NIAAA Director’s Report on Institute Activities to The 127th Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism

Thursday, June 9, 2011

CONTENTS

A. Legislation, Budget, and Policy

B. Director’s Activities

C. NIAAA Staff and Organization

D. Multi-Media Products from NIAAA

E. News Media Interactions

F. NIAAA Program Announcement and Request for Applications Information

G. NIAAA Research Programs

A. Legislation, Budget, and Policy

Budget Update

FY 2011 Full Year Continuing Resolution

After a series of temporary funding measures, on April 15, 2011, the President signed H.R. 1473, the Department of Defense and Further Continuing Appropriations Act, 2011, as P.L. 112-10. This law extended the previous CR through September 30, 2011, providing funding for all federal agencies for the remainder of the year. The National Institutes of Health (NIH) received $30.7 billion, a $260 million or 8% reduction from the 2010 level. By contrast, an earlier House bill, H.R. 1, would have cut NIH's budget by more than $1.5 billion to $29.5 billion.

The FY 2011 full year Continuing Resolution for NIAAA provides $458.3 million. This represents a $4.1 million or .8% decrease from the enacted FY 2010 level.

The FY 2011 budget will enable NIAAA to support approximately 683 research project grants (RPGs) for a total of $263.6 million, including 147 new and competing awards. This compares to 706 total and 189 new and competing RPGs in FY 2010. NIAAA will follow the NIH grant funding policy for noncompeting RPGs. Non-modular research projects grants, from all ICs, with the single exception of NCI, will be reduced to 1 percent below the FY 2010 award level. Though there is more variability among NIH Institutes for modular RPGs, NIAAA is applying the same reductions to modular as well. For NIAAA, this translates to a 4% reduction to grantee commitments of record as reflected on the FY 2010 Notice of Award. In addition, NIAAA is applying this policy to all other types of research grants with the exception of SBIR/STTR awards, Research Career (K) Awards, Conference (R13 and U13) grants, and National Research Service Award (NRSA) Individual Fellowships & Institutional Training Grants. Awards that already have been made in FY 2011, which are impacted by this policy, will be revised.

Under the Research Centers budget mechanism, NIAAA will support 21 awards, the same number as in FY 2010. For the other key extramural grant mechanisms, 93 research careers, 1 cooperative clinical grant and 26 other research related grants will receive funding. In addition, 287 full time training positions under the National Research Service Award (NRSA) Program will be supported with a 2 percent stipend increase.

FY 2012 President’s Budget Request

The FY 2012 President’s budget request was released in February of this year. For the NIH, the total request is $31.8 billion, an increase of +$0.5 billion or 1.9% over FY 2010. For NIAAA, the request is $469.2 million. This represents a $7.1 million or a 1.5% increase over the FY 2010 comparable level of $462.1 million.

The Senate hearing was held on May 11th. Dr. Collins was accompanied by Drs. Harold Varmus, Director, NCI; Anthony S. Fauci, Director, NIAID; Griffin Rodgers, Director, NIDDK; and Susan Shurin, Acting Director, NHLBI. As of this writing no House hearing has been scheduled. In the mean-time lawmakers continue negotiations aimed at debt reduction and the passage of a budget resolution.

FY 2013

Preliminary work on the budget for FY 2013 has begun. After intermediate stages of review, the President’s budget request for FY 2013 will be presented to Congress in February 2012, at which time it will become available to the public.

B. Director’s Activities

NIAAA Acting Director Kenneth R. Warren, Ph.D. spoke or otherwise participated at the following recent meetings:

Research Seminar Program on Alcohol Abuse in Russia, Moscow
April 2nd – 8th, 2011

Introduction for the NIAAA Honorary Mendelson Lecture presented by Anna-Mae Diehl
April 12th, 2011

NIH Clinical Center Grand Rounds – “Fetal Alcohol Spectrum Disorders”
April 27th, 2011

Keynote Introduction to the Conference “Alcoholism and Stress, A Framework for Future Treatment Strategies” Volterra Italy
May 3 –6, 2011

On May 3 to 6, the meeting was held in Volterra, Italy. This conference was cosponsored by several European foundations, pharmaceutical companies and industries. This meeting brought together researchers from fourteen countries. NIAAA provided travel stipends to young investigators and conference speakers from the US to enable their participation in this international summit on medication development for stress related alcohol abuse. NIAAAA Acting Director Dr. Kenneth Warren gave the opening plenary lecture highlighting the global impact of alcoholism, reviewed the NIAAA sponsored research linking stress and alcoholism and identified future research opportunities. Dr. Antonio Noronha, Director of the Division of Neuroscience and Behavior, co-chaired the Young Investigators Awards session. Dr. Sam Zakhari, Director of the Division of Metabolism and Health Effects, summarized neuroimmunology presentations. NIAAA Project Officer Dr. Joanne Fertig gave a presentation on the NIAAA Clinical Investigations Group (NCIG) at a Clinical Treatments Roundtable and NIAAA Project Officer Lindsey Grandison led the discussion at a symposium on Post Traumatic Stress Disorder and Alcohol Dependence. NIAAA intramural scientists Markus Heilig, Marguerite Camp, Verginia Cuzon Carlson, Veronica Alvarez, David Lovinger and Melanie Schwandt gave scientific presentations.

On May 9th and 10th, NIAAA and the University of Rome, La Sapienza, School of Medicine co-sponsored a faculty development and continuing education course for Italian physicians, nurses, and psychologists, “Alcohol Across the Lifespan, what Clinician’s Need to Know.” The first day featured lectures by key U.S. alcohol researchers, who were in Italy attending an earlier scientific conference. NIAAA Acting Director Dr. Kenneth Warren gave the plenary address. Other speakers were Kathleen Sulik, Ph.D., University of North Carolina; Edward Riley, Ph.D., San Diego State University; Fulton Crews, Ph.D., University of North Carolina; Edith Sullivan, Ph.D., Stanford University; Sara Jo Nixon, University of Florida; and Lara Ray, Ph.D., UCLA. The second day was an interactive skill building session on screening and brief intervention and medical management of alcohol addiction in primary care settings led by Dr. Peggy Murray, director of NIAAA’s International Research Program, and included Dr. Christine Savage from the University of Cincinnati School of Nursing, Dr. Paul Seale from the Medical College of Georgia, and Dr. Richard Blondell from the Research Institute on Addictions in Buffalo, NY.

Prenatal Alcohol SIDS and Stillbirth Network Face-to-Face Steering Committee
May 12 - 13, 2011

Fetal Alcohol Spectrum Disorders Lecture - Georgetown University Hospital
May 18, 2011

C. NIAAA Staff and Organization

Staff Honors

Dr. Pal Pacher, Acting Chief of the Section on Oxidative Stress Tissue Injury in the NIAAA Laboratory of Physiologic Studies, was selected by Editor in Chief Dr. Paul A. Insel and Associate Editors of the American Journal of Physiology-Cell Physiology to receive a title of “Star Reviewer” of the year, which was announced at the Experimental Biology 2011 Meeting, April 9-13, 2011, in Washington, DC.

Staff changes

Mr. Melvin Carter, Committee Management Specialist in the Office of Extramural Activities moved to the Department of Homeland Security (DHS) in March, 2011 to become a Program Analyst.

Captain Angela Martinelli of the Division of Treatment and Recovery Research, will leave NIAAA in June, 2011 to begin a new position in the Congressionally Directed Medical Research Program (CDMRP) at Fort Derick, Maryland.

Dr. Kwan-Hoon Moon, a former Research Fellow in the Laboratory of Membrane Biochemistry and Biophysics, left NIAAA in March to join the Department of Biochemistry and Pharmacology, Loyola University School of Medicine, Chicago, as a Research Assistant Professor.

Dr. Seong-Ho Yoo, a former Visiting Fellow in the Laboratory of Membrane Biochemistry and Biophysics, returned to Korea on March 28 to join the Department of Forensic Medicine, Seoul National University College of Medicine, in Seoul, Korea, as an Assistant Professor.

Dr. Max Guo left NIAAA in May to take a position at the National Institute on Aging as the Chief, Branch of Genetics and Cell Biology, Division of Aging Biology. Dr. Guo had served NIAAA since 2006 as a co-Leader of “Mechanism of Alcohol Action and Injury Team,” the leader of “Informatics/Computation and Systems Biology Team,” the SBIR/STTR coordinator, and the Deputy Director of Division of Metabolism and Health Effects.

Outreach

Brain Awareness Week: NIH and the National Museum of Health and Medicine at Walter Reed Army Medical Center hosted the Museum’s 12th annual Brain Awareness Week on March 16 and 17. 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. NIAAA staff (Dr. Ivana Grakalic, Dr. Larry Baizer, Dr. Matt Reilly, Diana Urbanas, and Jo-Ann Kriebel) presented the “Cool Spot Carnival” that started with a presentation on alcohol and adolescent brain development. Students learned about the effects of alcohol on teen/tween brains and the lifelong consequences of underage drinking. Some of the material presented was based on the NIAAA Web site for kids, www.thecoolspot.gov. 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. Other Carnival activities included flip-board games that gave youngsters a chance to “pick your no’s”, demonstrating the best way to say “no” to alcohol, and dispel the myth that “everybody is drinking.”

Take Your Child to Work Day: NIH celebrated its 17th annual Take Your Child to Work Day on April 28. Through educational and fun activities, children ages 5-15 experienced the world of biomedical research at NIH as well as critical services and resources needed to support it. NIAAA’s “Cool Spot Carnival” hosted by Dr. Ivana Grakalic, Dr. Larry Baizer, Dr. Matt Reilly, and Diana Urbanas started with a presentation on alcohol and adolescent brain development. Students also played a football-toss game while wearing “Fatal Vision” goggles to simulate being under the influence of alcohol. Another game, “Pick Your No’s”, demonstrated effective ways to say no to alcohol, and dispel the myth that “everybody is drinking.”

Dr. Lawrence Baizer of the Division of Neuroscience and Behavior, gave a presentation on the effects of alcohol on the nervous system at the Thomas Jefferson High School for Science and Technology’s Symposium to Advance Research (tjSTAR) in Alexandria, Virginia. This day-long school symposium on June 1 showcased student research projects at TJ, helped students to explore future research options, and described the research aspects of potential careers.

Dr. Ralph Hingson, director of the Division of Epidemiology and Prevention Research, presented “Recent Trends and Findings Regarding the Magnitude and Prevention of College and Underage Drinking Problems,” to the following:

• West Virginia’s Collegiate Initiative to Address High Risk Alcohol Use Training Institute: Promoting Healthy Campus Environments,” Davis & Elkins College, Elkins, WV, May 18, 2011.

• Edmonton’s Third International Conference on Urban Traffic Safety: Moving Forward: Creative Approaches to Improving Urban Traffic Safety in Our Communities, Edmonton, Canada, April 19, 2011.

• University of Queensland Seminar, Brisbane, Australia, March 30, 2011.

• Plenary Address: New Jersey Prevention Network: 11th Annual Addiction Conference, Atlantic City, NJ, March 4, 2011.

• Plenary Address: Texans Standing Tall: Statewide Summit to Create Healthier and Safer Communities, Austin, TX, March 2, 2011.

• Virginia Department of Alcoholic Beverage Control: 2011 College Conference: “Saving Lives,” Fairfax, VA, February 26, 2011.

• Webinar: Dartmouth Expert Session on High-Risk Drinking, February 2, 2011.

Extramural Staff Activities

Dr. Abe Bautista, director of the Office of Extramural Activities co-chaired the sessions on “Therapeutic Strategies Targeting Neuroimmune Modulation” and the “NIH Grantsmanship Workshop” at the 17th Scientific Conference of the Society for Neuroimmune Pharmacology held in Clearwater Fl on April 6-10, 2011. Dr Ranga Srinivas, Chief of Extramural Project Review Branch participated in the “NIH Grantsmanship Workshop” at the same meeting.

Dr. Ellen Witt and Dr. Bob Huebner co-organized a symposium entitled “Implicit Cognition and Mechanisms of Behavior Change, “presented at the 23rd Annual Meeting of the Association for Psychological Science, Washington, D.C. on May 27, 2011. The purpose of this symposium was twofold: 1) to present NIAAA-funded research on the neural and physiological mechanisms of implicit cognitions and emotions that influence alcohol and other substance use behaviors; and 2) to discuss how the behavioral and neural underpinnings of implicit cognitive and emotional constructs may translate to health-promoting change, particularly intervention response and potential for relapse. Speakers included Patricia Janak, Ph.D., Susan Ames, Ph.D., Marsha Bates, Ph.D., Tibor Palfai, Ph.D., and Jon Morgenstern, Ph.D.

Dr. Changhai Cui of the Division of Neuroscience and Behavior (DNB) co-chaired a symposium on “The Consequences of Substance Abuse and HIV on Stem Cell Biology” at the conference of the Society on NeuroImmune Pharmacology, April 6-10, 2011, in Clearwater Beach, Florida. Dr. Cui was also a panelist for NIH workshop on grant funding held at the same conference.

Several Program Officers from the Division of Neuroscience and Behavior attended the 6th Annual Conference on Amygdala and Stress sponsored by the Center for the Study of Traumatic Stress at the Uniformed Services University of the Health Sciences in Bethesda, MD. The theme for this year’s conference was “Fear in the Human Mind” and included oral presentations and posters on basic neurobiological mechanisms and translational applications.

Dr. Roz Breslow of the Division of Epidemiology and Prevention Research was an Invited Speaker: “Prospective study of alcohol consumption quantity, frequency, and cancer-specific mortality in the US population,” Session Title: “Diet and Cancer: Translational, Clinical and Survivorship Issues,” Experimental Biology 2011, Washington, D.C., April 11, 2011.

Dr. Roz Breslow was an Expert judge for poster sessions at the Nutrition & Food Science Research Day 2011, National Agricultural Library, Beltsville, MD, May 6, 2011.

Drs. Sam Zakhari, Gamal Esmat, and Scott Friedman, served as guest editors for the liver section of the May 2011 issue of Alcoholism: Clinical & Experimental Research, where the proceedings of the 4th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis are published.

Dr. Sam Zakhari, director of the Division of Metabolism and Health Effects, represented NIAAA on the Committee to revamp the High Risk High Reward (HRHR) research including the T-R01 and EUREKA mechanisms.

Dr. Sam Zakhari of the Division of Metabolism and Health Effects hosted a seminar by Drs. Mark Feitelson and Alla Arzumanyan from Temple University on Hepatitis Viruses and Ethanol Interactions, April 6, 2011.

Dr. Sam Zakhari, of the Division of Metabolism and Health Effects, co-edited with Drs. Manfred Singer, Steven Dooley, and Craig McClain a special issue of “Digestive Diseases: Clinical Reviews” that included the proceedings of the “Liver and Pancreatic Diseases: Consequences of Chronic Alcohol Consumption” meeting held in Freiburg, Germany, October 2010.

Dr. Gary Murray of the Division of Metabolism and Health Effects, represented NIAAA at a virtual workshop of the Common Fund Working Group on Metabolomics. At the conclusion of their four months long evaluation of program needs in translation of metabolomics research into clinical research, the Working Group generated a new program proposal “Increasing Metabolomics Research Capacity” for consideration by the NIH Director and the Council of councils.

Drs. William Dunty and Dale Hereld of the Division of Metabolism and Health Effects, together with NIAAA grantee Dr. Eva Redei, co-organized a symposium for the upcoming Annual RSA meeting in Atlanta titled "Epigenetic Insights Into Fetal Alcohol Spectrum Disorders."

The trans-NIAAAA Biomarkers Working Group has organized a satellite session to take place at the June 2011 Annual Meeting of the Research Society on Alcoholism entitled “Development and Applications of Biomarkers of Alcohol Abuse and Alcohol-induced Tissue Damage”. The session will take place from 2:00PM to 5:00PM on Saturday, June 25, 2011.

Dr. Peter Gao will organize a symposium on “Stem Cell and Alcohol” during the annual RSA meeting on June 26th in Atlanta, GA.

Dr. Andras Orosz and Dr. Max Guo have co-organized a Satellite Symposium for the RSA: "Cellular Organelles and Cytoskeleton in Alcohol Induced Disorders".

Dr. Raye Litten presented Medications Development for Alcohol Treatment: Advances, Challenges, and Vision to the NIDA Clinical Trials Network Steering Committee in Bethesda, Maryland on March 17, 2011.

Dr. Ralph Hingson presented “Strategies to Reduce Driving Under the Influence,” at Edmonton’s Third International Conference on Urban Traffic Safety: Moving Forward: Creative Approaches to Improving Urban Traffic Safety in Our Communities, Edmonton, Canada, April 18, 2011.

Dr. Ralph Hingson presented “Alcohol-Impaired Driving and Other Injury Prevention: From Global to Local,” at the Centre for Accident Research and Road Safety in Queensland (CARRS-Q), Brisbane, Australia, March 30, 2011.

Dr. Ralph Hingson presented a Report from the Working Group on Production and Dissemination of Knowledge, at the World Health Organization’s First Meeting of the Global Network of National Counterparts for the Implementation of the Global Strategy to Reduce the Harmful Use of Alcohol, Geneva, Switzerland, February 9, 2011.

D. Multi-Media Products from NIAAA

Special Supplemental Issue on Alcohol–to Celebrate the 40th Anniversary of the NIAAA

Brain Behavior and Immunity. (2011) 25, Supplement 1, 1-178. Edited by Fulton Crews with the help of staff from the Division of Neuroscience and Behavior (Changhai Cui, Lindsey Grandison, and Antonio Noronha, Director of DNB), this special supplemental issue includes articles based on talks presented at the NIAAA-supported Satellite Symposium at the 2010 Society for Neuroscience annual meeting, and invited contributions from researchers in the neuroimmune and alcohol fields.

NIAAA Spectrum -- Issue 6 of the Institute's online webzine, will be released in June, 2011

Neuroimmune Mechanisms of Brain Function and Alcohol Related Disorders

Cui C, Grandison L, Noronha A.

Brain Behavior and Immunity. (2011)25, s1-s3

College Drinking Website Internet Advertising Pilot Project

In early 2011, NIAAA began conducting a pilot test of internet banner advertising for the college website. Banner advertising is a low-cost way to raise awareness and drive traffic directly to a website because it provides immediate "click through" access from the ad itself. The four distinct audiences targeted in this pilot were college presidents, alcohol prevention and student affairs staff, students, and parents. Separate ads were created for each audience, with links to the specific section of the website most relevant to them. The ads were also placed on different websites, depending on the targeted audience. Ads targeted to college presidents were run on the sites for the Chronicle of Higher Education and the American Council of Education. Ads for prevention and student affairs staff were run in the Chronicle of Higher Education and NASPA, an organization of Student Affairs Administrators in Higher Education. Student-focused ads were placed in the Princeton Review and in U.S. News & World Report's Best Colleges site, where the parents' ad also ran. In addition, the project used Google banner ads and Google adwords, which placed the materials on search pages and websites according to particular keywords generated by the user. Preliminary results indicate that the targeted pages of the website experienced a 36% increase in traffic compared to the same period in 2010. Results were particularly promising for professional audiences: there was a 120% increase in traffic to the staff pages and a 30% increase for the presidents' page. The parents' page had an 11% increase and the student page had an impressive 37% increase. Of the methods used, Google advertising was particularly cost-effective. NIAAA staff will continue to explore the potential of banner advertising and refine strategies for maximum return on investment.

E. News Media Interactions

Recent News Media Interviews

Dr. Vivian Faden, director of the NIAAA Office of Science Policy and Communications (OSPC) and associate director of Behavioral Research, was invited by the American Psychological Association to be their guest expert for an Alcohol Awareness Month (April) Web feature that focused on alcohol use among college-age individuals.

Dr. Faden was also interviewed by:

• Victoria Carlborg of the Community Anti-Drug Coalitions of America (CADCA) newsletter, re parental messages that can help prevent or delay underage drinking

Dr. Aaron White of the Division of Epidemiology and Prevention Research, provided outside comment on a recent paper by Spanish researchers in the journal Alcoholism: Clinical & Experimental Research, that reported verbal declarative memory deficits associated with binge drinking among college students in interviews with:

• Darin Moriki of the Oregon Daily-Emerald (Univ of Oregon)

• Deborah Kotz of the Boston Globe

• Randy Dotinga of Healthday News

Dr. Ellen Witt, deputy director of the NIAAA Division of Neuroscience and Behavior, was interviewed by Dr. Regina Rei Lamourelle of the BAM Radio network on the topic of alcohol and the teen brain. Dr. Witt discussed detrimental brain effects of teen drinking and long-term consequences of early initiation of alcohol use.

Dr. Howard Moss, NIAAA Associate Director for Clinical and Translational Research, recently was interviewed by Alison Knopf of Alcoholism & Drug Abuse Weekly for articles about:

• DSM 5 alcohol criteria. Dr. Moss noted that a recent study by Australian researchers suggests that a larger number of individuals will have an Alcohol Use Disorder under DSM-V diagnostic criteria, suggesting that more individuals will qualify for treatment.

• Burden of alcohol dependence in U.S. In an interview about the recent article that he co-authored with other NIAAA scientists in Alcoholism: Clinical & Experimental Research titled “Disaggregating the Burden of Substance Dependence in the United States,” Dr. Moss discussed estimates of prevalence and conditional probability of alcohol and other substance dependence as revealed through analyses of data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

Dr. Robert Huebner, acting director of the NIAAA Division Of Treatment and Recovery Research, discussed strategies for identifying drinking problems and cutting down on drinking that are outlined in NIAAA’s Rethinking Drinking materials Rethinking Drinking in interviews with:

• Anya Martin of MarketWatch.com

• Sally Chew of TheFix.com

Dr. Sam Zakhari, director of the NIAAA Division of Metabolism and Health Effects, gave interviews to:

• Melanie Mannarino of Health magazine on the topic of alcohol and women.

• Marissa Alanis of eHow.com on the topic of alcohol and cardiovascular health

• Judy Mcguire of Thefix.com re health risks of moderate drinking.

Dr. Li Zhang, medical officer in the NIAAA Laboratory for Integrative Neuroscience, gave interviews re his recent paper, published in Nature Chemistry and Biology, and entitled “Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia,” to the following outlets:

• Hristio Boytchev of spiegel.de (German online news site)

• Sheena Goodyear of QMI Agency (Canadian newswire)

• Mathieu Perreault of La Presse (Canada)

• Tessa Lange of Redactie Bionieuws (Dutch biology magazine)

• Alessandro Greco of Brazilian news website iG

• Nick McCabe of CBC Radio

• Silvia Sanides of FOCUS German News Magazine

Dr. Joseph Hibbeln, Acting Chief, NIAAA Section on Nutritional Neurosciences, was invited by the American Journal of Clinical Nutrition to participate in a video project to promote selected works from the AJCN. Dr. Hibbeln’s recent AJCN paper, “Changes in consumption of omega-3 and omega-6 fatty acids in the U.S. during the 20th century,” was selected for possible inclusion in this project.

Dr. David Goldman, chief of the NIAAA Laboratory of Neurogenetics, was interviewed by KQED Radio in San Francisco about alcoholism and impulsivity. Dr. Goldman discussed his December, 2010 Nature paper in which he and colleagues reported that a genetic variant (HTR2B) of the serotonin receptor may contribute to violently impulsive behavior when people who carry it are under the influence of alcohol.

F. NIAAA Program Annoucement and Request for Applications Information

• PA-11-178 (R01) and PA-11-179(R21): Circadian Rhythms and Alcohol-induced Tissue Injury.

• PAR-11-174 Program Project on Alcohol-Related Research (P01)

• RFA-AA-12-002 Specialized Alcohol Research Centers (P50)

• RFA-AA-12-003 Comprehensive Alcohol Research Centers (P60)

• NIAAA and NIDA issued a RFA-DA-12-003, 004 (R01, R21) on the Placebo Effect: Mechanisms and Methodology. The RFA solicits research to elucidate the underlying pathways that lead to placebo effects and to better understand how to recognize and enhance the therapeutic benefit of placebo effects in clinical research and practice. Dr. Joanne Fertig is the NIAAA Scientific Contact

G. NIAAA Research Programs

NIAAA Clinical Investigations Group (NCIG)

NCIG is an Institute-directed Phase 2 clinical trials program created to test promising medications for the treatment of alcohol use disorders. The purpose of the program is to design and conduct rapid Phase 2 proof of concept (POC) trials (within 12 to 18 months) of promising compounds that are supported by theory; pilot data in humans and animal models; and acceptable tolerability, safety, and interaction data. If an efficacy signal is detected, an effort will be made to further advance the compound. Sources of candidate compounds include novel compounds developed by pharmaceutical companies and those already marketed for different indications.

A Data Coordinating Center provides scientific and logistical support, clinical forms and documentation development, monitoring services, and data processing. NIAAA program staff is actively involved in design and protocol development, overseeing of the conduct, and analysis of the data. A Data Safety and Monitoring Board composed of independent outside experts, meets at trial initiation and at least every six months during the course of the study. A Medical Monitor from NIAAA Intramural reviews all Serious Adverse Events according to FDA requirements and is available for questions that may arise concerning potential drug interactions and questions regarding medical or psychiatric conditions of potential participants. Informed Consent documents are reviewed by NIAAA, the Coordinating Center, and the DSMB, and must be approved by the participating sites’ IRBs before trial initiation. An IND (or an exemption) is obtained from the FDA for each study. Lastly, a Certificate of Confidentiality is issued for each clinical site.

The treatment phase of first trial, evaluating the atypical antipsychotic quetiapine (N = 240), is complete and the main paper has been submitted for publication. A second study evaluating the antiseizure medication levetiracetam (N = 130), was completed well ahead of schedule, data analysis is underway and the study close out meeting was held June 7th. The kick off meeting for the third study evaluating the efficacy of the smoking cessation drug varenicline was held in January and recruitment is currently in progress.

The NCIG program is housed within the Division of Treatment and Recovery Research. Team members consist of Drs. Litten, Falk, Fertig, and Ms. Ryan.

NIAAA College Presidents Working Group

On May 25, 2011 NIAAA held a successful kickoff meeting of the new NIAAA College Presidents Working Group, which was created to bring national attention to the college drinking issue and to make relevant recommendations to college administrators. It is co-chaired by Dr. Jim Yong Kim, President of Dartmouth College and Dr. Robert Carothers, immediate past president of the University of Rhode Island. Dr. Kim is highly engaged in this issue, both on his own campus and in collaboration with other leaders in higher education. Dr. Carothers took bold steps to reduce drinking at URI and was a key participant on NIAAA’s original Task Force on College Drinking. Members of the working group, who were invited because of their distinguished work in this area, include:

• Dr. Thomas Buchanan, President of the University of Wyoming

• Dr. Alice Gast, President of Lehigh University

• Dr. Jonathan Gibralter, President of Frostburg State University

• Dr. Roderick McDavis, President of Ohio University

• Dr. Mark Nordenberg, Chancellor of the University of Pittsburgh

• Dr. Harris Pastides, President of the University of South Carolina

• Dr. Judy Sakaki, Vice President for Student Affairs for the University of California system

• Dr. David Skorton, President of Cornell University

• Dr. Samuel Stanley, President of Stony Brook University

The original Task Force on College Drinking helped establish NIAAA as the lead federal agency for research on harmful drinking among college students. In 2002, the Task Force turned a national spotlight on this important public health issue. Its reports, which were mailed to every college president in the United States, have been influential in the college alcohol and other drug (AOD) field. Statistics first introduced by this group are now used routinely to convey the magnitude of college drinking consequences, supporting research papers have been cited more than 2000 times in the scientific literature, and the NIAAA college website has received more than 150 million hits.

College drinking research remains a priority for NIAAA, and the new Presidents Working Group is an important part of this commitment. As research continues to yield new information, the goal of the Working Group is to share it with colleges and universities in accessible and practical ways to facilitate its use as a foundation for prevention and intervention activities. Toward that end, members of the Working Group will suggest strategies for communicating with college administrators and make recommendations for new NIAAA college-related materials and possible future research initiatives.  They will also participate in media opportunities that may arise from this project.

The kickoff meeting began with discussions and a video of press coverage of the 2002 NIAAA College Task Force report.  Subsequent presentations by researchers showed how college alcohol research has evolved during the past decade, and how this evolving body of knowledge can inform campus AOD efforts. There were also a number of presentations and discussions on the nature of the college alcohol problem from the presidents’ perspectives and the challenges of getting information to college executives. The Working Group members offered thoughtful and practical recommendations for activities that this group could undertake.  Dr. Kim endorsed the need for bold presidential involvement. Moving forward, NIAAA has dedicated resources to support this working group and develop new college materials and possible research projects based on the working group’s recommendations.

RESEARCH REPORTS

The following items represent examples of the breadth and quality of research conducted and supported by NIAAA.

Scientists Shed New Light on Binge Drinking Pathway in Rat Brain.

Episodes of heavy alcohol consumption leading to intoxication are associated with many health and safety problems, including unintentional injuries, sexual assault, domestic violence and alcohol poisoning. Previous studies have shown that brain molecules called GABAA receptors appear to play a role in excessive drinking. In a new study, researchers used an established rat model of binge drinking to investigate how GABAA receptors interact with other brain molecules to influence excessive drinking. The researchers established, for the first time, a direct connection between a molecule known as Toll-like receptor 4 (TLR4) and GABAA receptors. TLR4 is an innate immune system molecule that contributes to the inflammation and brain damage brought on by excessive drinking. Using gene therapy techniques, the researchers targeted TLR4 and GABAA receptors in brains of heavy-drinking rats. They found that silencing the genes for TLR4 and GABAA receptors in certain areas of the brain caused the rats to lose interest in alcohol, an effect that lasted for two weeks after the procedure. The new findings provide exciting new knowledge about the biology of binge drinking in this animal model. It is an important step in understanding brain pathways involved in excessive alcohol consumption and reveals new targets for exploring therapeutic interventions for human drinking. (Liu J, et al. Proc Natl Acad Sci U S A., Volume 15, Issue 108, March 2011, Pages 4465-70.)

Study Shows that a Specific GABA(A) Receptor Plays a Critical Role in Alcohol Intake.

Recent research suggests that extrasynaptic delta-subunit-containing receptors for the neurotransmitter GABA(A) are sensitive to alcohol, raising the possibility that these receptors might help produce alcohol’s reinforcing effects after consuming one or a few drinks. In the current study, researchers tested the hypothesis that such receptors in an area of the brain called the nucleus accumbens (NAc) are necessary for oral alcohol consumption. They used genetic-engineering technology to reduce expression of the GABA(A) receptor delta-subunit in adult rats in regions of the NAc. They found that by inhibiting in this way the delta-subunit in the medial shell region of the NAc, but not in the ventral or lateral shell or in the core, reduced the rats’ alcohol intake. In contrast, delta-subunit inhibition in the medial shell did not affect intake of a 2% sucrose solution, suggesting that the effects of GABA(A) receptor delta-subunit reduction are specific to alcohol. The findings provide strong evidence that extrasynaptic delta-subunit-containing GABA(A) receptors in the medial shell of the NAc are critical for the reinforcing effects of oral ethanol. (Nie H, et al. Proc Natl Acad Sci U S A., Volume 15, Issue 108, Number 11. March 15, 2011, Pages 4459-64).

Previous Ethanol Experience Enhances Synaptic Plasticity of NMDA Receptors in the Ventral Tegmental Area (VTA).

Alcohol interferes with learning and memory processes in humans and animals. However, alcohol addiction is also thought to arise, in part, from the enduring memory of alcohol experiences. In this study, researchers explored the mechanisms that underlie the formation of memories associated with repeated alcohol exposure. Using electrophysiological recordings combined with pharmacological approaches, researchers showed that repeated ethanol exposure enhances NMDA receptor-mediated synaptic plasticity of dopaminergic neurons in the ventral tegmental area (VTA), which promotes memory of the ethanol experience. The enhancement of NMDA receptor plasticity was mediated by increased mGluR-IP3-Ca2+ signaling associated with the ethanol treatment. Furthermore, acute application of corticotropin-releasing factor (CRF) in the VTA potentiated the IP3 signaling and repeated ethanol exposure also enhanced subsequent place conditioning induced by cocaine. These results suggest that IP3 signaling in the VTA may serve as the convergence point of stress and ethanol-induced neuroadaptation, which cross-sensitizes the subsequent learning of other drug-associated stimuli. (Bernier BE, et al., J Neurosci. 2011 Apr 6;31(14):5205-12.)

The Mu Opioid Receptor Is Not Involved in Ethanol-Stimulated Dopamine Release in the Ventral Striatum of Mice.

The mu-opioid receptor (MOR) system has been implicated in mediating ethanol intake and ethanol-induced mesolimbic dopamine release. However, in this study, researchers reveal that MOR does not play a critical role in ethanol-induced mesolimbic dopamine release. Using MOR knockout mice coupled with a pharmacological approach, the researchers examined the role of MOR in ethanol-induced dopamine release in the ventral striatum. Interruption of MOR, by either gene knockout or an irreversible antagonist, did not affect dopamine release in responding to various doses of ethanol. These results suggest that MOR is not exclusively involved in mediating ethanol-induced mesolimbic dopamine release. Given that a previous study has demonstrated the interaction between genotype and sex in the regulation of mesolimbic dopamine release by MOR, genetic factors related to sex may determine whether MOR plays a role in the dopamine release, information that is particularly important for designing therapeutic strategies that use an opiate antagonist to treat alcohol dependence. (Ramachandra V, et al. Alcohol Clin Exp Res. 2011 Feb 5. [Epub ahead of print]).

Adolescent Binge Drinking Alters Adult Brain Neurotransmitter Gene Expression, Behavior, Brain Regional Volumes, and Neurochemistry in Mice.

Adolescent binge drinking is common but the long-term consequences of high levels of ethanol exposure during this critical period of brain development have not been determined systematically. In this study, researchers used a mouse model of adolescent binge drinking to assess the effects of ethanol exposure during a restricted developmental period on brain structure and function in adulthood. Exposure to binge-like levels of ethanol during adolescence resulted in profound alterations in levels of expression of neurotransmitter-associated genes, changes in the volume of specific brain regions, and deficits in a spatial learning paradigm in young adult animals. Other analyses showed a reduction in basal forebrain cholinergic neurons in alcohol-exposed animals. Importantly, neurotransmitter-associated gene expression levels were not altered significantly after a similar exposure to ethanol in adult animals. Thus, the adolescent nervous system appears to be uniquely sensitive to the deleterious effects of ethanol, which can involve several aspects of brain structure and function and manifest in adulthood. (Coleman LG Jr, et al. Alcoholism: Clinical and Experimental Research 35(4):671-688. April 2011,).

Effects of Adrenal Sensitivity, Stress- and Cue-Induced Craving, and Anxiety on Subsequent Alcohol Relapse and Treatment Outcomes.

Alcoholism is a chronic, relapsing illness in which stress and alcohol cues contribute significantly to relapse risk. Dysregulation of the hypothalamic-pituitaryadrenal (HPA) axis, increased anxiety, and high alcohol craving have been documented during early alcohol recovery, but their influence on relapse risk has not been well studied. Researchers investigated these responses in treatment engaged, 1-month–abstinent, recovering alcohol dependent patients relative to matched controls, and also assessed whether HPA axis function, anxiety, and craving responses are predictive of subsequent alcohol relapse and treatment outcome. The researchers found significant HPA axis dysregulation, marked by higher basal corticotropin level and lack of stress- and cue-induced corticotropin and cortisol responses, higher anxiety, and greater stress- and cue-induced alcohol craving, in the alcohol-dependent patients vs the control group. Stress- and cue-induced anxiety and stress induced alcohol craving were associated with fewer days in aftercare alcohol treatment. High provoked alcohol craving to both stress and to cues and greater neutral, relaxed–state cortisol to corticotropin ratio (adrenal sensitivity) were each predictive of shorter time to alcohol relapse. The results identify a significant effect of high adrenal sensitivity, anxiety, and increased stress and cue-induced alcohol craving on subsequent alcohol relapse and treatment outcomes. Findings suggest that new treatments that decrease adrenal sensitivity, stress and cue-induced alcohol craving, and anxiety could be beneficial in improving alcohol relapse outcomes. (Sinha R, et al. Arch Gen Psychiatry. Published online May 2, 2011.)

The Effect of Naltrexone on Alcohol’s Stimulant Properties and Self-Administration Behavior in Social Drinkers: Influence of Gender and Genotype.

Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some. To investigate potential predictors of these differential responses, social drinkers were administered 6 days of treatment with naltrexone vs. placebo. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1). Researchers found that naltrexone decreased the ethanol-induced ‘euphoria’ to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages regardless of gender or genotype. The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use. (Setiawan, E, et al. Alcohol Clin Exp Res, Vol 35, No 6, June 2011: pp 1134–1141)

Gabapentin Combined With Naltrexone for the Treatment of Alcohol Dependence

In this study, researchers conducted a clinical trial to evaluate whether the combination of naltrexone and gabapentin was better than naltrexone alone and/or placebo during early drinking cessation phase, and if so, whether this effect persisted. All participants received medical management. Researchers found that during the first 6 weeks of drinking cessation, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone-alone group, which had an interval similar to that of the placebo group; had fewer heavy drinking days than the naltrexone-alone group, which in turn had more than the placebo group; and had fewer drinks per drinking day than the naltrexone alone group and the placebo group. The addition of gabapentin to naltrexone improved drinking outcomes over naltrexone alone during the first 6 weeks after cessation of drinking. This effect did not endure after gabapentin was discontinued. (Anton, RF, et al. Am J Psychiatry, AJP in Advance. Published March 31, 2011.)

Drinking motives, protective behavioral strategies, and experienced consequences: Identifying students at risk.

Researchers explored the association between drinking motives and protective behavioral strategies among college students, including whether individuals with different drinking motives were more or less likely to use protective behavioral strategies and whether the combination of drinking motives and use of protective strategies may help identify individuals at elevated risk for alcohol-related problems. They found that individuals who had greater enhancement and social motives for drinking used protective strategies less frequently, while those who had greater conformity motives used protective strategies more frequently. Interactions of drinking motives with the number of protective strategies tended to be non-significant; however, significant interactions indicated that greater coping and conformity motives were especially associated with negative outcomes among individuals who used fewer protective strategies. The findings suggest motives to drink influence whether students use protective strategies to avoid alcohol related consequences. The findings also show that the use of protective strategies helps to minimize alcohol-related consequences, suggesting that prevention programs that focus on helping students develop protective strategies could help protect against alcohol-related harms. (Patrick ME, et al. Addict Behav. 2011 Mar;36(3):270-3.)

Does distraction reduce the alcohol-aggression relation? A cognitive and behavioral test of the attention-allocation model.

Investigators examined the cognitive underpinnings of the attention-allocation model and attempted to replicate and extend past behavioral findings for this model as an explanation for alcohol-related aggression. A diverse sample of men between ages 21 and 35 were randomly assigned to 1 of 2 beverage conditions (i.e., alcohol, no-alcohol control) and 1 of 2 distraction conditions (i.e., distraction, no-distraction). Following beverage consumption, participants were provoked via reception of electric shocks and a verbal insult from a fictitious male opponent. Participants' attention allocation to aggression words (i.e., aggression bias) and physical aggression were measured using a dot probe task and a shock-based aggression task, respectively. Intoxicated men whose attention was distracted displayed significantly lower levels of aggression bias and enacted significantly less physical aggression than intoxicated men whose attention was not distracted. However, aggression bias did not account for the lower levels of alcohol-related aggression in the distraction, relative to the no-distraction, condition. The results replicate and extend past evidence that cognitive distraction is associated with lower levels of alcohol-related aggression in highly provoked males and provide the first known cognitive data to support the attentional processes posited by the attention-allocation model, and provide preliminary support for the development of interventions that aim to redirect intoxicated men’s attention toward stimuli that is nonaggressive, nonprovocative, and/or prohibitive of aggressive behavior, and support the use of techniques that refocus intoxicated individuals before aggression can escalate. (Gallagher KE, Parrott DJ. J Consult Clin Psychol. 2011 Apr 18. [Epub ahead of print]).

How trajectories of reasons for alcohol use relate to trajectories of binge drinking: National panel data spanning late adolescence to early adulthood.

Understanding the ways in which reasons for use and alcohol behaviors change across young adulthood is important for describing development and for intervening to promote health and reduce negative consequences associated with excessive alcohol use. In the current study, researchers investigated developmental changes in both alcohol use behaviors and self-reported reasons for alcohol use among men and women participating in the Monitoring the Future national study. Results revealed developmental changes in reasons for use and correlations between the patterns of change in frequency of binge drinking and change in reasons for use. In particular, an increase in binge drinking between ages 18 and 22 was correlated with using alcohol to get high and because of boredom. Continued binge drinking between ages 22 and 30 was correlated with using alcohol to get away from problems. Almost no moderation by gender, race, college attendance, employment, or marital status was found. Binge drinking and reasons for alcohol use traveled together, illustrating the ongoing and dynamic connections between changes in binge drinking and changes in reasons for use across late adolescence and early adulthood. (Patrick ME, Schulenberg JE. Dev Psychol. 2011 Mar;47(2):311-7.)

The Minimum Legal Drinking Age and Public Health

Alcohol consumption and its harms are extremely common among young people, including those who are below the legal drinking age of 21. Some activists and policymakers have put forth proposals to lower the drinking age from 21 to 18, arguing that the current age-21 drinking limit in the United States is “not working.” In the current study, researchers conducted economic analyses to estimate the effects of the minimum legal drinking age (MLDA) on deaths, injuries, crime, and alcohol consumption, and to identify the costs and benefits of lowering the drinking age to 18. They report that a large and compelling body of empirical evidence shows that setting the MLDA at 21 clearly reduces alcohol consumption and its major harms. They estimate that if the drinking age were lowered to 18, there would be an additional 8 deaths per 100,000 person years for the 18–20 age group. Using a common estimate of the value of a statistical life of $8.72 million, this suggests that for every 100,000 young adults allowed to drink legally for a year, the cost in terms of increased mortality is about $70 million. The researchers also estimate that lowering the drinking age would impose additional costs on others for crime, health care, and deaths of non-drinking drivers and passengers of at least $12 million annually for every 100,000 newly legal drinkers. These estimates suggest that each extra drink consumed as a result of lowering the MLDA would generate harms valued at more than $15 to the drinker plus at least an additional $2.63 in harms imposed on others, all in addition to the purchase price of the drink. These costs are likely considerably larger than the value that people would place on the additional drinking. The researchers conclude that “…the evidence strongly suggests that setting the minimum legal drinking age at 21 is better from a cost and benefit perspective than setting it at 18 and that any proposal to reduce the drinking age should face a very high burden of proof.” (Carpenter, C and Dobkin, C. Journal of Economic Perspectives—Volume 25, Number 2—Spring 2011—Pages 133–156).

Husbands' and wives' alcohol use disorders and marital interactions as longitudinal predictors of marital adjustment.

In this longitudinal study, investigators tested the relationships among wives' and husbands' lifetime alcoholism status, marital behaviors, and marital adjustment. Participants were 105 couples from the Michigan Longitudinal Study (MLS), an ongoing multimethod investigation of substance use in a community-based sample of alcoholics, nonalcoholics, and their families. Husbands and wives completed a series of diagnostic measures, and lifetime diagnosis of alcohol use disorder was assessed. Couples completed a problem-solving marital interaction task 3 years later, which was coded for the ratio of positive to negative behaviors. Couples also completed a measure of marital adjustment in subsequent follow-up sessions. Results showed that husbands' lifetime AUD predicted lower levels of their wife's positive marital behaviors 3 years later but was not related to their own or their wife's marital adjustment 9 years from baseline. By contrast, wives' lifetime AUD had direct negative associations with their own and their husband's marital satisfaction 9 years later, and wives' marital behaviors during the problem-solving task predicted their own and their husband's marital satisfaction 6 years later. Findings indicate that marital adjustment in alcoholic couples may be driven more by the wives' than the husbands' AUD and marital behavior. More generally, this study highlights the importance of assessing both partners over time to better understand the effects of AUDs on marriage. (Cranford JA, et al. J Abnorm Psychol. 2011 Feb;120(1):210-22.)

Alcohol consumption and depressive symptoms over time: A longitudinal study of patients with and without HIV infection.

The impact of alcohol consumption on depressive symptoms over time among patients who do not meet criteria for alcohol abuse or dependence is not known. Therefore, scientists undertook the current study to evaluate the impact of varying levels of alcohol consumption on depressive symptoms over time in patients with and without HIV infection, using data from the Veterans Aging Cohort Study (VACS), a prospectively enrolled cohort study of HIV-infected patients and age-, race- and site-matched HIV uninfected patients. The researchers found that, at baseline, depressive symptoms were higher in hazardous and binge drinkers than in past and non-hazardous drinkers, and similar to those with abuse or dependence. There was no difference in the association between alcohol-related category and depressive symptoms by HIV status. Hazardous drinkers and binge drinkers were more than two times more likely to meet criteria for depression when compared to non-hazardous drinkers. The associations between alcohol consumption and depressive symptoms persisted over three years and were responsive to changes in alcohol-related categories. The researchers conclude that HIV-infected and HIV-uninfected hazardous and binge drinkers have depressive symptoms that are more severe than non-hazardous and non-drinkers and similar to those with alcohol abuse or dependence. Patients who switch to a higher or lower level of drinking experience a similar alteration in their depressive symptoms. These findings raise the possibility that clinicians caring for these patients may consider alcohol treatments, such as brief interventions, which may decrease alcohol consumption in those with hazardous and binge drinking, to improve depressive symptoms. (Sullivan LE, et al. Drug Alcohol Depend. 2011 Feb 21. [Epub ahead of print]).

The role of heavy alcohol use in the developmental process of desistance in dating aggression during adolescence.

Researchers examined the role of heavy alcohol use in the developmental process of desistance in physical dating aggression during adolescence. Using data spanning grades 8 through 12 they tested the hypotheses that (a) higher levels of early heavy alcohol use would be associated with decreased deceleration from dating aggression during late adolescence and (b) higher levels of heavy alcohol use during time-points in late adolescence would be associated with elevated levels of dating aggression at those same time points. Contrary to their expectations, the researchers reported that the effects of both early and continuing heavy alcohol use on dating aggression were strong during early adolescence but tended to diminish over time. Unexpectedly, the contemporaneous effects of alcohol use on dating aggression were stronger in the spring than in the fall semesters. The findings highlight the importance of applying a developmental perspective to increase understanding of how the interrelations among health risk behaviors and their determinants are embedded in the life-course. A better understanding of this developmental pattern, which mirrors that of other antisocial behaviors, will require more theorizing and research into the mechanisms that explain this normative shift towards desistance and further study of both the distal and proximal factors that may influence the desistance process. (Reyes HL, et al. J Abnorm Child Psychol. 2011 Feb;39(2):239-50.)

Alcohol outlets, neighborhood characteristics, and intimate partner violence: ecological analysis of a California city.

Neighborhood indicators of social disadvantage, such as poverty and unemployment, are associated with intimate partner violence (IPV). Despite the well-established link between heavy drinking and IPV, few studies have analyzed the contribution of alcohol outlet density to the occurrence of IPV. In the current study, researchers used ecological data to determine if alcohol outlet density (number of bars, restaurants serving alcohol, and off-premise outlets per unit area) is related to rates of IPV-related police calls and IPV-related crime reports in Sacramento, California. The results showed that each additional off-premise alcohol outlet is associated with an approximate 4% increase in IPV-related police calls and an approximate 3% increase in IPV-related crime reports. Bars and restaurants were not associated with either outcome. The findings suggest that alcohol outlet density, especially off-premise outlets, appear to be related to IPV events. Further research is needed to understand the mechanisms by which neighborhood factors, such as alcohol outlet density, affect IPV behaviors. Understanding these mechanisms is of public health importance for developing environmental IPV prevention strategies, such as changes in zoning, community action, education, and enforcement activities. (Cunradi CB, et al. J Urban Health. 2011 Apr;88(2):191-200.)

A CHRNA5 allele related to nicotine addiction and schizophrenia.

Schizophrenia and nicotine addiction are both highly heritable phenotypes. Because individuals with schizophrenia have a higher rate of smoking than those in the general population, genes associated with smoking might be overrepresented in schizophrenia and thus help explain their increased smoking incidence. Although a number of genes have been proposed to explain the increased smoking risk in schizophrenia, none of them have been consistently linked to smoking and schizophrenia, and thus difficult to explain the increased smoking in schizophrenia. A functional smoking-related nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) has recently been discovered and replicated. Researchers tested whether this variant contributes to smoking in schizophrenia in a sample of 313 schizophrenia patients and 525 controls. A variant of the CHRNA5 gene is significantly associated with smoking severity independently in schizophrenia patient smokers and control smokers. The same variant is significantly associated with schizophrenia in both Caucasian and African-American nonsmoker schizophrenia patients compared with control nonsmokers. Intriguingly, researchers found that this gene variant was not significantly associated with smoking status (smokers vs. nonsmokers) in either schizophrenia patients or controls. Thus, while their study identifies a genetic variant that is simultaneously linked to smoking and schizophrenia in the same cohort, whether the variant contributes to the increased smoking prevalence in schizophrenia patients requires additional studies. (Hong LE, et al. Genes Brain Behav. 2011 Mar 18. [Epub ahead of print]).

Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol.

The hippocampus is a key brain region involved in both short- and long-term memory processes and may play critical roles in drug-associated learning and addiction. In this study, researchers found extensive hippocampal gene expression changes common to both cocaine-addicted and alcoholic individuals that may reflect neuronal adaptations common to both addictions. They also observed functional changes that were related only to long-term cocaine exposure, particularly the inhibition of mitochondrial inner membrane functions related to oxidative phosphorylation and energy metabolism, which has also been observed previously in neurodegenerative diseases. Cocaine- and alcohol-related histone H3K4me3 changes highly overlapped, but greater effects were detected under cocaine exposure. There was no direct correlation, however, between either cocaine- or alcohol- related histone H3k4me3 and gene expression changes at an individual gene level, indicating that transcriptional regulation as well as drug-related gene expression changes are outcomes of a complex gene-regulatory process that includes multifaceted histone modifications. (Zhou Z, et al. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6626-31. Epub 2011 Apr 4.)

Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver.

The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB(1)R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB(1)R in the control of liver regeneration. In the current study, researchers report that mice lacking CB(1)R globally or in hepatocytes only and wild-type mice treated with a CB(1)R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB(1)R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hydrolase. In wild-type but not CB(1)R(-/-) mice, PHX induces robust up-regulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB(1)R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression. (Mukhopadhyay B, et al. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6323-8. Epub 2011 Mar 7.)

Zinc supplementation improves lung health in alcohol-fed rats.
Chronic alcohol abuse causes a variety of physiologic and immunologic impairments that increase the risk for pneumonia and acute lung injury. Researchers recently found that chronic alcohol ingestion in rats decreases zinc levels and macrophage function in the alveolar space of the lung, provocative findings in that zinc is essential for normal immune and antioxidant defenses. In the current study, researchers investigated whether dietary zinc supplementation could improve lung function in alcohol-fed rats. They tested 3 different groups of rats: control-fed, alcohol-fed, and alcohol-fed with zinc supplementation. They then inoculated the rats with bacteria that cause pneumonia. The researchers found that alcohol-fed rats had a 5-fold decrease in lung bacterial clearance compared to control-fed rats. Dietary zinc supplementation of alcohol-fed rats normalized bacterial clearance and mitigated oxidative stress in the alveolar space, suggesting that such a strategy could decrease the risk of pneumonia and lung injury in individuals with alcohol use disorders. (Mehta AJ, et al. Alcohol Clin Exp Res. 2011 35(8):1-10.)

Study provides new details about how alcohol interferes with neural cell adhesion.
Scientists believe that neural cell adhesion proteins may play a critical role in brain development and may be an important target for ethanol in the pathogenesis of fetal alcohol spectrum disorders (FASD). In the current study, researchers defined an alcohol binding “pocket” on brain cells in culture that appears to be involved in the regulation L1, a specific cell adhesion protein. The finding advances our understanding of the mechanisms by which alcohol promotes FASD and may guide development of preventive agents capable of blocking alcohol's inhibitory effect on L1 function. (Dou X, et al. J Biol Chem. 2011 286(18):16131-9.

MicroRNA-155 contributes to the development of alcoholic liver injury.
MicroRNAs (miRs) are small noncoding RNA molecules that regulate the expression of target genes involved in a wide range of biological processes. Among them, miR-125b, miR-146a and miR-155 have been identified as central mediators of innate immune responses and inflammation. Considering the potential role that miRs may play in the inflammatory processes involved in alcoholic liver disease (ALD), the current study evaluated the hypothesis that miR-155, miR-146a and/or miR-125b could play a role in the development of alcoholic liver injury. Researchers demonstrated that chronic alcohol exposure augments TNFα production via miR-155 in liver macrophages. In addition, they found that miR-155 stabilizes TNFα mRNA after alcohol exposure, thus increasing the release of this inflammatory mediator. These data support the concept that miRs contribute to the development of alcoholic liver injury and indicate that miR-155 could be a potential therapeutic target in ALD. (Bala S, et al. J Biol Chem. 2011 Jan 14;286(2):1436-44.)
 

Study helps define mechanisms of liver damage by obesity and alcohol.
Epidemiological evidence suggests that obesity and alcohol consumption act synergistically to induce a variety of liver problems, ranging from steatosis (fatty liver) to an increased risk for liver cancer in humans. Similar effects have been seen in animal studies. In the current study, conducted in mice, researchers showed that moderate obesity plus alcohol act synergistically to induce steatohepatitis in an alcohol dose-dependent manner. Moreover, a heightened synergism was observed with a higher dose of alcohol, which led to such effects as severe steatohepatitis, pericellular fibrosis, and intensified nitrosative stress in the liver. Unexpectedly, mice exhibiting these synergistic effects also exhibited increased levels of plasma adiponectin and activated hepatic AMPK (p-AMPK). These results suggest the likelihood that the synergism between obesity and alcohol is mediated at least in part, by adiponectin resistance, and this resistance appears to be downstream of p-AMPK. (Xu J, et al. J Hepatol 2011 Jan 20 [Epub ahead of print]).