chronic intermittent ethanol intoxication. These neurons exhibit a pronounced deficit in metabotropic glutamate receptor subtype 2 (mGluR(2)). Also, alcohol-dependent rats do not respond to mGluR(2/3) agonist treatment with reducing extracellular glutamate levels in the nucleus accumbens. Together these data imply a loss of autoreceptor feedback control. Alcohol-dependent rats show escalation of ethanol seeking, which was abolished by restoring mGluR(2) expression in the infralimbic cortex via viral-mediated gene transfer. Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR(2) transcripts compared to control subjects, suggesting that mGluR(2) loss in the rodent and human corticoaccumbal neurocircuitry may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse. Normalization of mGluR(2) function within this brain circuit may be of therapeutic value. (Meinhardt MW, Hansson AC, Perreau-Lenz S, Bauder-Wenz C, Stählin O, Heilig M, Harper C, Drescher KU, Spanagel R, Sommer WH. J Neurosci. 2013 Feb 13;33(7):2794-806)
Risk for Exposure to Alcohol, Tobacco, and Other Drugs on the Route to and from School: The Role of Alcohol Outlets
As national campaigns are encouraging children to walk to school, it is essential to determine what children are exposed to on the route to school. Identifying these factors is especially important as the exposure is repeated daily for several months each year. Using logistic regression models, researchers estimated the association between the presence of alcohol outlets on the route to school, alcohol and drug exposure, and self-reported safety. Children with an alcohol outlet on the route to school were more likely to be offered alcohol, tobacco, and other drugs (ATOD), as well as be exposed to drug selling, and seeing people using drugs.
Despite the national push encouraging children to walk to school, little work has been done to examine what hazards children encounter on the route to school. This study examined the association between the presence of alcohol outlets on children's route to school and perceived safety on the route to school as well as exposure to alcohol, tobacco, and other drugs (ATOD). Data come from a community-based epidemiological study of 394 urban elementary school students. Participants' residential address, school location, and alcohol outlet data were geocoded and the route to school was mapped. The route to school layer and the geocoded alcohol outlet data were joined to determine the number of alcohol outlets children pass on the route to school. Logistic regression models estimated the association between the presence of alcohol outlets on the route to school, alcohol and drug exposure, and self-reported safety. Children with an alcohol outlet on the route to school were more likely to be offered ATOD (OR = 2.20, p = 0.02) as well as be exposed to drug selling (OR = 1.72, p = 0.02) and seeing people using drugs (OR = 1.93, p = 0.02). After adjusting for individual-level variables, the relationship between presence of alcohol outlets and being offered ATOD and seeing people using drugs remained significant. However, after adjusting for individual-level control variables and a proxy for the larger neighborhood context, the association between the presence of alcohol outlets and exposure to ATOD was no longer significant. As national campaigns are encouraging children to walk to school, it is essential to consider what children are exposed to on the route to school. (Milam AJ, Furr-Holden CD, Cooley-Strickland MC, Bradshaw CP, Leaf PJ. Prev Sci. 2013 Feb 14. [Epub ahead of print])
Aberrant Histone Deacetylase2-Mediated Histone Modifications and Synaptic Plasticity in the Amygdala Predisposes to Anxiety and Alcoholism
This study has important implications for tailoring specific epigenetic medications to treat alcoholism based on genetic make-up. It is the first to compare the role of histone deacetylase isoforms (HDACs) in the genetic predisposition to alcoholism in the P and NP selected rat lines. There was a higher HDAC activity in the alcohol-preferring (P) line as well as increased protein levels of HDAC2 in the amygdala compared to the alcohol-non preferring (NP) line. Further, the P line was more sensitive to changes in HDAC activity and protein levels after acute ethanol exposure compared to the NP line. Finally, genetic inhibition of HDAC2 in the P line resulted in reduced anxiety and drinking that was linked to changes in bdnf and arc expression.
BACKGROUND: Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown. METHODS: We measured amygdaloid HDAC activity, levels of HDAC isoforms, and histone H3 acetylation in selectively bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 small interfering RNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density. RESULTS: We found that P rats innately display higher nuclear HDAC activity and HDAC2 but not HDAC 1, 3, 4, 5, and 6 protein levels and lower acetylation of H3-K9 but not H3-K14, in the CeA and medial nucleus of amygdala compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (Bdnf and Arc)-specific histone acetylation, and attenuated anxiety-like behaviors in P rats but had no effects in NP rats. The HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol but not sucrose consumption in P rats and increased histone acetylation of Bdnf and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density. CONCLUSIONS: These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism. (Moonat S, Sakharkar AJ, Zhang H, Tang L, Pandey SC. Biol Psychiatry. 2013 Apr 15;73(8):763-73)
Nicotinic Acetylcholine Receptors are Sensors for Ethanol in Lung Fibroblasts
Chronic alcohol consumers often have an “alcoholic lung phenotype,” making them asymptomatic, yet highly susceptible to infection and to acute lung injury. Investigations focus on the nicotinic acetylcholine receptor as a possible sensor for alcohol, or for the oxidant stress induced by alcohol and demonstrate that although ethanol is not a ligand for the receptor, active nAch receptors are required for ethanol effects on lung fibroblasts, suggesting that nAChR signaling of the presence of ethanol occurs in a ligand independent fashion. Thus, nAChRs may serve as sensors for ethanol-induced oxidant stress.
BACKGROUND: Chronic ethanol (EtOH) abuse in humans is known to independently increase the incidence of and mortality due to acute lung injury in at-risk individuals. However, the mechanisms by which EtOH affects lung cells remain incompletely elucidated. In earlier work, we reported that EtOH increased the expression in lung fibroblasts of fibronectin, a matrix glycoprotein implicated in lung injury and repair. This effect was blocked by α-bungarotoxin, a neurotoxin that binds certain nicotinic acetylcholine receptors (nAChRs) thereby implicating nAChRs in this process. Here, we examine the identity of these receptors. METHODS: Mouse lung fibroblasts were stimulated with EtOH (60 mM) or acetylcholine (100 to 500 μM) and evaluated for the expression of fibronectin and nAChRs. Inhibitors to nAChRs or the antioxidant N-acetyl cysteine (NAC) were used to assess changes in fibronectin expression. Animals exposed to EtOH for up to 6 weeks were used to evaluate the expression of nAChRs in vivo. RESULTS: First, in EtOH-treated fibroblasts, we observed increased expression of α4 and α9 nAChR subunits. Second, we found that acetylcholine, a natural ligand for nAChRs, mimicked the effects of EtOH. Dihydro-β-erythroidin hydrobromide, a competitive inhibitor of α4 nAChR, blocked the increase in fibronectin expression and cell proliferation. Furthermore, EtOH-induced fibronectin expression was inhibited in cells silenced for α4 nAChR. However, EtOH-treated cells showed increased α-bungarotoxin binding suggesting that α4 nAChR mediates the effects of EtOH via a ligand-independent pathway. Knowing there are several important cysteine residues near the ligand-binding site of α4 nAChRs, we tested the antioxidant NAC and found that it too blocked the induction of fibronectin expression by EtOH. Also, fibroblasts exposed to oxidant stress showed increased fibronectin expression that was blocked with α-bungarotoxin. Finally, we showed increased expression of α4 nAChRs in the lung tissue of mice and rats exposed to EtOH suggesting a role for these receptors in vivo. CONCLUSIONS: Altogether, our observations suggest that α4 nAChRs serve as sensors for EtOH-induced oxidant stress in lung fibroblasts, thereby revealing a new mechanism by which EtOH may affect lung cells and tissue remodeling and pointing to nAChRs as potential targets for intervention. (Ritzenthaler JD, Roser-Page S, Guidot DM, Roman J. Alcohol Clin Exp Res. 2013 Jun;37(6):914-23)
Disrupted Ventromedial Prefrontal Function, Alcohol Craving, and Subsequent Relapse Risk
In alcoholics most likely to relapse, activity within the prefrontal cortex remains hyperactive in response to relaxing imagery. In non-alcoholics, these brain regions regulating emotion show markedly reduced activity during relaxing imagery. The research may give clues about which people in recovery from alcoholism are most likely to return to drinking.
IMPORTANCE Alcohol dependence is a chronic relapsing illness; stress, alcohol-related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear. OBJECTIVES To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues. DESIGN Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group. SETTINGS Inpatient treatment setting in a community mental health center and hospital-based research unit. PATIENTS Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons. INTERVENTION Twelve-step recovery-based addiction treatment for the patient group. MAIN OUTCOMES AND MEASURES Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity). RESULTS Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue-induced and stress-induced craving in early recovering AD patients (x = 6, y = 43, z = -6; P < .01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P < .01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F = 6.42; P < .01, whole-brain corrected). CONCLUSIONS AND RELEVANCE Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse. (Seo D, Lacadie CM, Tuit K, Hong KI, Constable RT, Sinha R. JAMA Psychiatry. 2013 May 1:1-13 [Epub ahead of print])
A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis
This study provides direct evidence that catecholamine and corticotropin-releasing factor (CRF) interaction modulates the glutamatergic pathway projecting from the BNST to the VTA and reveals a potential mechanism contributing to stress-induced excessive alcohol intake.
A growing literature suggests that catecholamines and corticotropin-releasing factor (CRF) interact in a serial manner to activate the bed nucleus of the stria terminalis (BNST) to drive stress- or cue-induced drug- and alcohol-seeking behaviors. Data suggest that these behaviors are driven in part by BNST projections to the ventral tegmental area (VTA). Together, these findings suggest the existence of a CRF-signaling pathway within the BNST that is engaged by catecholamines and regulates the activity of BNST neurons projecting to the VTA. Here we test three aspects of this model to determine: (1) whether catecholamines modify CRF neuron activity in the BNST; (2) whether CRF regulates excitatory drive onto VTA-projecting BNST neurons; and (3) whether this system is altered by ethanol exposure and withdrawal. A CRF neuron fluorescent reporter strategy was used to identify BNST CRF neurons for whole-cell patch-clamp analysis in acutely prepared slices. Using this approach, we found that both dopamine and isoproterenol significantly depolarized BNST CRF neurons. Furthermore, using a fluorescent microsphere-based identification strategy we found that CRF enhances the frequency of spontaneous EPSCs onto VTA-projecting BNST neurons in naive mice. This action of CRF was occluded during acute withdrawal from chronic intermittent ethanol exposure. These findings suggest that dopamine and isoproterenol may enhance CRF release from local BNST sources, leading to enhancement of excitatory neurotransmission on VTA-projecting neurons, and that this pathway is engaged by patterns of alcohol exposure and withdrawal known to drive excessive alcohol intake. (Silberman Y, Matthews RT, Winder DG. J Neurosci. 2013 Jan 16;33(3):950-60)
Patterns of alcohol use and expectancies predict sexual risk taking among non-problem drinking women
This study highlights the importance of continuing to examine patterns of both alcohol use behaviors and alcohol expectancies in predicting sexual risk taking. Although moderate drinking was associated with some indices of sexual risk taking, women who reported heavier drinking exhibited the highest STI risk indicators, especially those who also reported greater expectations for the social/physical pleasure effects of alcohol.
OBJECTIVE: Although alcohol consumption and sexual risk taking are associated, not everyone who drinks alcohol engages in risky sexual behavior. The purposes of the present study were to identify patterns of alcohol use behaviors and alcohol expectancies among women who are non-problem drinkers and to examine how these patterns are associated with indices of sexual risk. METHOD: Data from 758 non-problem drinking women who have sex with men and were not in committed relationships were analyzed using latent profile analysis to determine patterns of alcohol use and alcohol-related expectancies. RESULTS: Of the four patterns observed, three classes had similar alcohol-related expectancies but differed with respect to drinking behavior (moderate drinking, regular heavy episodes, and frequent heavy episodes), and the fourth class consisted of moderate drinkers with low expectancies (low expectancies). Results revealed that those in the frequent heavy episodes class had the greatest number of sexual partners in the past year and drank the most alcohol before having sex compared with the other women. Both the regular and frequent heavy episodes classes reported greater likelihood of having unprotected sex in the future, more positive beliefs about casual sex, and greater subjective intoxication before having sex than women in the moderate drinking or low expectancies classes. Women in the low expectancies class reported less positive beliefs about condoms than those in the moderate drinking and regular heavy episodes classes. CONCLUSIONS: Results suggest that different patterns of expectancies and drinking behaviors are associated with different indices of sexual risk taking and highlight the importance of individually tailored programs for prevention of sexually transmitted infections. (Stappenbeck CA, Norris J, Kiekel PA, Morrison DM, George WH, Davis KC, Zawacki T, Jacques-Tiura AJ, Abdallah DA. J Stud Alcohol Drugs. 2013 Mar;74(2):223-32)
Facial dysmorphism across the fetal alcohol spectrum
Facial features of fetal alcohol syndrome (FAS) are well defined but less is known about the full range of facial phenotypes caused by prenatal alcohol exposure. The current study from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) uses novel strategies of dense surface modeling and signature analysis of 3-dimensional (3D) facial images to better recognize facial abnormalities over a range of prenatal alcohol exposures. These findings may ultimately improve the identification of affected children who lack diagnostic facial features of FAS but exhibit alcohol-induced neurocognitive deficits.
OBJECTIVE: Classic facial characteristics of fetal alcohol syndrome (FAS) are shortened palpebral fissures, smooth philtrum, and thin upper vermillion. We aim to help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially among nonsyndromal heavily exposed (HE) individuals without classic facial characteristics. METHODS: Of 192 Cape Coloured children recruited, 69 were born to women who reported abstaining from alcohol during pregnancy. According to multifaceted criteria, the remainder were allocated clinically to the FAS (n = 22), partial FAS (n = 26) or nonsyndromal HE (n = 75) categories. We used dense surface modeling and signature analyses of 3-dimensional facial photographs to determine agreement between clinical categorization and classifications induced from face shape alone, to visualize facial differences, and to consider predictive links between face shape and neurobehavior. RESULTS: Face classification achieved significant agreement with clinical categories for discrimination of nonexposed from FAS alone (face: 0.97-1.00; profile: 0.92) or with the addition of partial FAS (face: 0.90; profile: 0.92). Visualizations of face signatures delineated dysmorphism across the fetal alcohol spectrum and in half of the nonsyndromal HE category face signature graphs detected facial characteristics consistent with prenatal alcohol exposure. This subgroup performed less well on IQ and learning tests than did nonsyndromal subjects without classic facial characteristics. CONCLUSIONS: Heat maps and morphing visualizations of face signatures may help clinicians detect facial dysmorphism across the fetal alcohol spectrum. Face signature graphs show potential for identifying nonsyndromal heavily exposed children who lack the classic facial phenotype but have cognitive impairment. (Suttie M, Foroud T, Wetherill L, Jacobson JL, Molteno CD, Meintjes EM, Hoyme HE, Khaole N, Robinson LK, Riley EP, Jacobson SW, Hammond P. Pediatrics. 2013 Mar;131(3):e779-88)
Trauma histories, substance use coping, PTSD, and problem substance use among sexual assault victims
This study builds on and extends past research by testing a theoretical model of the predictors of problem drinking and drug use in a large, diverse sample of adult sexual assault victims. These findings suggest that trauma history, substance use to cope, and PTSD help to explain alcohol and drug problems in sexual assault victims and may be used to enhance treatment of victimized women with PTSD and substance use problems. Specific trauma types should be assessed in both research and treatment, because they may have distinct effects on PTSD and substance use coping, both of which impact substance use problems in sexually assaulted women.
Sexual assault history is associated with higher risk of problem drinking and drug use in women, yet little is known about mechanisms linking trauma histories in general to women's drinking or drug use problems. This study examined how various types of trauma, substance use coping, and PTSD relate to past-year problem drinking and drug use in women who experienced sexual assault. Data from a large, diverse sample of women who had experienced adult sexual assault were analyzed with structural equation modeling to test a theoretical model of the relationship between trauma types, substance use coping, PTSD symptoms, and past-year drinking and drug use (N=1863). Results show that PTSD symptoms fully mediated the association between non-interpersonal trauma and the use of substances to cope. However, the association between both interpersonal trauma and child sexual abuse severity on substance use to cope was only partially mediated by PTSD symptoms. In turn, use of substances to cope fully mediated the relationship between PTSD and problem drug use as well as partially mediated the effect of PTSD on problem drinking. These results suggest that different trauma types and substance use coping may be important risk factors distinguishing sexually assaulted women who develop PTSD and problematic substance use from those who do not. Identifying women's histories of different traumas may help to identify those at greater risk for substance use problems. (Ullman SE, Relyea M, Peter-Hagene L, Vasquez AL. Addict Behav. 2013 Jun; 38 (6):2219-23)
Alcohol-Induced Epigenetic Alterations to Developmentally Crucial Genes Regulating Neural Stemness and Differentiation
Alcohol has been shown to alter both DNA methylation and histone modifications in various tissues. In this study, researchers have begun to explore the role these epigenetic mechanisms play in the genesis of fetal alcohol spectrum disorders (FASD). Neural stem cells exposed to alcohol in culture display aberrant posttranslational histone modifications within the regulatory regions of key genes controlling both precursor cell identity and neural differentiation and alters the transcription of a select subset of these genes.
BACKGROUND: From studies using a diverse range of model organisms, we now acknowledge that epigenetic changes to chromatin structure provide a plausible link between environmental teratogens and alterations in gene expression leading to disease. Observations from a number of independent laboratories indicate that ethanol (EtOH) has the capacity to act as a powerful epigenetic disruptor and potentially derail the coordinated processes of cellular differentiation. In this study, we sought to examine whether primary neurospheres cultured under conditions maintaining stemness were susceptible to alcohol-induced alterations in the histone code. We focused our studies on trimethylated histone 3 lysine 4 and trimethylated histone 3 lysine 27, as these are 2 of the most prominent posttranslational histone modifications regulating stem cell maintenance and neural differentiation. METHODS: Primary neurosphere cultures were maintained under conditions promoting the stem cell state and treated with EtOH for 5 days. Control and EtOH-treated cellular extracts were examined using a combination of quantitative RT-PCR and chromatin immunoprecipitation techniques. RESULTS: We find that the regulatory regions of genes controlling both neural precursor cell identity and processes of differentiation exhibited significant declines in the enrichment of the chromatin marks examined. Despite these widespread changes in chromatin structure, only a small subset of genes including Dlx2, Fabp7, Nestin, Olig2, and Pax6 displayed EtOH-induced alterations in transcription. Unexpectedly, the majority of chromatin-modifying enzymes examined including members of the Polycomb Repressive Complex displayed minimal changes in expression and localization. Only transcripts encoding Dnmt1, Uhrf1, Ehmt1, Ash2 l, Wdr5, and Kdm1b exhibited significant differences. CONCLUSIONS: Our results indicate that primary neurospheres maintained as stem cells in vitro are susceptible to alcohol-induced perturbation of the histone code and errors in the epigenetic program. These observations indicate that alterations to chromatin structure may represent a crucial component of alcohol teratogenesis and progress toward a better understanding of the developmental origins of fetal alcohol spectrum disorders. (Veazey KJ, Carnahan MN, Muller D, Miranda RC, Golding MC. Alcohol Clin Exp Res. 2013 Mar 12 [Epub ahead of print])
The development and implications of peer emotional support for student service members/veterans and civilian college students
The findings from this study indicate that although emotional support from peers increased over time for student service members/veterans, given their initial deficit compared with civilian students, student service members/veterans never reached the same level of emotional support as their civilian counterparts. This investigation expands our current understanding of student service members/veterans enrolled in higher education by examining the emotional support these individuals receive from their university peers. Student service members/veterans do not receive the same amount of emotional support as their civilian peers, and the beneficial effects of peer emotional support were more strongly related to civilian students’ mental health as compared with student service members/veterans. To ensure successful transition, institutions of higher education must enact holistic approaches that will minimize the stress, isolation, and difficulties experienced by student service embers/veterans.
Student service members/veterans represent a growing population on college campuses. Despite this growth, scholarly investigations into their health- and adjustment-related issues are almost nonexistent. The limited research that is available suggests that student service members/veterans may have trouble connecting with their civilian counterparts and be at risk for social isolation. The present study compared the development and implications of emotional support from peers among 199 student service members/veterans and 181 civilian students through 3 distinct occasions over the course of 1 calendar year. Data were collected via electronic survey. Measured constructs included perceived emotional support from university friends, mental health, alcohol use, and academic functioning. A series of multilevel models revealed that student service members/veterans reported less emotional support from their peers compared with their civilian counterparts; yet, emotional support from peers increased similarly for both groups over time. Although, increasing peer emotional support was generally related to better academic and mental health outcomes for both groups, the links between emotional support and mental health were stronger for civilian students. Results suggest that mental health practitioners, particularly those on college campuses, should be prepared to deal with veteran-specific experiences that occur before and during college. (Whiteman SD, Barry AE, Mroczek DK, Macdermid Wadsworth S. J Couns Psychol. 2013 Apr;60(2):265-78)