NIAAA Director's Report on Institute Activities to the 128th Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism

Tuesday, September 13, 2011

Contents:

A. Legislation, Budget, and Policy
B. Director's Activities
C. NIAAA Staff and Organization
D. Press Releases
E. Multi-Media Products
F. News Media Interactions
G. NIAAA Program Announcement and Request for Applications Information
H. NIAAA Research Programs

A. Legislation, Budget, and Policy

Budget Update -

FY 2011

The NIAAA is currently closing out FY 2011.  The FY 2011 full year Continuing Resolution for the Institute is $458.3 million and reflects a decrease of about $4.1 million or 0.8% from the FY 2010 enacted 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 followed the NIH grant funding policy for noncompeting RPGs.  Non-modular research projects grants, from all ICs, with the single exception of NCI, were reduced to 1 percent below the FY 2010 award level.  Though there is more variability among NIH Institutes for modular RPGs, NIAAA applied the same reductions to modular grants 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 applied 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.   

FY 2012

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.   The House held no NIH appropriations hearing this spring.  In addition, no House or Senate mark-ups of the FY 2012 budget have been scheduled.

As expressed by Dr. Collins at the 102nd meeting of the Advisory Committee to the NIH Director in June, “This is a very uncertain time.”  Although the FY 2012 President’s budget for the NIAAA of $469.2 million represents almost a 2.5% increase over the FY 2011 comparable level, it would be unlikely for this to be approved by Congress and some reductions from our current FY 2011 budget level are anticipated.

Once again, the NIH is expecting to begin the new fiscal year under a temporary or series of temporary Continuing Resolutions.

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:

C. NIAAA Staff and Organization Staff Honors

Dr. Peter B. Silverman, Deputy Scientific Director and Technology Development Coordinator, received the Martin K. Trusty Excellence in Management Award in June.   The Trusty Award recognizes long-term outstanding commitment to and excellence in the management of the NIAAA.

Dr. Pal Pacher, Acting Chief of the Section on Oxidative Stress Tissue Injury in the NIAAA Laboratory of Physiologic Studies, has been elected a Fellow of the American College of Cardiology.

Dr. Markus Heilig, NIAAA Clinical Director, has been selected to deliver the 2012 Archibald Lecture at the Centre for Addiction and Mental Health in Toronto. This annual scientific lecture series was established to honor the late H. David Archibald, the Founder of the Addiction Research Foundation, and has continued under the auspices of the Centre for Addiction and Mental Health.  Dr. Heilig will lecture on the theme of Biomedical Research.

Dr. Joseph Hibbeln, Acting Chief of the Section of Nutritional Neurosciences, NIAAA Laboratory of Membrane Biochemistry and Biophysics, received the 2011 Albert Hogan Lectureship Award of the University of Missouri-Columbia.

Staff Changes

Dr. Marc Rigas of the Science Policy Branch moved to the National Science Foundation in August, 2011.

Extramural Staff Activities

Dr. Ranga (RV) Srinivas, Chief of Extramural Project Review Branch served as co-leader of the breakout session during the NIAAA/NIH Grantsmanship Workshop at the Annual Meeting of the Research Society on Alcoholism held in Atlanta GA on June 28, 2011.

Dr. Abe Bautista, Director of the Office of Extramural Activities co-chaired Symposium Eight on Investigation of HIV Viral Proteins: Molecular and Behavioral Mechanisms at the Annual Meeting of the National Hispanic Science Network held in Miami Fl on August 26, 2011. Dr. Bautista, Dr. Srinivas and Dr. Philippe Marmillot, Scientific Review Officer chaired a workshop on NIH Grantsmanship/Peer Review at the same meeting in Miami.

Dr. Antonio Noronha co-organized and chaired a symposium with Dr. Barbara Mason from The Scripps Research Institute entitled “Alcoholism: Cellular Mechanisms and Potential Treatment Targets” at the 3rd International Drug Abuse Research Society & International Society for Neurochemistry Satellite Meeting in Istanbul, Turkey, August 22-26, 2011.  He also gave a presentation entitled “Advances in Medications Development to treat Alcoholism”.

Dr. Antonio Noronha gave a presentation at the RSA symposium on “Receptors and Enzymes: New Molecular Targets for the Treatment of Alcohol Abuse Disorders” in Atlanta, Georgia, June 25-29, 2011.

Dr. Robert Huebner, Acting Director, DTRR presented an update on the NIAAA treatment research agenda at the 8th Annual RSA Satellite Conference on Mechanisms of Behavior Change in Atlanta on July 25th.

Dr. Lawrence Baizer and Dr. Joe Wang co-chaired a symposium entitled “Development and Applications of Biomarkers of Alcohol Abuse and Alcohol-induced Tissue Damage” as a satellite at the Research Society on Alcoholism meeting in Atlanta, Georgia on June 25, 2011. The session was organized by the trans-NIAAA Biomarkers Working Group and the goals were 1) to discuss the strengths and limitations of available biomarkers and 2) describe several innovative approaches for discovery and validation of new alcohol biomarkers. Speakers included Drs. Raye Litten, Bill Freeman, Cynthia Bearer, Albert Fornace and Sally Nelson.

NIAAA and NIDA worked closely together on two important workshop activities associated with  the 19th World Congress of Psychiatric Genetics held on September 10 - 14, 2011 in Washington, DC. The Mini convention that took place on September 9, 2011 was entitled,” NIDA/NIAAA Mini-convention on Genetics of Substance Abuse”. The speakers included leaders in genetic studies of both alcohol and drug abuse. The purpose of this Mini-convention was to develop a consensus research strategy based on new developments in the areas of genetics, genetic epidemiology, and epigenetics of alcohol and substance use. The NIAAA staff who contributed to the NIDA/NIAAA Mini convention included Abbas Parsian, Matt Reilly, Lindsey Grandison and Antonio Noronha.  

Dr. Abbas Parsian, program director for human genetics /genomics in the Division of Neuroscience & Behavior organized and co-chaired the NIAAA/NIDA workshop on September 10, 2011 at the 19th World Congress of Psychiatric Genetics held on September 10 - 14, 2011 in Washington, DC. Dr. Matt Reilly chaired one of the sessions. This NIAAA/NIDA Workshop was entitled,” Next Generation Sequencing Technologies and Medical Sequencing Approaches for Complex Disorders”. The purpose of this satellite meeting was to develop a consensus research strategy based on new developments in next generation sequencing (NGS) technologies. The production of large numbers of low cost sequence data will make the NGS platform useful for many applications especially human genomics. Dr. Parsian gave an overview of the challenges in gene mapping for complex human disorders including alcoholism, use of NGS in identification of rare variation, ethical issue with such data and the introduction to the workshop. The workshop was very well attended by alcohol researchers, neuropsychiatric genetics community and human geneticists.

Dr. Peter Gao organized a symposium on “Stem Cells and Alcohol” at the 2011 RSA annual meeting on June 28 in Atlanta, GA.

Dr. Peter Gao and Dr. Gary Murray represented DMHE/NIAAA in the outreach program at the 2011 NIH Director’s New Innovator Awardee Meeting on July 28, 2011.

Dr. Bill Dunty presented introductory remarks for the symposium entitled "Epigenetic Insights Into Fetal Alcohol Spectrum Disorders" held during the 34th annual meeting of the Research Society on Alcoholism.  The symposium was organized by Drs. Dale Hereld and Bill Dunty along with NIAAA grantee Dr. Eva Redei of Northwestern University.

Dr. Svetlana Radaeva co-organized/co-chaired the “Gene-Nutrient Interactions in Disease Development  in Alcoholics: Folates and Retinoids” symposium at the 34th Annual RSA Conference in Atlanta, GA.

Dr. Andras Orosz and Dr. Max Guo organized a satellite symposium titled "Cellular Organelles and Cytoskeleton in Alcohol Induced Disorders" at the 34th Annual RSA Conference in Atlanta, GA.

Dr. Max Guo and Dr. Jan Hoek of Thomas Jefferson University co-organized a symposium on “Systems Biology Studies of Alcohol-Induced Liver Injury” at the 34th Annual RSA Conference in Atlanta, GA.

The trans-NIAAA Biomarkers Working Group has organized a satellite session, “Development and Applications of Biomarkers of Alcohol Abuse and Tissue Damage, Cancer and Neurodegeneration” to take place at the annual meeting of the American Association of Pharmaceutical Scientists , October 23, 2011, in Washington, DC. Co-organizers are Dr. Kathy Jung, and Dr. Lawrence Baizer.

DMHE is organizing a new meeting of the Extramural Advisory Board on “Alcoholic Hepatitis”.  DMHE staff and outside experts will present to the EAB and the National Advisory Council at the February, 2012 meeting.

Dr. Ralph Hingson presented “Recent Trends and Findings Regarding the Magnitude and Prevention of College and Underage Drinking Problems,” at the Community Anti-Drug Coalitions of America’s (CADCA) Mid-Year Training Institute in Anaheim, CA, July 28, 2011. 

Dr. Ralph Hingson presented “Preventing Alcohol-Related Injuries: From Global to Local,” at The Catholic University of America: National Catholic School of Social Service, Class: Social Welfare Policy and Services II, Washington, D.C., July 12, 2011. 

Dr. Ralph Hingson presented “Current Trends in College Drinking,” at the Research Society on Alcoholism’s 34th Annual Scientific Meeting, Atlanta, GA, June 29, 2011.

Dr. Ralph Hingson presented “Alcohol and Drug Use in Fatally Injured Drivers in U.S. States that Test Over 80% of Deceased Drivers for Both Alcohol and Drugs,” at the Research Society on Alcoholism’s 34th Annual Scientific Meeting, Atlanta, GA, June 28, 2011. 

Dr. Ralph Hingson presented “Improving Health through Policy and Partnerships: Alcohol-Impaired Driving and Other Injury Prevention: From Global to Local,” at the Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD, June 23, 2011.

Dr. Rosalind Breslow organized and Co-Chaired a NIAAA Expert Panel on Alcohol & Chronic Disease Epidemiology, at the National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, August 2-3, 2011.

Dr. Robert Freeman organized and Co-Chaired the panel: “Advances In Understanding Alcohol-Related Sexual Aggression In Males: New Evidence From The Laboratory And Survey Research,” at the Annual Meeting of the Research Society on Alcoholism, Atlanta, June, 2011.

Dr. Robert Freeman was a panel discussant in, “From Recruitment To Intervention: An Overview Of Research  Methodologies Using Social Networking Sites,” at the Annual Meeting of the Research Society on Alcoholism, Atlanta, June, 2011.

Dr. Robert Freeman organized and moderated, “Preventing Alcohol-Related Violence: 3 Promising North American Interventions Conducted in Bars, at the Border, and in the Emergency Department,” at the Society for Prevention Research 19th Annual Meeting, Washington, DC, June, 2011.

Dr. Robert Freeman was a panelist on, “Federal Partners in Bullying Prevention: Emerging Research on the Prevention of Bullying,” at the Society for Prevention Research 19th Annual Meeting, Washington, DC, June, 2011.

Dr. Robert Freeman was a member of the Program Planning Committee and Chair of the “Efficacy Research” Thematic Sub-Committee for the Society for Prevention Research 19th Annual Meeting, Washington, DC, June, 2011.

Dr. Robert Freeman was a panel moderator for: “Designing Interventions for Special Populations,” at the NICHD Summer Training Institute on Applied Research in Child and Adolescent Development, Potomac MD, June 19-23, 2011.

Dr. Sam Zakhari represented NIAAA on the Trans-NIH Advisory Group for the Therapeutics for Rare and Neglected Diseases (TREND) Program; Trans-NIH Committee on Viral Hepatitis, and the Trans-NIH Common Fund High Risk High Reward Committee.

Dr. Sam Zakhari co-organized and gave presentations in two symposia: 1) Roles of ALDH2 in Alcohol and Non-Alcohol Induced Organ Damage: New Findings from Basic and Clinical Research; and 2) Molecular Mechanisms of Alcoholic and Non-Alcoholic Fatty Liver Diseases: Adipokines, Oxidative Stress and Endocannabinoids.

Dr. Sam Zakhari co-organized and co-chaired a symposium on Alcoholic Liver Disease: From Pathogenesis to Treatment, at the 13th Congress of the European Society for Biomedical Research on Alcoholism, September 2011.

D. Press Releases

The following press materials are based on research supported by NIAAA:

7/11/2011: (press release) Receptor limits the rewarding effects of food and cocaine: NIH scientists help show molecule's crucial role in dopamine regulation

Researchers have long known that dopamine, a brain chemical that plays important roles in the control of normal movement, and in pleasure, reward and motivation, also plays a central role in substance abuse and addiction. In a new study conducted in animals, scientists NIAAA and colleagues at the Institute for Research on Genetic Engineering and Molecular Biology in Argentina and the University of Michigan Medical School found that a specific dopamine receptor, called D2, on dopamine-containing neurons controls an organism’s activity level and contributes to motivation for reward-seeking as well as the rewarding effects of cocaine.  The study, coauthored by David M. Lovinger, Ph.D., chief of NIAAA’s Laboratory for Integrative Neuroscience, was published in Nature Neuroscience.

8/23/2011: (press statement) Study links low DHA levels to suicide risk among U.S. military personnel

NIAAA scientists led by CAPT Joseph R. Hibbeln, M.D., teamed with researchers at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, Md., to analyze a sample of suicide deaths among U.S. military personnel on active duty between 2002 and 2008. The researchers compared levels of omega-3 fatty acids of 800 individuals who committed suicide with those of 800 randomly selected controls--service members who were matched with the suicide cases by age, sex, and rank.  They found that all the service members had low omega-3 levels, and that suicide risk was greatest among individuals with the lowest levels of docosahexaenoic acid (DHA), the major omega-3 fatty acid concentrated in the brain.  The study was reported in the Journal of Clinical Psychiatry.

9/1/2011: (press release) NIH-support studies show online course helps reduce harmful college drinking

An online alcohol prevention course can help reduce harmful drinking among college freshmen, but the benefits in the fall don’t last through the spring, according to a study supported by NIAAA.  Led by Mallie J. Paschall, Ph.D., and colleagues at the Pacific Institute for Research and Evaluation in Berkeley, Calif., the research evaluated the effectiveness of AlcoholEdu, a commercially available Internet-based alcohol misuse prevention course.  As reported in the American Journal of Preventive Medicine, the researchers found that students who took the online course reported significantly reduced alcohol use and binge drinking during the fall semester, compared with control students.  These beneficial effects, however, did not persist into the spring semester.  The researchers conclude their recent findings suggest that use of the Internet-based prevention course should be reinforced with effective environmental prevention strategies.

E. Multi-Media Products from NIAAA

NIAAA Spectrum -- Issue 7 of the Institute's online webzine, will be released in September, 2011

Alcohol Research & Health
Fetal Alcohol Spectrum Disorders, Vol. 34, No. 1, 2011 is now available online

Alcohol and Cancer, a new book published by Springer in 2011. All members of DMHE staff contributed chapters for the book, which is based on presentations to NIAAA’s  Extramural Advisory Board and the NIAAA National Advisory Council in June 2010.

NIAAA meets with MTV

In August, Fred Donodeo and Vivian Faden met with executives at MTV to promote NIAAA as a source of technical assistance, tools, and other resources for their teen and young adult audiences.  While a number of potential long-term arrangements were discussed, the meeting has already paid dividends.  In the week following the meeting, MTV discussed NIAAA’s products on a network blog promoting one of their new shows. They also tweeted that NIAAA facts and tools are helpful resources, a message that reached more than a million twitter followers.

New seasonal fact sheet generates interest

In late June, NIAAA added a new fact sheet on Summer Safety to its seasonal outreach series. Developed with input from the National Association of State Boating Law Administrators, the fact sheet offered statistics and messages related to alcohol, and swimming, boating, other water sports, and driving during the summer months. It was distributed through PR Newswire and received substantial pickup - a total of 304 clips representing a total audience of 15,580,000 people.  In August, NIAAA disseminated its popular seasonal fact sheet titled “Fall Semester—A Time for Parents to Discuss the Risks of College Drinking.” This release generated a total of 173 clips, representing a total audience on 133,972,000 people. Additionally, the fact sheet was disseminated by five major universities (University of Colorado, Oklahoma State, Colorado State, Texas A & M, and Minnesota) to parents of incoming freshmen.

Upcoming papers

White, A., Hingson, R., Pan, I., Ye-Yi, H.  Hospitalizations for alcohol and drug overdoses in young adults ages 18-24 in the United States, 1999-2008.  J Stud Alcohol Drugs (in press). 

Hingson, R., Heeren, T., Edwards, E., Saitz, R.  Young adults at risk for excess alcohol consumption are often not asked or counseled about drinking alcohol.  Journal of General Internal Medicine, in press.

F. 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 interviewed by Celia Vimont of Join Together (a daily news service re substance abuse prevention, treatment and recovery) regarding NIAAA’s new College President’s Working Group.

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:

•  Dr. Collins' announcement in June (conveyed by Dr. Tabak to the NIAAA Advisory Council Mtg) that the NIAAA and NIDA merger is  going to take additional time.

•  NIAAA’s response to the new definition of addiction released by the American Society of Addiction Medicine in August.

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

•  Melinda Beck, Wall Street Journal on the topic of factors that influence reaching a 0.08 BAC.

•  Deborah Kotz, Boston Globe and Gil Kaufman of MTV News regarding the possible dangerous health consequences of an alcoholic quitting alcohol abruptly.

•  Glen Warchol, Salt Lake Tribune, on the potential pitfalls of drinking alcohol for health benefits

•  Stephanie Booth, Cosmopolitan Magazine, regarding alcohol metabolism in women

Dr. Deidra Roach, of the NIAAA Division of Treatment and Recovery Research, was interviewed about alcohol and women by:

•  Brittany Risher, Women's Health magazine, and

•  Catherine Pearson, Huffington Post.

•  Leslie Wade, CNN

Dr. Joseph Hibbeln, Acting Chief, NIAAA Section on Nutritional Neurosciences, discussed the relationship of omega 3 fatty acid consumption to mental health and human behavior in interviews with:

•  Thomas Breinholt, Danish Broadcasting Corporation

•  Faye Flam, Philadelphia Inquirer

•  Thea Singer, More magazine

Dr. Hibbeln discussed his recent paper on the link between low DHA levels and suicide risk among U.S. military personnel in interviews with:

•  Deborah Brauser, Medscape Medical News

•  Patricia Kime, Army Times

•  Stephen Daniells, NutraIngredients-USA.com

•  Lori Solomon, Diagnostics Testing & Technology Report

Dr. Ralph Hingson, Director, NIAAA Division of Epidemiology and Prevention Research, was interviewed about college and underage drinking prevention by:

•  Regina Zilbermints, Des Moines Register

•  Steve Kraske, KCUR – NPR affiliate in Kansas City, MO

•  Glenn Augustine, WIBC -- Indianapolis talk radio

•  Sonya Humphrey, National Geographic channel

G. NIAAA Program Announcement and Request for Applications Information

• PAR 11-174 Program Projects on Alcohol Related Research (P01):  10 grant applications were received.
   
• RFAs AA-11-006 Integrated Neuroscience Initiative on Alcoholism (INIA) Consortia (U01):  2 consortium applications were received, one with 24 components and one with 16 components.
   
• Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grants (T32)- NIAAA receipt date May 25, 2011:  14 applications received.
   
• Zha, W. of DEPR participated in NCI’s PA-11-238 (R01), PA-11-239 (R21) and PA-11-240 (R03): Spatial Uncertainty: Data, Modeling, and Communication.

H. NIAAA Research Programs

RESEARCH REPORTS

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

A Drosophila Model for Alcohol Reward
Identifying genes associated with alcoholism in humans is a slow, labor intensive process due to such factors as genetic heterogeneity and the inability to control for numerous (often unknown) environmental factors that can alter risk.  Scientists have used drosophila for many years to investigate basic genetic mechanisms due to their amenability to genetic manipulation.  Previous studies in drosophila have identified genes associated with specific aspects of alcoholism, namely tolerance.  Tolerance is a readily accessible phenotype in drosophila, because it is based on fly motor behavior which is easy to observe and has significant face validity to the human condition.   Other more complex aspects of alcoholism, such as alcohol’s ability to reinforce behavior by its rewarding properties, have not been modeled in flies because of the lack of a reliable method of measuring rewarding behavior in the fly.  The present study, by the Heberlein laboratory, is the first study to use drosophila to identify genes associated with alcohol reward.  This was accomplished by the design of an elegant fly conditioned place preference assay adopted from the rodent literature.  The authors demonstrate that the fly assay measures reward for alcohol.  (Kaun et al. (2011), Nature Neuroscience, 14(5):612-9).

Prodynorphin Gene Methylation Linked to Human Alcohol Dependence
Epigenetics, the molecular modifications to DNA and chromatin, is fundamental to the regulation of gene expression.  The most well known epigenetic modification is the addition of a methyl-group to the cytosine DNA base.  Several previous studies have found alterations in DNA methylation in blood from alcoholics.  Although these types of studies using blood are important, they do not directly address potential causative factors that underlie alcoholism.  In a new study, altered DNA methylation was found in post-mortem brain tissue obtained from alcoholics.  Specifically, elevated methylation was observed in the gene encoding  prodynorphin, a gene which was previously associated with alcoholism.  This study is the first to link an epigenetic modification in the brain to alcoholism, and provides a basis for investigating the epigenetic mechanisms underlying alcohol dependence.  (Taqi et al. (2010) Addict Biol 16(3):499-509.)

Sex-Specific Role for Adenylyl Cyclase Type 7 in Alcohol Dependence
Risk for developing alcoholism is partially controlled by genetic factors in both men and women.  However, most gene identification studies have focused only on male alcoholics, leaving a need for gene identification studies in females.  In this new study a gene encoding the enzyme adenylyl cyclase type 7 (AC7) was found to be associated with regulation of alcohol consumption in female mice, but not in male mice.  To translate this finding to humans, a candidate gene association study was performed in a cohort of male and female alcoholics.  Genetic variants of AC7 were found to be associated with alcohol consumption only in females.  This study provides insight into gender differences in alcohol consumption and the genetic factors that may contribute to differences in susceptibility to alcoholism in men and women.   (Desrivières et al., (2011) Biol Psychiatry 69(11):1100-8).

Brain Growth Factor Implicated in Alcohol Reward and Seeking
Glia cell line-derived neurotrophic factor (GDNF) is an important growth factor for activity maintenance of mid-brain dopaminergic neurons. Activation of the GDNF pathway in the ventral tegmental area (VTA) causes elevation of dopamine levels in the nucleus accumbens (NAc). In this study, Barak et al. examined effects of GDNF on alcohol withdrawal associated dopamine deficiency and alcohol reward and seeking behavior. They demonstrated that intra-VTA infusion of GDNF compensated the dopamine deficiency-induced by alcohol withdrawal, inhibited conditioned place preference to alcohol, and produced a downward shift in the alcohol dose response. Their results suggest that GDNF reduces alcohol drinking behavior by reversing an alcohol withdrawal-induced dopamine deficiency in the mesolimbic system. Importantly, unlike alcohol, GDNF is not rewarding on its own and does not alter locomotor activity. These results, together with previous studies, suggest that GDNF decreases the motivation of alcohol seeking by normalizing dopamine abnormalities associated with both positive and negative reinforcement. (Barak S, et al., J Neurosci. 2011 Jul 6; 31(27):9885-94.)

Neuropeptide Y (NPY) Blocks the Transition to Alcohol Dependence in Rats
In this study, researchers investigated the effects of treatment with the neurotransmitter neuropeptide Y (NPY) in a rat model of alcohol dependence.  They found that chronic NPY treatment blocked excessive operant alcohol-reinforced responding associated with alcohol dependence induced by alcohol vapor inhalation, as well as gradual increases in alcohol-reinforced behavior in intermittently tested nondependent control rats. NPY decreased baseline GABAergic transmission and reversed alcohol-induced enhancement of inhibitory transmission in the central amygdala by suppressing GABA release via actions at presynaptic Y(2) receptors. This finding has major implications for NPY Y(2) as a medication target for alcohol dependence. Y(2) receptor antagonists were once considered to be a promising avenue for medication development for alcohol dependence.  This study suggests NPY Y(2) agonists would be more likely to produce desirable therapeutic effects.( Gilpin NW, et al. Biol Psychiatry 69(11):1091-9).

Ethanol Enhances Neurosteroidogenesis in Hippocampal Neurons by NMDA Receptor Activation
During acute ethanol intoxication, individuals can perform complex acts for which they later have no recollection, a state referred to as a “blackout.” Ethanol is thought to impair memory by inhibiting cellular mechanisms associated with memory processing. Previous studies have shown that ethanol partially blocks N-methyl-D-aspartate (NMDA) receptors in the brain, and that it inhibits some memory-related mechanisms through the action of neurosteroid molecules. However, it is not clear which neural cells are responsible for neurosteroidogenesis and how ethanol promotes steroid production. This study showed that certain neurosteroids are confined to a region of the hippocampus that is a key structure in learning and memory formation. High but not moderate concentrations of ethanol increased the level of these neurosteroids in that part of the hippocampus. Moreover, exposure to high ethanol levels activates unblocked NMDA receptors, which then leads to an increased synthesis of neurosteroids, and ultimately to deficits in memory formation. These results indicate that the effects of acute alcohol on brain cells are mainly functional impairment instead of structural damage, and may be helpful in understanding the mechanisms underlying cognitive effects of alcohol (such as blackouts) and also the development of novel strategies to prevent alcohol-induced cognitive impairment. (Tokuda K, et al. Journal of Neuroscience 2011; 31, 9905–9909).

Ion Channel Changes in Primate Brain Following Alcohol Withdrawal and Abstinence
Brain cells adapt to chronic ethanol intoxication through changes that allow them to become more excitable, thereby counterbalancing the inhibition caused by alcohol.  Delirium tremens occurs when those counterbalancing adaptations become unbalanced during alcohol withdrawal.  Little is known about whether the primate brain returns to normal with repeated bouts of alcohol abuse and abstinence.  In this study, researchers examined whether changes in ion channel currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.  The researchers found that specific changes in current in a brain region called the inferior olive were associated with prolonged alcohol exposure.  During abstinence, reversal in current was apparent and this reversal persisted during long term abstinence.  The changes observed in the inferior olive may explain dysfunction that occurs during both alcohol exposure and following abstinence.  Medications targeting these ion channels may have relevance for treatment of the long term consequences of alcoholism. (Welsh JP, et al. Proc Natl Acad Sci U S A. 2011 Jun 3. [Epub ahead of print])

Gender Differences in the Association Between Family Conflict and Adolescent Substance Use Disorders
Researchers examined whether the association between childhood family conflict and the risk of substance use disorders (SUDs) in adolescence differs by gender, and whether anxious/depressive symptoms and conduct problems explain this association among adolescent males and females.  They found that girls living in families with elevated levels of conflict were more likely to engage in acting out behaviors, which was associated with the development of SUDs. They note that future epidemiologic research is needed to help determine when this exposure is most problematic with respect to subsequent mental health outcomes and the most crucial time to intervene.  The study provides insights into the influence of parental behavior mediated by adolescent behavioral and psychosocial problems with important implications for future intervention research across developmental life course phases.  (Skeer MR, et al. J Adolesc Health. 2011 Aug;49(2):187-92. Epub 2011 Mar 23.)

ALDH2 and ADH1B Interactions and Sensitivity to Alcohol in Asian-American College Students
In this study, researchers examined whether possession of 2 alcohol-metabolizing gene variations, the aldehyde dehydrogenase ALDH2*2 allele and the alcohol dehydrogenase ADH1B*2 allele, was associated with self-reported sensitivity to alcohol at low doses and at initial use among Asian-American college students.   They found that students who had an ALDH2*2 allele were more likely to report experiencing low-dose symptoms and having heightened initial response to alcohol. They also found an interaction between ALDH2*2 and ADH1B*2, with ADH1B*2 being associated with heightened self-reported sensitivity to alcohol only in individuals who also possessed 1 ALDH2*2 allele.  The findings suggest the effects of ADH1B*2 may be felt more strongly in Asians who already have some heightened sensitivity to alcohol from possessing 1 ALDH2*2 allele, but who are not too sensitized to alcohol from possessing 2 ALDH2*2 alleles. These results offer additional insight into the discrepant findings that have been reported in the literature for the role of ADH1B*2 in response to alcohol and the development of alcohol-related problems, and could help researchers develop tailored interventions based on genetically-related risk and protective factors and specific responses to environmental exposures.  (Luczak SE, et al. Alcohol Clin Exp Res. 2011 Jul;35(7):1238-45.)

Impact of Partner Violence Perpetration, Mental Health and Substance Use on Perceived Unmet Need for Mental Health Care Among Men
Scientists examined the relationship between intimate partner violence (IPV) perpetration, serious mental illness (SMI), and substance use and perceived unmet need for mental health treatment in the past year among men in the general population.  They found that the proportion of men reporting unmet treatment need was greater among IPV perpetrators than nonperpetrators. Hazardous drinking, illicit drug use, alcohol and drug abuse/dependence, and SMI were also more common among perpetrators. Perpetrators were twice as likely to report unmet need for treatment after taking predisposing, enabling, and need factors into account. Alcohol abuse/dependence, drug abuse/dependence, substance abuse treatment, and SMI were independently associated with perceived unmet need for treatment.  The findings suggest that men who perpetrate IPV are at increased risk of perceived unmet need for mental health care. This study also emphasizes the need to identify substance use disorders and mental health problems among IPV perpetrators identified in health, social service, or criminal justice settings. The researchers note the need for additional studies to address barriers to care specific to men who perpetrate IPV beyond economic factors, as well as studies of the social and cultural factors that may interact with partner violence and mental health needs to clarify barriers to care, with regard to ethnic- specific factors as well as those related to gender roles. (Lipsky S, et al. Soc Psychiatry Psychiatr Epidemiol. 2011 Jun 26. [Epub ahead of print])

Drinking Style and Dating Violence Among Urban Youth
This study examined childhood abuse, problem behavior, drinking style, and dating violence (DV) to assess whether (a) alcohol use-related beliefs and behaviors ("drinking style") would be associated with DV perpetration and victimization, (b) drinking style would mediate the relationship between childhood abuse and DV, and (c) the drinking style-DV relationship would be attributable to propensity for problem behavior. Researchers found that for both males and females, past-year DV was associated with a more risky drinking style, characterized by more frequent alcohol use, alcohol-aggression expectancies, drinking to cope, and beliefs that alcohol is disinhibiting and that being drunk provides a "time-out" from behavioral expectations. Researchers conclude that drinking style was associated with DV for males and females and mediated the relationship between childhood victimization and DV. The relationship between drinking style and DV appeared to reflect adolescents' propensity for problem behavior. Additional research that will advance knowledge on this topic will include daily diary or momentary assessment studies that permit the assessment of potential acute effects of alcohol consumption on DV, and longitudinal studies that investigate potential trajectories from early alcohol use to later DV, controlling for other potentially causal factors. (Rothman EF, et al. J Stud Alcohol Drugs. 2011 Jul;72(4):555-66.)

Alcohol Affects Uterine Vascular Adaptations During Pregnancy
Pregnancy-induced utero-placental growth, angiogenic remodeling, and enhanced vasodilation are all partly regulated by estradiol-17β-mediated activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. However, very little is known about the effects of alcohol on these maternal utero-placental vascular adaptations during pregnancy and its potential role in the pathogenesis of Fetal Alcohol Spectrum Disorders (FASDs).  In this study, researchers examined the direct effects of alcohol on uterine vascular adaptations at the level of the uterine endothelium.  Their results suggest a vulnerability of the maternal uterine vasculature to chronic binge-like alcohol that is mediated in part by alterations to the NO system.  Alcohol decreases uterine arterial eNOS expression and negatively impacts its multisite phosphorylation state and associated proteins cav-1 and AKT, indicating reduced eNOS enzyme activity.  Alcohol negatively modulates uterine angiogenesis, as a measure of uterine vascular adaptation, by blunting the dose-dependent proliferative effects of estradiol-17β.  These data advance our understanding of the mechanism by which alcohol may promote FASD though effects on the maternal uterine vasculature.  (Ramadoss J, et al., Alcohol Clin Exp Res. vol. 35, no. 9, September 2011)

Rosiglitazone Improves ARDS Symptoms in Alcohol-fed Mice
Scientists hypothesize that a two-hit model explains the higher incidence of acute respiratory distress syndrome (ARDS) in chronic alcoholics. The two-hit model posits that chronic alcohol primes the lung by elevating expression of oxidative enzymes, while not compromising baseline lung function.  When an infection occurs (the second hit), NADPH oxidase and endothelial nitric oxide synthase (eNOS) expression are elevated further; their increased activity leads to generation of reactive oxygen and reactive nitrogen species (ROS and NOS).  Enhanced oxidative stress is associated with alveolar-capillary barrier dysfunction.  In this study, researchers report that administration of rosiglitazone in vivo in chronically alcohol-fed mice reduced expression of eNOS and related enzymes, reduced ROS, and provided protection from barrier dysfunction.  This therapeutic approach has some advantages over others proposed, in which test drugs must be administered during the full duration of alcohol consumption (an unlikely clinical occurrence). Rosiglitazone administration in mice, starting at the time of infection, was effective, providing a more realistic therapeutic approach. While drawbacks have been associated with rosiglitazone therapy, the fact that it is already an approved drug for type II diabetes might speed translation of its use as an ARDS therapy. (Wagner MC, et al. Alcohol Clin Exp Res. 2011 Jul 18. [Epub ahead of print])

Study Identifies a Novel Effector of Alcohol's Toxicity in Developing Brain Cells
Prenatal alcohol exposure causes significant neurodevelopmental deficits in the fetus. Previous animal studies have shown that clinically relevant ethanol concentrations disrupt development of an area of the fetal brain called the neural crest through mobilization of an intracellular calcium transient. How the calcium transient initiates neural crest cell death is unknown. In the current study, also conducted in animals, researchers identified signaling molecules called Ca2+/calmodulin-dependent protein kinases II (CaMKII) as the calcium target responsible for ethanol-induced neural crest cell death. Treatment with CaMKII-selective inhibitors but not those directed against CaMKIV or PKC completely prevented the cell death. This is the first identification of CaMKII as a critical mediator of ethanol-induced cell death. Because neural crest differentiates into several neuronal lineages, the findings offer novel insights into how ethanol disrupts early neurogenesis. Defining this and other mechanisms by which prenatal alcohol disrupts fetal development is a critical step toward understanding the pathogenesis of Fetal Alcohol Spectrum Disorders and identifying strategic targets for preventive or therapeutic interventions. (Garic A, et al. J Neurochem. vol. 118, no. 4:646-57, 2011.)

Cellular DNA methylation program during neurulation and its alteration by alcohol exposure
Epigenetic changes are believed to be among the earliest key regulators for cell fate and embryonic development. To support this premise, it is important to understand whether or not systemic epigenetic changes coordinate with the progression of development. Previous studies have shown that DNA methylation is programmed when neural stem cells differentiate. In the current study, scientists analyzed the DNA methylation events that occur during early neural tube development. They found that the DNA methylation marks – 5-methylcytosine (5-MeC), DNA methylation binding domain 1 (MBD1), and DNA methytransferases 1 (DNMT1) were highly coordinated in temporal and spatial patterns that paralleled the progress of embryonic development. Alcohol exposure during fetal development, however, which is known to cause fetal alcohol spectrum disorder, altered the density and distribution of the DNA methylation marks. The researchers further demonstrated that the direct inhibiting of DNA methylation with 5-aza-cytidine (5-AZA) resulted in similar growth retardation. Alcohol delayed the cellular DNA methylation program and also retarded embryonic growth. Since direct inhibiting of DNA methylation resulted in similar retardation, alcohol thus can affect embryonic development through a epigenetic pathway. The findings suggest that alcohol's effects on development may result from its ability to interfere with programmed DNA methylation during embryogenesis. (Zhou FC, et al. Birth Defects Res A Clin Mol Teratol vol. 91, no. 8:703-15, 2011)