NIAAA Director's Report on Institute Activities to the 134th Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism

Thursday, September 19, 2013

Table of Contents

• NIAAA DIRECTOR’S NOTE

• NIAAA BUDGET

• DIRECTOR’S ACTIVITIES

• STAFF TRANSITIONS & AWARDS

• NEW RFA’S/PA’S

• NIAAA COMMUNICATIONS & MEDIA COVERAGE

• SELECT NIAAA STAFF ACTIVITIES

• WHAT’S AHEAD

• NIAAA RESEARCH HIGHLIGHTS

Director’s Note

Fall Activities at NIAAA – International Fetal Alcohol Spectrum Disorders Awareness Day &
Back to School

Fall is nearly here and with it come several notable events for NIAAA. First, September 9th marked International Fetal Alcohol Spectrum Disorders Awareness Day, an important reminder that there is no known “safe” amount of alcohol during pregnancy. Fetal alcohol spectrum disorders are 100% preventable; in fact, they are the leading preventable cause of birth defects in the United States.

While you may have recently seen conflicting messages about the safety of light drinking during pregnancy, not enough is known about the potential effects of drinking alcohol while pregnant to declare any amount safe. For this reason, NIAAA, together with the CDC, U.S. Surgeon General, American Academy of Pediatrics, and the American Congress of Obstetricians and Gynecology advise against any drinking during pregnancy.

Here at NIAAA, we continue to gain new insights into the nature of fetal alcohol spectrum disorders and potential intervention and treatment strategies. For the public, our message on September 9th (and every day) is a simple one: there is no known safe level of drinking while pregnant. Women who are, who may be, or who are trying to become pregnant, should not drink alcohol.

With the arrival of fall, we also see the yearly transition from high school to college. The first six weeks of the college fall semester are a critical adjustment period for students, one which can be derailed by underage drinking. NIAAA continues to work with a group of college presidents to help meet their needs and inform them of research-supported strategies to reduce harmful drinking on campus.

As we do every year, NIAAA is also reaching out to parents of college students to help them talk to their sons and daughters about drinking. Our seasonal fact sheet, “Fall Semester—A Time for Parents to Discuss the Risks of College Drinking,” was distributed through PR Newswire in August. The fact sheet provides statistics on the consequences of college drinking, ways for parents to stay involved, and additional NIAAA resources.

Research supports that parents can make a difference in their child’s attitudes and decisions about drinking. With this in mind, fall is a critical period for parents to discuss this topic with their college student.   
Lastly, I’d like to note that this is likely my final meeting as head of the advisory council before NIAAA starts a new chapter with new leadership. I’d like to say a resounding” thank you” to my colleagues and friends; it has been my pleasure to serve as acting director over these 5 years as we’ve advanced the field of alcohol research together.  In short, it has been an honor.

Best,

Kenneth R. Warren
NIAAA Acting Director

NIAAA BUDGET

FY 2013

The NIAAA is currently closing out FY 2013. In FY 2013 NIH received a total of $29.1 billion after an across the board reduction and the Secretary’s transfer.

The FY 2013 appropriation for NIAAA provided $432.9 million. This represented a $25.7 million or a 6% decrease over the FY 2012 comparable level of $458.6 million. NIAAA supported a total of 655 research project grants (RPGs) in FY 2013, including 150 competing awards.

FY 2014

House Action:  The House Appropriations Subcommittee on Labor, HHS FY2014 mark-up scheduled for July 25 was postponed.

Senate Action:  On July 11, 2013, the Senate Appropriations Committee reported out S. 1284, the FY2014 Labor, HHS, Education Appropriations bill.  The bill has been placed on the Senate Calendar.

The NIH level proposed by the Senate Committee is $30.9 billion.  For NIAAA, the Senate recommended amount is $460.7 million, a 3.1 million or 0.6% decrease from the requested level.

Congress was in August recess and returned on Monday, September 9, 2013.

FY 2015

Preliminary work on the budget for FY 2015 is beginning. After intermediate stages of review, the President’s budget request for FY 2015 will be presented to Congress in February 2014, at which time it will become available to the public.

* Enacted base differs slightly from FY 2013 appropriation figure due to transfers, recessions, and comparable adjustments, etc.

DIRECTOR’S ACTIVITIES

Upcoming Events

Photo taken during a recent meeting with the Rector of Danylo Halytsky Lviv National Medical University in Lviv, Ukraine. (Pictured From L to R: Prof., Dr. Borys S. Zimenkovsky, Dr. Kenneth R. Warren, Dr. Peggy Murray, International Officer for NIAAA, and Dr. Christina Chambers, of the University of California San Diego, who is leading an NIAAA supported study conducted through the Medical University of Lviv on nutritional factors in the prevention of fetal alcohol spectrum disorders.)

STAFF TRANSITIONS

Ms. Kathleen Tepas-Wise recently joined the Office of Science Policy as NIAAA’s Legislative Coordinator following completion of NIH’s Management Intern (MI) Program.  As part of the MI program, Ms. Tepas-Wise gained valuable experience working in the NIH Office of Legislative Policy and Analysis (OLPA), on The Hill with the U.S. Senate Committee on Health, Education, Labor and Pensions, and at other NIH Institutes.  Prior to entering the MI Program, Ms. Tepas-Wise served as a nurse in the NIH Clinical Center, moving from direct patient care to providing clinical expertise in protocol implementation, data abstraction, collection and reporting for a variety of clinical trials conducted for the National Cancer Institute (NCI). 
Her responsibilities within the Science Policy Branch will include tracking legislation, coordinating courtesy visits by the incoming NIAAA Director to The Hill, and working with the Communications Branch and public liaison groups to increase the visibility of NIAAA.

Ms. LaToya S. Sewell of the United States Public Health Service joins NIAAA as a Family Nurse Practitioner for the Laboratory of Clinical and Translational Studies (LCTS).  Before coming to NIAAA she served as a Nurse Practitioner in the Clinical Neurocardiology Section at NINDS working with patients with autonomic function disorders.  In her new position she is the Clinical provider for LCTS outpatient service.

STAFF AWARDS

Dr. Robert Huebner was awarded the 2013 Research Society on Alcoholism (RSA) Seixas Award.  It is one of the RSA’s most prestigious honors, and recognizes the recipient’s significant service to the field of alcohol research.  Dr. Huebner was selected to receive this award by the RSA Board of Directors, and was presented with this honor at the end of the RSA Annual Conference.

NEW RFA’S/PA’S

• NIAAA’s research with American Indian/Alaska Native populations has markedly increased with the addition of 5 awards issued in FY2013.  These include two applications received under PAR 11-346: Tribal Colleges and Universities Behavior Wellness Study (TCU-BeWell) (PI Duran); and Motivational Interviewing and Culture for Urban Native American Youth (MICUNAY) (PIs D’Amico & Dickerson). NIDA is contributing $200,000 per year to the MUCUNAY award for each of 5 years. OBSSR has provided co-funding for nearly all five years of the innovative treatment project, Contingency Management Treatment of Alcohol Abuse American Indian People (PIs – Buchwald & McDonell). NIAAA is funding two Native American Research Centers for Health (NARCH) projects:  Development of a Model & Support network for FASD (PI: Chambers) and Perceptions of Alcohol use and Sobriety among Alaska Native People (PI: Dillard).
   
• NIAAA is participating in initiative PAR-13-233 (R01): Chronic Inflammation and Age-related Disease, with the National institute on Aging.  The purpose of this solicitation is to encourage research on the role that inflammation plays in age-related disease and reduced resistance to infection.  Alcohol and aging, separately and together, are associated with disrupted regulation of inflammation, thought to contribute to many disorders. (Drs. Kathy Jung and Joe Wang, DMHE, coordinated NIAAA’s participation in initiative.)
   
• Alcohol Research Resource Awards (R24): The objective of this Notice of Funding Opportunity (NOFO) is to provide general support of already established research resources that serve the alcohol research community. Under special circumstances, the mechanism may be used to support development of a new resource.
• Proteostasis (Protein Homeostasis) Project, a Common Fund idea for FY15 that was submitted on behalf of NIAAA was cleared by the Council of Councils (one of final six proposals). IC directors’ meeting will decide funding at a future date. (Dr. Andras Orosz, DMHE)
   
• Dr. Bob Freeman is the NIAAA contact on the new Program Announcements titled “Implications of New Digital Media Use for Underage Drinking, Drinking-Related Behaviors, and Prevention Research (R01/R21)” (PA-13-262/263)
   
• Dr. Matthew Reilly represents NIAAA on the Extracellular RNA Communication Common Fund initiative.  Recent research has indicated that RNAs can play a role in a variety of complex cellular functions, including newly discovered mechanisms of cell-to-cell communication. RNA can be exported from cells in extracellular vesicles or bound to lipids or proteins, to circulate through the body and affect cells at a great distance. These extracellular RNAs, or “exRNAs,” may also be absorbed from food, the microbes that live in our bodies, or the environment, potentially eliciting a variety of biological responses. However, the actual impact of these exRNAs is not known.  The NIH is supporting 24 collaborative, multidisciplinary awards to explore this novel form of RNA cell communication.  New discoveries made from this program have the potential to advance alcohol research. 
   
• Dr. Reilly also represents NIAAA on the NIH Common Fund’s Library of Integrated Network-based Cellular Signatures (LINCS) program.  This program aims to develop a “library” of molecular signatures that describes how different types of cells respond to a variety of perturbing agents.  Dr. Reilly initiated a collaborative project between alcohol researchers and the LINCS program to explore how alcohol and medications used to treat alcoholism affect cellular response signatures. This program has potential to discover new mechanisms of action of alcohol and discover new targets for medications development.  The second phase of the LINCS program is set to begin next year and Dr. Reilly was nominated to be a science officer on one of the LINCS projects.

NIAAA COMMUNICATIONS & MEDIA COVERAGE 

NEW MULTI-MEDIA PRODUCTS

Online Course on Youth Alcohol Screening

NIAAA recently developed an online course for health care professionals to learn more about screening youth for alcohol problems. Doctors, nurses, psychologists, and others can take the online training to earn continuing medical education credits. The course, produced jointly with Medscape, shows providers how to conduct fast, evidence-based alcohol screening and brief intervention for patients 9 – 18 years of age. Since its launch in August, more than 5,000 health care professionals have earned credit for the course. Learn more at: http://www.nih.gov/news/health/aug2013/niaaa-12.htm

NEW AND UPDATED PUBLICATIONS

NIAAA Summer Fact Sheet – For the 2013 summer vacation season, NIAAA continued its seasonal outreach series with its fact sheet, “Don't Let Alcohol Put a Chill on Your Summer Fun.”  Fact sheets in the seasonal outreach series contain relevant statistics, practical science-based commentary, and NIAAA website information. They are disseminated through electronic media and in print upon request. The summer safety fact sheet, which was developed with input from the U.S. Coast Guard and National Association of State Boating Law Administrators, focused on the dangers of risky drinking when combined with water recreation and other summer activities.

NIAAA distributed the fact sheet to the national media through PR Newswire prior to the Independence Day holiday. The release also targeted writers who have expressed interest in receiving information related to water sports/boating and health. In combination, these efforts generated more than 355 clips on online media outlets, including Yahoo!, The Boston Globe, The Cincinnati Inquirer, The Miami Herald, and Michigan Live, as well as business journals, industry publications, and numerous major television network (FOX, NBC, CBS, ABC) local affiliates nationwide, reaching a total audience of more than 57.8 million. Additionally, the fact sheet graphic appeared on the Reuters Times Square and PR Newswire Las Vegas Fashion Show Mall billboards. NIAAA also reached out to organizations with an interest in promoting water safety and the following groups partnered with us to disseminate hard copies of the fact sheet:

• National Safe Boating Council
• Association of Surf Angling Clubs
• Massachusetts Harbormasters Association
• Massachusetts Boating and Yacht Club Association

OTHER NEW AND UPDATED PUBLICATIONS/MEDIA

A new permanent exhibit showcasing NIAAA was installed on May 24th in Building 31 on NIH’s main campus.

Alcohol Research: Current Reviews, Volume 35, Number 1 (“Epigenetics—New Frontier for Alcohol Research”) is now available on the NIAAA website.

NIAAA has updated the underage drinking prevention poster for teens. The poster shows a vending machine featuring all the activities kids could be doing instead of drinking alcohol.

NIAAA has also recently updated many of the fact sheets for the general public posted on the web.

OTHER NOTEWORTHY PUBLICATION STATS

As of August, there were:

• 20,132 subscribers to the Alcohol Alert;
• 19,872 to Alcohol Research: Current Reviews;
• 15,238 to the NIAAA Newsletter;
• 13,240 to receive general information; and
• 12,648 to the Spectrum.

OUTREACH ACTIVITIES

INTERNATIONAL FETAL ALCOHOL SPECTRUM DISORDERS (FASD) AWARENESS DAY 

In September, NIAAA recognized International Fetal Alcohol Spectrum Disorders (FASD) Awareness Day, which takes place each year on September 9. The event serves as a reminder that drinking during pregnancy is the leading preventable cause of birth defects and developmental disabilities in the U.S. Working with Dr. Ken Warren, NIAAA issued a NIH Statement to the Media, which can be viewed at www.niaaa.nih.gov/news-events/news-releases/nih-statement-international-fasd-awareness-day.

“Almost 40 years have passed since we recognized that drinking during pregnancy can result in a wide range of disabilities for children, of which fetal alcohol syndrome (FAS) is the most severe. Yet up to 30 percent of women report drinking alcohol during pregnancy.

…For many years, NIAAA has supported research to understand how alcohol exposure during pregnancy interferes with fetal development and how FASD can be identified and prevented. Scientists continue to make tremendous strides, providing important new insights into the nature of FASD and potential intervention and treatment strategies.

The message is simple, not just on Sept. 9, but every day.  Women who are, who may be, or who are trying to become pregnant, should not drink alcohol.”

Dr. Warren also recorded an in-studio message about International FASD Awareness Day that was posted to the National Organization on Fetal Alcohol Syndrome (NOFAS) website and the NIAAA site.

Graphics announcing the day (pictured above) were added to the rotating web displays at NIH.gov and NIAAA.gov. Tweets about the event were also sent out by NIAAA and other institutes.

NIAAA BILLBOARDS ON ALCOHOL AND SUMMER SAFETY

In July and August, as an addition to the seasonal outreach effort, NIAAA ran a series of outdoor ads in select locations across the mid-Atlantic region. The billboards complemented and extended the themes and colorful graphics of the summer safety fact sheets.

The placement strategy called for targeted ads along the popular roadways leading to popular New Jersey, Delaware and Maryland beaches. In addition, in an arrangement that may serve as a model for future efforts, NIAAA partnered with a community organization in Maryland, the Prevention Works in Somerset County Coalition, to develop and place an electronic billboard along a major road outside of Ocean City, MD. The summer safety project was a continuation of the partnership that began with a similar effort focusing on graduation and teen drinking this past spring.  In both efforts, NIAAA provided graphics and the coalition paid for all billboard fees.

NIAAA is currently evaluating the audience metrics and other results of these efforts, and these data will inform future decisions about this type of outreach.

Messages from NIAAA’s summer fact sheet  appeared on several blogs and ran on a billboard in Times Square:

The ecoXplorer blog (7/22/13): Alcohol and Hot Weather Don't Mix

New York Times Square Billboard: July 4, 2013

Jen's Blog of Random Thoughts (6/26/13): Risky Drinking Can Put a Chill on Your Summer Fun

RECENT NEWS MEDIA INTERVIEWS

Dr. Rosalind Breslow, Division of Epidemiology and Prevention Research, spoke with the following outlets on the topic of drinking and nutrition:
•      Amy Gorin, Weight Watchers Magazine (6/14/13)
•      Sumathi Reddy, Wall Street Journal (7/31/13)
•      Fox News Channel -- Happening Now with Jon Scott & Jenna Lee (8/13/13)

Dr. PJ Brooks of the Division of Metabolism and Health Effects spoke with Marina Hutchinson of the Associated Press about Cockayne syndrome (Dr. Brooks is also a program officer in the Office of Rare Diseases Research, NCATS). (8/1/13)

Mr. Fred Donodeo, Office of Science Policy and Communications, was interviewed on Federal News Radio’s “The Federal Drive” on the subject of alcohol and summer safety.

Dr. Bill Dunty and Dr. Dale Hereld of the Division of Metabolism and Health Effects spoke with Catherine Saint Louis of The New York Times about alcohol and pregnancy. Drs. Dunty and Hereld debunked assertions about the safety of drinking during pregnancy that have been made in a recent book.  (7/24/13)

Dr. David Goldman, Section of Human Neurogenetics, and Dr. Raye Litten, Division of Treatment and Recovery Research, spoke with Vabe Watts of Psychiatric News regarding a new finding on the use of ondansetron for treating alcohol dependence. (8/12/13)

Dr. Ralph Hingson spoke with Ted Gregory of the Chicago Tribune about drunk driving and NTSB’s 0.05 BAC proposal. (8/14/13)

Dr. Raye Litten, Division of Treatment and Recovery Research, spoke with Kathleen Miles of HuffPost LA regarding neurofeedback treatment for alcohol dependence.  (7/2/13)

Dr. Gary Murray, Division of Metabolism and Health Effects , spoke with:

• Amir Vera of the Pittsburgh Post-Gazette about the dangers of inhaling vaporized alcohol. (7/2/13)
• Radio PA about summertime alcohol safety, particularly regarding how alcohol can contribute to dehydration on hot summer days. (7/18/13)
• Ted Gregory of the Chicago Tribune about alcohol metabolism. (8/14/13)

Dr. Vijay Ramachandani of Laboratory of Clinical and Translational Studies discussed pharmacological effects of alcohol with Kat Austen of New Scientist Magazine. (9/4/13)

Dr. Deidra Roach of the Division of Treatment and Recovery Research was a guest on Sirius XM Radio’s Maggie Linton Show to discuss alcohol problems among women. (8/8/13)

Dr. Roach also spoke with Patrick Hruby of Washingtonian magazine for an article about alcohol and women. (8/1/13)

Dr. Aaron White, Division of Epidemiology and Prevention Research, has been interviewed about binge drinking among college students by:

• Daniel Blas of USA Today (7/29/13)
• Gwen Breitstein and Mike Sacks of HuffPost Live (8/7/13)
• David Glovin of Bloomberg News (8/21/13)
• Cynthia Hua of the Yale Daily News (8/26/13)
• Rachel Roubein, Carroll County Times (8/27/13)
• Mary Jones, The Talk of Connecticut (radio) (9/3/13)
• Peter Jacobs, Business Insider (9/4/13)
• Chris Palmer, Philadelphia Inquirer (9/6/13)
• John Hechinger, Bloomberg News (9/6/13)
• Steven Holbrook, Tuscaloosa News (9/9/13)

Dr. White also discussed the emergence of online support groups for alcohol dependence with Pam Kragen of the San Diego Union-Tribune. (8/27/13)

PRESS RELEASES & RESEARCH NEWS

NIH study identifies brain circuits involved in learning and decision making (July 8, 2013)
Finding has implications for alcoholism and other patterns of addictive behavior

Research from the National Institutes of Health has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help to explain the brain processes that govern choice and the ability to adapt behavior based on the end results.

Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions

3-D Image Analysis Promises to Improve Detection of Children Affected by Prenatal Alcohol (July 25, 2013)

Computerized image analysis can be a useful tool for detecting the sometimes subtle changes in facial features that occur when children are exposed to alcohol before birth, according to a recent study conducted through the NIAAA-funded Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD).  As reported in the journal Pediatrics, the study suggests that three-dimensional (3-D) imaging could soon help clinicians identify children at high risk for cognitive impairments due to prenatal alcohol exposure.

Disrupting Drinking Memories May Help Prevent Relapse (July 26, 2013)

New research supported by NIAAA suggests that a drug currently used to prevent the rejection of transplanted organs could someday help lessen the alcohol cravings that often lead to relapse among people with drinking problems. Alcohol-related memories, or cues—such as the smell of alcohol—can trigger cue-induced alcohol craving.

New insight on how the brain forms habits (August 2, 2013)
New data offers a glimpse into the neurobiological mechanisms underlying the formation of habitual actions, such as addiction to alcohol.

In a study conducted in mice and rats, scientists in NIAAA’s Laboratory for Integrative Neuroscience examined the cellular basis for learning and memory in the dorsolateral striatum, a part of the brain involved in habit learning. A particular receptor in the dorsolateral striatum, the cannabinoid type 1 receptor (CB1), is critical for habit learning.

Gene combinations help predict treatment success for alcoholism medication (August 2, 2013)
NIH-funded study says five-marker genotype panel can guide ondansetron use

An experimental treatment for alcohol dependence works better in individuals who possess specific combinations of genes that regulate the function and binding of serotonin, a brain chemical affected by the treatment, according to a study supported by the National Institutes of Health.  A report of the finding appears online in the American Journal of Psychiatry.

NIH Study Explains Neuroscience of Habit Breaking (August 6, 2013)

Recent research from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) sheds new light on habitual behaviors, specifically the circuits in the brain that allow mice to break from routine actions. Such shifting between old habits and new behavior aimed at accomplishing a particular goal are critical to flexible decision-making in everyday life. It also has important implications for mental health and substance abuse interventions.

NIH issues online course on screening youth for alcohol problems (August 12, 2013)

A new online training course will help health care professionals conduct fast, evidence-based alcohol screening and brief intervention with youth. The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, produced the course jointly with Medscape, a leading provider of online continuing medical education.

Endocannabinoids trigger inflammation that leads to diabetes (August 19, 2013)
NIH scientists identify possible treatment target for type 2 diabetes

Researchers at the National Institutes of Health have clarified in rodent and test tube experiments the role that inflammation plays in type 2 diabetes, and revealed a possible molecular target for treating the disease.  The researchers say some natural messenger chemicals in the body are involved in an inflammatory chain that can kill cells in the pancreas, which produces insulin.

NIH study finds chronic alcohol use shifts brain's control of behavior (August 21, 2013)

Chronic alcohol exposure leads to brain adaptations that shift behavior control away from an area of the brain involved in complex decision-making and toward a region associated with habit formation, according to a new study conducted in mice by scientists at the National Institutes of Health.

The finding provides a biological mechanism that helps to explain compulsive alcohol use and the progression to alcohol dependence. A report appears online in the Proceedings of the National Academy of Sciences (PNAS).

NIH statement on International Fetal Alcohol Spectrum Disorders Awareness Day (September 6, 2013)

International Fetal Alcohol Spectrum Disorders Awareness Day, recognized every year on the ninth day of the ninth month, is an important reminder that prenatal alcohol exposure is the leading preventable cause of birth defects and developmental disorders in the United States. Almost 40 years have passed since we recognized that drinking during pregnancy can result in a wide range of disabilities for children, of which fetal alcohol syndrome is the most severe. Yet up to 30 percent of women report drinking alcohol during pregnancy.

SELECT NIAAA STAFF ACTIVITIES

• Dr. Raye Litten and Ms. Megan Ryan co-organized the training session “Human Research Protection Training: An Interactive Mock IRB Review,” presented by Dr. Ann Hardy and Ms. Maria Stagnitto of NIH/OEP, Rockville, MD, June 6, 2013.
   
• Drs. Raye Litten, Joanne Fertig, Daniel Falk, and Ms. Megan Ryan presented “A Phase 2, double-blind, randomized, placebo controlled trial to assess the efficacy of ABT-436 for alcohol dependence” to the Food and Drug Administration on June 10, 2013.
   
• Dr. Aaron White participated in two webinars on underage drinking epidemiology and prevention at SAMHSA’s Northwoods Coalition Annual Meeting and Training in Eau Claire, WI, on June 17, 2013.
   
• Dr. Daniel Falk presented a portfolio analysis of the Division of Treatment and Recovery Research’s grants related to mechanisms of behavior change at the 9th Annual Mechanisms of Behavior Change Satellite Session at the 36th Annual Scientific Meeting of the Research Society on Alcoholism (RSA) in Orlando, FL, on June 22, 2013. This Satellite was co-sponsored by NIAAA and had over 100 attendees.
   
• Dr. Bill Dunty presented introductory remarks for the symposium entitled "Body, Brain, and Behavior in Relation to Maternal-Fetal Interface in FASD" held during the Research Society on Alcoholism Meeting. The symposium was organized and chaired by Dr. Bill Dunty along with NIAAA grantee Dr. Jay Ramadoss of the University of Texas Medical Branch. 
   
• Dr. Joe Wang and Dr. Kathy Jung co-chaired a satellite session on animal models at the annual meeting of Research Society on Alcoholism on June 22, 2013. The session, entitled “Animal Models for Alcoholic Liver Disease (ALD) and Beyond: Can They Help us Move from Bench to Bedside?” was centered on the applications of a newly developed chronic-binge feeding paradigm in different disease end points.
   
• Dr. Peter Gao organized a symposium of “New Insights into the Role of Ethanol and Its Interactions with Other Risk Factors in Pathogenesis of Pancreatitis and Pancreatic Cancer” at the Annual Scientific Meeting of the Research Society on Alcoholism on June 26, 2013.
   
• Dr. Andras Orosz organized and co-chaired an RSA symposium “Alcohol and the Cardiovascular System: Emerging Targets in Pathology and Therapy” with Dr. Charles H. Lang (Penn State College Medicine).
   
• Dr. Raye Litten presented “Strategies to Meet the Challenges of Drug Development for Alcohol Treatment,” at RSA.
   
• Dr. Dale Hereld delivered a presentation on NIAAA's FASD-related activities to the FASD Study Group, which met on June 22, 2013, in conjunction with the annual RSA meeting.
   
• Drs. Bill Dunty and Dale Hereld presented remarks for the symposium entitled "Developmental Origins of Adult Health and Disease: Influences of Prenatal Alcohol Exposure" held during RSA. The symposium was co-organized by Drs. Dunty and Hereld along with NIAAA grantee Dr. Joanne Weinberg of the University of British Columbia.
   
• Dr. Gary Murray provided discussion and comments in the symposium of “Alcohol And Cancer: New Insights And Future Directions” at RSA, on  June 26, 2013
   
• Dr. Bob Freeman was the Panel Organizer and Chair of the panel titled “Migration, Economic Recession, and Victimization: New Insights into Exposure to Lifetime Adversities and Development of Problem Drinking” at RSA on June 26, 2013. This panel featured presentations by NIAAA grantees Judith Richman, Lareina LaFlair, Sarah Ullman, and Kurt Organista, with Sarah Zemore as discussants and Andrea Swartzendruber as moderator. At RSA, Dr. Freeman also participated in the “Grantsmanship Workshop” on June 25, 2013.
   
• Dr. Antonio Noronha co-organized and co-chaired a symposium with Dr. Fulton Crews of UNC entitled, “Neurobiological and Behavioral Consequences of Adolescent Alcohol Exposure” at RSA. He also summarized and discussed the preclinical studies presented using different models of adolescent alcohol exposure resulting in persistent long-term changes in adulthood.
   
• Dr. Antonio Noronha also gave a presentation highlighting both animal and human research on the consequences of adolescent alcohol exposure at a symposium entitled, “Consortium on Alcohol and Neurodevelopment in Adolescence: The Foundational Research” organized by Drs. Susan Tapert and Sandra Brown at RSA.
   
• Drs. Qi-Ying Liu and Antonio Noronha organized a Satellite Meeting entitled, “Alcohol Consumption, Seizure and Epilepsy: Molecular, Cellular and Neural Circuit Mechanisms.” This one-day translational conference reviewed the most recent progress in the research of alcoholism and epilepsy and explored measures for a better management of seizure and epilepsy in alcohol use population. Speakers included NIAAA intramural and NIAAA-funded investigators and well-established epilepsy investigators, such as Drs. David Lovinger, Leslie Morrow, Richard Olsen, Daniel Savage and Helen Scharfman.  Dr. Liu gave an overview of the state of science as an introduction to the symposium.
   
• Dr. Changhai Cui co-chaired a symposium with Dr. Fernando Valenzuela on “Modulation of Glutamatergic Transmission by Alcohol: New Insights from Rodent and Human Studies” at RSA. This symposium highlighted dynamic ethanol’s regulation on the glutamatergic system associated with alcohol exposure and abstinence.  Dr. Cui gave introductory remarks to the symposium. Speakers include Drs. Fernando Valenzuela, Jun Wang, Tiffany Wills, and Dieter Meyerhoff.
   
• Dr. Cui was a discussant for the symposium on “Neuroimmune, Microglia, and Alcohol Addiction,” at the 2013 annual meeting of RSA.  This symposium was organized and chaired by Drs. Dipak Sarkar and Fulton Crews.
   
• In a symposium entitled, “Genetic and Genomic Approaches to Alcohol Disorders,” at the annual RSA meeting, Dr. Abbas Parsian gave an overview of the challenges in gene mapping for complex human disorders including alcoholism, use of RNA-Sequencing in identification of transcriptomes and candidate gene sequencing to detect rare variations. The speakers included Marissa Ehringer, Howard Edenberg, Robert Hitzemann, David Goldman and Adron Harris.
   
• Dr. Aaron White presented, “Alcohol induced blackouts and poisonings – Forensics considerations,” at the FBI Academy, Marine Corps Base Quantico, in Quantico, VA, on June 27, 2013.
   
• Dr. Kathy Jung has been appointed as Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) Coordinator for NIAAA.
   
• Following Council endorsement in June, the Medications Development Group (NCIG) (Drs. Raye Litten, Joanne Fertig, Daniel Falk and Ms. Megan Ryan) anticipates that a new RFP for a Coordinating Center to conduct additional proof of concept clinical trials will be issued within the next several months.
   
• Dr. Raye Litten and Ms. Megan Ryan participated in the Trans-NIH Clinical Trials Working Group that was charged with making recommendations to Dr. Francis Collins on the stewardship, leadership and management of clinical trials and clinical trial networks and the enhancement of the quality and transparency of NIH-supported clinical trials.  The final report and the meeting with Dr. Collins occurred on August 13.
   
• Dr. Ralph Hingson gave the keynote address at the 2013 Conference of the International Council on Alcohol, Drugs and Traffic Safety (ICADTS) in Brisbane, Australia, on August 26, 2013. His address was titled “Overview of the World Health Organization’s (WHO) Initiative on Alcohol-Related Problems Around the World.” 

          At the meeting, Dr. Hingson gave the opening presentation to the pre-conference workshop on preventing alcohol- and drug-related traffic crashes, injuries, and deaths in low/middle income countries. In his outside activity as Past President of ICADTS, Dr. Hingson has long encouraged ICADTS to recruit low/middle income members because 80-90% of the 1.4 million annual global traffic deaths occur in those countries. Their economic expansion has stimulated more vehicle use, higher alcohol consumption, and a 25% increase in traffic deaths over the past two decades. Low/middle income countries were represented in unprecedented numbers at the conference.

          Of note, three NIAAA researchers received the most prestigious ICADTS research awards at the conference. Jim Fell of the Pacific Institute for Research and Evaluation (PIRE) and Jean Shope of the University of Michigan School of Public Health were each recipients of the Widmark Award, and Dr. Robert Voas of PIRE received the Borkenstein Award.

• In conjunction with his work for the NIH Common Fund Health Economics Program, Gregory Bloss and co-editor Dr. John Haaga of the National Institute on Aging edited a special issue of the Forum for Health Economics and Policy devoted to the economics of personalized health care and prevention. Along with an introduction jointly authored by Bloss and Haaga, the special issue includes invited contributions from a distinguished group of researchers. The special issue grew out of a July 2012 NIH-sponsored teleconference that also led to an RFA titled, “Determinants and Consequences of Personalized Health Care and Prevention (U01)” (RFA-RM-12-024).
   
• Dr. Lindsey Grandison and Dr. Ellen Witt, representing NIAAA, co-organized a workshop with the NIH Office of Dietary Supplements, NIDDK, NICHD, NCI, OBSSR, NIDA, NIMHD, and USUHS, entitled, “The Use and Biology of Energy Drinks:  Current Knowledge and Critical Gaps,” which was held at the Neuroscience Center in Rockville, MD on August 15-16, 2013. The workshop covered many the use patterns, effects, and safety of energy drinks and their ingredients, including the prevalence and cognitive effects of the combined use of energy drinks and alcohol, particularly among adolescents. NIAAA funded speakers were Drs. Amelia Arria, Cecile Marczinski, and Emma Childs.
   
• Dr. Gary Murray provided discussion and comments in the symposium of “Alcohol, Cancer, Hepatitis and Fatty Liver: Interactions and Co-morbidities” at the 14th congress of the European Society for Biomedical Research on Alcoholism in Warsaw, Poland, on September 9, 2013.
   
• Dr. Antonio Noronha co-organized and co-chaired a symposium with Dr. Shubash Pandey entitled, “Epigenetic mechanisms of alcoholism: From the prenatal stage to adulthood” at the European Society on Biomedical Research (ESBRA) held in Warsaw, Poland on September 8-12, 2013.  Dr. Noronha presented recent findings on epigenetic changes due to alcohol exposure during different stages of the lifespan and possible therapeutics to be considered for the future.
   
• Dr. Antonio Noronha co-organized and co-chaired a symposium with Dr. Consuelo Guerri of Spain entitled, “Persistent Effects of Binge Drinking on Adolescent Brain” at the European Society on Biomedical Research (ESBRA). He presented research findings of the consequences of adolescent binge alcohol exposure on both the brain and behavior.

NEW AND UPCOMING PUBLICATIONS/MULTI-MEDIA PRODUCTS

Dr. Raye Litten, Dr. Daniel Falk, Ms. Meg Ryan, and Dr. Joanne Fertig authored an article, “Research opportunities for alcohol medications development: Addressing stakeholders needs,” that appears in the July issue of Alcoholism: Clinical and Experimental Research. This commentary poses a number of issues that must be addressed in order to advance the alcohol research field and to make medications a mainstream treatment for problematic drinking.

Drs. Ralph Hingson and Aaron White’s article titled “Trends in Extreme Binge Drinking among U.S. High School Seniors” was published in JAMA Pediatrics on September 16, 2013. This article discusses the implication of findings from a Monitoring the Future study that will be published in the same issue of JAMA Pediatrics titled “Extreme Binge Drinking among 12th-Grade Students in the US: Prevalence and Predictors” by Megan Patrick, et al. Their study showed that, between 2005 and 2011, the percentages of high school seniors nationwide who binge drink (5 or more drinks per occasion) have declined, but not the percentages who consume 15 or more drinks per occasion.

Dr. PJ Brooks published an article, “Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease” in the August issue of DNA Repair (Amst). The study sheds light on the mechanistic basis of a rare genetic condition known as Cockayne syndrome neurologic disease. A better understanding of this neurodevelopmental disorder is essential to the development of effective therapeutic strategies.

Drs. Bin Gao and Svetlana Radaeva published, “Natural killer and natural killer T cells in liver fibrosis,” as part of a special issue entitled: “Fibrosis: Translation of basic research to human disease” in Biochimica et Biophysica Acta (BBA). The article explores the current understanding of the role of natural killer and natural killer T cells in liver fibrosis and their use as potential therapeutic targets for anti-fibrotic therapy.

WHAT’S AHEAD?

OCTOBER

The NIAAA T32 Directors’ meeting will be held Oct 18 – 20, 2013, in San Diego, CA.

The 18th Annual Mark Keller Award and Lecture will be held October 22, 2013 at 1:30 – 3:30 p.m. in NIH’s Masur Auditorium. This year’s recipient, Dr. Edith V. Sullivan will present a lecture entitled, “Functional Compromise and Compensation in Alcoholism: Neuropsychology Meets Neuroimaging.” 

NOVEMBER

The 2013 Society for Neuroscience meeting will be held November 9-13, 2013, in San Diego, CA.  Dr. Matthew Reilly has organized a SfN symposium on November 11th entitled “The Role of Transposable Elements in Health and Diseases of the Central Nervous System.”  Several prominent neuroscientists, including Dr. Fred Gage, will present their latest findings on somatic retrotransposition in the brain. Somatic retrotransposition may serve as a novel mechanism that generates neuronal diversity and influence a number of psychiatric disorders including alcoholism. 

The Division of Neuroscience and Behavior will sponsor a satellite symposium on "Brain Pathways to Recovery from Alcohol Dependence" in conjunction with the Society for Neuroscience Annual Meeting, November 8, 2013, San Diego, CA. A panel of scientists from the alcohol and addiction research fields will be brought together to present their insights on fundamental brain mechanisms that may contribute to the recovery from alcohol dependence. The sessions will also encompass multilevel studies exploring mechanisms underlying relapse and craving associated with sustained alcohol abstinence. The panel discussion will identify priorities and research opportunities, and engender novel research ideas in this area. For meeting agenda and registration, please visit http://www.niaaa.nih.gov/news-events/meetings-events-exhibits/brain-pathways-recovery. If you have any questions, please contact Changhai Cui at changhai.cui@nih.gov or Antonio Noronha at anoronha@willco.niaaa.nih.gov.

 
NIAAA RESEARCH HIGHLIGHTS

Intramural Research

GLUN2B IN CORTICOSTRIATAL CIRCUITS GOVERNS CHOICE LEARNING AND CHOICE SHIFTING

Significance: Research from the National Institutes of Health has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help to explain the brain processes that govern choice and the ability to adapt behavior based on the end results. Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions.

A choice that reliably produces a preferred outcome can be automated to liberate cognitive resources for other tasks. Should an outcome become less desirable, behavior must adapt in parallel or it becomes perseverative. Corticostriatal systems are known to mediate choice learning and flexibility, but the molecular mechanisms of these processes are not well understood. We integrated mouse behavioral, immunocytochemical, in vivo electrophysiological, genetic and pharmacological approaches to study choice. We found that the dorsal striatum (DS) was increasingly activated with choice learning, whereas reversal of learned choice engaged prefrontal regions. In vivo, DS neurons showed activity associated with reward anticipation and receipt that emerged with learning and relearning. Corticostriatal or striatal deletion of Grin2b (encoding the NMDA-type glutamate receptor subunit GluN2B) or DS-restricted GluN2B antagonism impaired choice learning, whereas cortical Grin2b deletion or OFC GluN2Bantagonism impaired shifting. Our convergent data demonstrate how corticostriatal GluN2B circuits govern the ability to learn and shift choice behavior. (Brigman JL, Daut R, Wright T, Gunduz-Cinar O, Graybeal C, Davis MI, Jiang Z, Saksida LM, Jinde S, Pease M, Bussey TJ, Lovinger DM, Nakazawa K, Holmes A. Nature Neuroscience. 2013 Aug;16(8):1101-10.)

CHRONIC ALCOHOL PRODUCES NEUROADAPTATIONS TO PRIME DORSAL STRIATAL LEARNING.

Significance: Chronic alcohol exposure leads to brain adaptations that shift behavior control away from an area of the brain involved in complex decision-making and toward a region associated with habit formation, according to a new study conducted in mice by scientists at the National Institutes of Health. The finding provides a biological mechanism that helps to explain compulsive alcohol use and the progression to alcohol dependence.

Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptor-dependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism. (DePoy L, Daut R, Brigman JL, MacPherson K, Crowley N, Gunduz-Cinar O, Pickens CL, Cinar R, Saksida LM, Kunos G, Lovinger DM, Bussey TJ, Camp MC, Holmes A. PNAS. 2013 Aug 20. [Epub ahead of print])

ORBITOFRONTAL AND STRIATAL CIRCUITS DYNAMICALLY ENCODE THE SHIFT BETWEEN GOAL-DIRECTED AND HABITUAL ACTIONS

Significance: This research sheds new light on habitual behaviors, specifically the circuits in the brain that allow mice to break from routine actions. Such shifting between old habits and new behavior aimed at accomplishing a particular goal are critical to flexible decision-making in everyday life. The finding may have important implications for mental health and substance abuse interventions.

Shifting between goal-directed and habitual actions allows for efficient and flexible decision making. Here we demonstrate a novel, within-subject instrumental lever-pressing paradigm, in which mice shift between goal-directed and habitual actions. We identify a role for orbitofrontal cortex (OFC) in actions following outcome revaluation, and confirm that dorsal medial (DMS) and lateral striatum (DLS) mediate different action strategies. Simultaneous in vivo recordings of OFC, DMS and DLS neuronal ensembles during shifting reveal that the same neurons display different activities depending on whether presses are goal-directed or habitual, with DMS and OFC becoming more and DLS less engaged during goal-directed actions. Importantly, the magnitude of neural activity changes in OFC following changes in outcome value positively correlates with the level of goal-directed behavior. Chemogenetic inhibition of OFC disrupts goal-directed actions, whereas optogenetic activation of OFC specifically increases goal-directed pressing. These results also reveal a role for OFC in action revaluation, which has implications for understanding compulsive behavior. (Gremel CM, Costa RM. Nature Communications. 2013 Aug 6;4:2264.)

ACTIVATION OF THE NLRP3 INFLAMMASOME IN INFILTRATING MACROPHAGES BY ENDOCANNABINOIDS MEDIATES BETA CELL LOSS IN TYPE 2 DIABETES

Significance:  NIH researchers have conducted rodent and test tube experiments that clarify the role of inflammation in type 2 diabetes and reveal a possible molecular target for treating the disease.  The researchers say some natural messenger chemicals in the body are involved in an inflammatory chain that can kill cells in the pancreas, which produces insulin.

Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient (Cnr1-/-) or Nlrp3-/- mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM. (Jourdan T, et al. Nature Medicine. 2013 August 18. [Epub ahead of print])

VOLTAGE DRIVES DIVERSE ENDOCANNABINOID SIGNALS TO MEDIATE STRIATAL MICROCIRCUIT-SPECIFIC PLASTICITY

Significance: New data offers a glimpse into the neurobiological mechanisms underlying the formation of habitual actions, such as addiction to alcohol. In a study conducted in mice and rats, scientists in NIAAA’s Laboratory for Integrative Neuroscience examined the cellular basis for learning and memory in the dorsolateral striatum, a part of the brain involved in habit learning. A particular receptor in the dorsolateral striatum, the cannabinoid type 1 receptor (CB1), is critical for habit learning.

The dorsolateral striatum and cannabinoid type 1 receptor (CB1) signaling mediate habitual action learning, which is thought to require a balance of activity in the direct and indirect striatal output pathways. However, very little is known about how the high CB1-expressing striatal inhibitory microcircuitry might contribute to long-term plasticity capable of sculpting direct and indirect pathway output. Using optogenetic and molecular interrogation of striatal GABAergic microcircuits, we examined voltage-dependent long-term depression of inhibitory synapses (iLTD) onto mouse and rat medium spiny projection neurons (MSNs). The observed iLTD involved recruitment of different endocannabinoid types and showed both presynaptic and postsynaptic selectivity for MSN subtypes, ultimately resulting in a powerful disinhibition of direct pathway MSNs. These results suggest a new role for voltage states in gating circuit-specific forms of synaptic plasticity and illuminate possible circuit dynamics underlying action control. (Mathur BN, Tanahira C, Tamamaki N, Lovinger DM. Nature Neuroscience. 2013 Sep;16(9):1275-83.)

EXTRAMURAL RESEARCH

DISRUPTION OF ALCOHOL-RELATED MEMORIES BY MTORC1 INHIBITION PREVENTS RELAPSE 

Significance: Inhibition of a new brain target mTORC1 in the amygdala and cortical regions of the brain may help prevent relapse drinking by altering alcohol- associated memories.

Relapse to alcohol abuse is an important clinical issue that is frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval during a memory reconsolidation process that depends on protein synthesis. Here we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins. Furthermore, systemic or central amygdalar inhibition of mTORC1 during reconsolidation disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse. Our findings provide evidence that the mTORC1 pathway and its downstream substrates are crucial in alcohol-related memory reconsolidation and highlight this pathway as a therapeutic target to prevent relapse. (Barak S, Liu F, Hamida SB, Yowell QV, Neasta J, Kharazia V, Janak PH, Ron D.  Nat Neurosci. 2013 Aug;16(8):1111-7.)

MACROPHAGE MIGRATION INHIBITORY FACTOR CONTRIBUTES TO ETHANOL-INDUCED LIVER INJURY BY MEDIATING CELL INJURY, STEATOHEPATITIS, AND STEATOSIS

Significance: Alcoholic liver disease (ALD) is one of the leading causes of preventable death and accounts for about 4% of global mortality. While multiple factors contribute to the development of ALD, emerging evidence indicates that chemokines may play a critical role. This study provide the first evidence that macrophage migration inhibitory factor (MIF) contributes to the pathophysiology of ethanol-induced liver injury in mice and suggests that inhibition of MIF activity with small molecule inhibitors of MIF, such as ISO-1, may be an important therapeutic approach to the treatment of ALD.

Macrophage migration inhibitory factor (MIF), a multipotent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and nonparenchymal cells. We hypothesized that MIF is a key contributor to liver injury after ethanol exposure. Female C57BL/6 or MIF-/- mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 (11% total kcal;early response) or 25 (32% kcal; chronic response) days. Expression of MIF messenger RNA (mRNA) was induced at both 4 days and 25 days of ethanol feeding. After chronic ethanol, hepatic triglycerides and plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased in wildtype, but not MIF-/-, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wildtype and MIF-/- to ethanol. Ethanol feeding for 4 days increased apoptosis of hepatic macrophages and activated complement in both wildtype and MIF-/- mice. However, tumor necrosis factor alpha (TNF-α) expression was increased only in wildtype mice. This attenuation of TNF-α expression was associated with fewer F4/80+ macrophages in liver of MIF-/- mice. After 25 days of ethanol feeding, chemokine expression was increased in wildtype mice, but not MIF-/- mice. Again, this protection was associated with decreased F4/80+ cells in MIF-/- mice after ethanol feeding. Chronic ethanol feeding also sensitized wildtype, but not MIF-/-, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver. Conclusion: Taken together, these data indicate that MIF is an important mediator in the regulation of chemokine production and immune cell infiltration in the liver during ethanol feeding and promotes ethanol-induced steatosis and hepatocyte damage. (Barnes MA, McMullen MR, Roychowdhury S, Pisano SG, Liu X, Stavitsky AB, Nagy LE. Hepatology. 2013 May;57(5):1980-91.)

TRENDS IN TOBACCO AND ALCOHOL BRAND PLACEMENTS IN POPULAR US MOVIES, 1996 THROUGH 2009

Significance: In the face of evidence that movies influence substance use behaviors by adolescents, this study provides compelling evidence that representations of alcohol use and brand appearances of alcohol products have increased steadily over 1996-2009 in popular youth-rated movies, in stark contrast to tobacco appearances, which have decreased sharply.

Tobacco and alcohol use in movies could be influenced by product placement agreements. Tobacco brand placement was limited by the Master Settlement Agreement (MSA) after 1998, while alcohol is subject to self-regulation only. OBJECTIVE: To examine recent trends for tobacco and alcohol use in movies. We expected that the MSA would be associated with declines in tobacco but not alcohol brand placement (hypothesis formulated after data collection).DESIGN: Content analysis. SETTING: Top 100 box-office hits released in the United States from 1996 through 2009 (N = 1400). INTERVENTION: The MSA, an agreement signed in 1998 between the state attorneys general and tobacco companies, ended payments for tobacco brand placements in movies. MAIN OUTCOMES AND MEASURES: Trend for tobacco and alcohol brand counts and seconds of screen time for the pre-MSA period from 1996through 1999 compared with the post-MSA period from 2000 through 2009. RESULTS: Altogether, the 1400 movies contained 500 tobacco and 2433 alcohol brand appearances. After implementation of the MSA, tobacco brand appearances dropped exponentially by 7.0% (95% CI, 5.4%-8.7%) each year, then held at a level of 22 per year after 2006. The MSA also heralded a drop in tobacco screen time for youth- and adult-rated movies (42.3% [95% CI, 24.1%-60.2%] and 85.4% [56.1%-100.0%], respectively). In contrast, there was little change in alcohol brand appearances or alcohol screen time overall. In addition, alcohol brand appearances in youth-rated movies trended upward during the period from 80 to 145 per year, an increase of 5.2 (95% CI, 2.4-7.9) appearances per year. CONCLUSIONS AND RELEVANCE: Tobacco brands in movies declined after implementation of externally enforced constraints on the practice, coinciding also with a decline in tobacco screen time and suggesting that enforced limits on tobacco brand placement also limited onscreen depictions of smoking. Alcohol brand placement, subject only to industry self-regulation, was found increasingly in movies rated for youth as young as 13 years, despite the industry's intent to avoid marketing to underage persons. (Bergamini E, Demidenko E, Sargent JD (2013). JAMA Pediatrics. 2013 Jul;167(7):634-9.)

ROLE FOR INTESTINAL CYP2E1 IN ALCOHOL-INDUCED CIRCADIAN GENE-MEDIATED INTESTINAL HYPERPERMEABILITY

Significance: Alcohol-induced gut-leakiness contributes to alcoholic liver disease and other alcohol-related pathology by allowing lipopolysaccharide (LPS) and other inflammatory bacterial products to enter the circulation. These investigators previously showed that alcohol-induced gut-leakiness depends on increased expression of circadian clock proteins CLOCK and PER2 in intestinal epithelial cells, which contribute to the gut-blood barrier.  In the current study, they refine this model by demonstrating that the alcohol metabolizing enzyme CYP2E1 is up-regulated by alcohol in intestinal epithelial cells and that associated oxidative stress leads to the increased expression of the clock proteins and elevated permeability of intestinal epithelial cell monolayers.  

We have shown that alcohol increases Caco-2 intestinal epithelial cell monolayer permeability in vitro by inducing the expression of redox sensitive circadian clock proteins CLOCK and PER2 and that these proteins are necessary for alcohol-induced hyperpermeability. We hypothesized that alcohol metabolism by intestinal Cytochrome-P450 2E1 (CYP2E1) could alter circadian gene expression (Clock and Per2) resulting in alcohol-induced hyperpermeability. Methods. In vitro Caco-2 intestinal epithelial cells were exposed to alcohol and CYP2E1 protein, activity, and mRNA were measured. CYP2E1 expression was knocked down via siRNA and alcohol-induced hyperpermeability and CLOCK and PER2 protein expression were measured. Caco-2 cells were also treated with alcohol or H2O2 ± N-acetylcysteine (NAC) anti-oxidant and CLOCK and PER2 proteins were measured at 4 or 2 hours. In vivo Cyp2e1 protein and mRNA were also measured in colon tissue from alcohol-fed mice. Results. 1) Alcohol increased CYP2E1 protein by 93% and enzyme activity by 69% in intestinal cells in vitro; 2) Alcohol feeding also increased mouse colonic Cyp2e1 protein by 73%. 3) mRNA levels of Cyp2e1 were not changed by alcohol in vitro or in mouse intestine; 4) siRNA knockdown of CYP2E1 in Caco-2 cells prevented alcohol-induced hyperpermeability and induction of CLOCK and PER2 proteins; 5) Alcohol-induced and H2O2-induced increases in intestinal cell CLOCK and PER2 were significantly inhibited by treatment with NAC. 6) Conclusion. Our data support a novel role for intestinal CYP2E1 in alcohol-induced intestinal hyperpermeability via a mechanism involving CYP2E1-dependent induction of oxidative stress and upregulation of circadian clock proteins CLOCK and PER2. (Forsyth CB, Voigt RM, Shaikh M, Tang Y, Cederbaum AI, Turek FW, Keshavarzian A. Am J Physiol Gastrointest Liver Physiol. 2013 Jul;305(2):G185-95.)

ALCOHOL OUTLET DENSITY AND YOUNG WOMEN'S PERPETRATION OF VIOLENCE TOWARD MALE INTIMATE PARTNERS

Significance: The study found that young women who lived in a neighborhood having relatively higher density of off-premise alcohol outlets (one or more outlets per square kilometer versus fewer) had significantly increased odds of reporting that they had perpetrated physical-only intimate partner violence (IPV) against their male partner in the past year.

This paper examines the relationships between alcohol outlet density, alcohol use, and perpetration of intimate partner violence (IPV) among young adult women in the US. Data were from Wave III of the National Longitudinal Study of Adolescent Health (Add Health; N = 4,430 in present analyses). Multinomial logistic regression was used to examine occurrence of past year IPV perpetration toward a male partner based on tract-level on-premise and off-premise alcohol outlet density, controlling for individuals' demographic, alcohol use, and childhood abuse characteristics and neighborhood socio-demographic factors. Higher off-premise alcohol outlet density was found to be associated with young women's perpetration of physical only IPV, controlling for individual-level and ecological factors. Alcohol use had an independent association with IPV perpetration but was not a mediator of the outlet density-IPV relationship. Findings suggest that considering alcohol-related environmental factors may help efforts aimed at preventing young women's use of physical violence toward partners. (Iritani BJ, Waller MW, Halpern CT, Moracco KE, Christ SL, Flewelling RL. J Fam Violence. 2013 Jul 1;28(5):459-470.)

A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL ASSESSING THE EFFICACY OF VARENICLINE TARTRATE FOR ALCOHOL DEPENDENCE

Significance: A smoking-cessation medication may be a viable option for the treatment of alcohol dependence, according to a study by scientists at the National Institutes of Health. The study found that varenicline (marketed under the name Chantix), approved in 2006 to help people stop smoking, significantly reduced alcohol consumption and craving among people who are alcohol-dependent.

To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial α4β2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. METHODS: Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. RESULTS: The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. CONCLUSIONS: Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence. (Litten RZ, et al. Journal of Addiction Medicine. 2013 July/August;7(4):277-286.)

THE PLACEBO EFFECT IN CLINICAL TRIALS FOR ALCOHOL DEPENDENCE: AN ANALYSIS OF 51 NALTREXONE AND ACAMPROSATE STUDIES

Significance: Response to placebo varied considerably across trials of naltrexone and acamprosate for alcohol dependence and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects.

The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. METHODS: Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis ofalcohol dependence. Pearson correlation coefficients (rp ) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients (rs ) were used to examine the strength of associations between study characteristics and placebo response. RESULTS: For the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (rp  = -0.55, p < 0.01 and rp = -0.20, p = 0.35, respectively) as well as in the acamprosate trials (rp  = -0.45, p = 0.09 and rp  = -0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (rs  = -0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (rs  = 0.57, p = 0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size. (Litten, R.Z., I-J Pan, D. Falk, M. Ryan, J. Fertig, C.M. Chen, and H. Yi. Alcoholism: Clinical and Experimental Research. 2013 Jul 24. [Epub ahead of print])

PDGFRA PROTECTS AGAINST ETHANOL-INDUCED CRANIOFACIAL DEFECTS IN A ZEBRAFISH MODEL OF FASD

Significance: This study provides insight into the genetic susceptibility to craniofacial defects caused by gestational exposure to alcohol. Using zebrafish, researchers suggest a model in which diminished growth factor signaling interacts with alcohol to further reduce the activity of PI3K/mTOR signaling, thus resulting in craniofacial defects. These findings also led to the identification of a gene-alcohol interaction associated with facial phenotypes in a cohort of alcohol-exposed subjects as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) consortium.

Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD. (McCarthy N, Wetherill L, Lovely CB, Swartz ME, Foroud TM, Eberhart JK.  Development. 2013 Aug;140(15):3254-65.)

QUANTITATIVE ASSESSMENT OF TET-INDUCED OXIDATION PRODUCTS OF 5-METHYLCYTOSINE IN CELLULAR AND TISSUE DNA

Significance: Researchers conducted the first direct comparison of the levels of four modified nucleosides in mammalian tissue samples. This analysis, when combined with manipulations of genes involved in Tet-mediated active cytosine demethylation pathway, may provide insight into whether these 5-mdC derivatives can be used as biomarkers for human diseases.

Recent studies showed that Ten-eleven translocation (Tet) family dioxygenases can oxidize 5-methyl-2'-deoxycytidine (5-mdC) in DNA to yield the 5-hydroxymethyl, 5-formyl and 5-carboxyl derivatives of 2'-deoxycytidine (5-HmdC, 5-FodC and 5-CadC). 5-HmdC in DNA may be enzymatically deaminated to yield 5-hydroxymethyl-2'-deoxyuridine (5-HmdU). After their formation at CpG dinucleotide sites, these oxidized pyrimidine nucleosides, particularly 5-FodC, 5-CadC, and 5-HmdU, may be cleaved from DNA by thymine DNA glycosylase, and subsequent action of base-excision repair machinery restores unmethylated cytosine. These processes are proposed to be important in active DNA cytosine demethylation in mammals. Here we used a reversed-phase HPLC coupled with tandem mass spectrometry (LC-MS/MS/MS) method, along with the use of stable isotope-labeled standards, for accurate measurements of 5-HmdC, 5-FodC, 5-CadC and 5-HmdU in genomic DNA of cultured human cells and multiple mammalian tissues. We found that overexpression of the catalytic domain of human Tet1 led to marked increases in the levels of 5-HmdC, 5-FodC and 5-CadC, but only a modest increase in 5-HmdU, in genomic DNA of HEK293T cells. Moreover, 5-HmdC is present at a level that is approximately 2-3 and 3-4 orders of magnitude greater than 5-FodC and 5-CadC, respectively, and 35-400 times greater than 5-HmdU in the mouse brain and skin, and human brain. The robust analytical method built a solid foundation for dissecting the molecular mechanisms of active cytosine demethylation, for measuring these 5-mdC derivatives and assessing their involvement in epigenetic regulation in other organisms and for examining whether these 5-mdC derivatives can be used as biomarkers for human diseases. (Liu S, Wang J, Su Y, Guerrero C, Zeng Y, Mitra D, Brooks PJ, Fisher DE, Song H, Wang Y. Nucleic Acids Res. 2013 Jul 1;41(13):6421-6429.)

ABERRANT HISTONE DEACETYLASE2-MEDIATED HISTONE MODIFICATIONS AND SYNAPTIC PLASTICITY IN THE AMYGDALA PREDISPOSES TO ANXIETY AND ALCOHOLISM

Significance: These findings provide further evidence for the role of amygdalar histone deacetylase activity and histone acetylation in ethanol consumption and associated anxiety. In particular, they suggest that ethanol-induced epigenetic changes may be particularly relevant to individuals with a genetic predisposition toward anxiety and alcohol consumption.

Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown. METHODS: We measured amygdaloid HDAC activity, levels of HDAC isoforms, and histone H3 acetylation in selectively bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 small interfering RNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density. RESULTS: We found that P rats innately display higher nuclear HDAC activity and HDAC2 but not HDAC 1, 3, 4, 5, and 6 protein levels and lower acetylation of H3-K9 but not H3-K14, in the CeA and medial nucleus of amygdala compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (Bdnf and Arc)-specific histone acetylation, and attenuated anxiety-like behaviors in P rats but had no effects in NP rats. The HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol but not sucrose consumption in P rats and increased histone acetylation of Bdnf and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density. CONCLUSIONS: These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism. (Moonat S, Sakharkar AJ, Zhang H, Tang L, Pandey SC. Biological Psychiatry. 2013 Apr 15;73(8):763-73.)

A SELECTIVE INSULAR PERFUSION DEFICIT CONTRIBUTES TO COMPROMISED SALIENCE NETWORK CONNECTIVITY IN RECOVERING ALCOHOLIC MEN 

Significance: Reduced blood flow to the insula in alcoholic individuals is proposed as a mechanism for disruptions in the brain’s ability to switch between different functional networks with subsequent negative effects on inhibitory control and behavior.

Alcoholism can disrupt neural synchrony between nodes of intrinsic functional networks that are maximally active when resting relative to engaging in a task, the default mode network (DMN) pattern. Untested, however, are whether the DMN in alcoholics can rebound normally from the relatively depressed task state to the active resting state and whether local perfusion deficits could disrupt network synchrony when switching from conditions of rest to task to rest, thereby indicating a physiological mechanism of neural network adaptation capability. METHODS: Whole-brain, three-dimensional pulsed-continuous arterial spin labeling provided measurements of regional cerebral blood flow (CBF) in 12 alcoholics and 12 control subjects under three conditions: pretask rest, spatial working-memory task, and posttask rest. RESULTS: With practice, alcoholics and control subjects achieved similar task accuracy and reaction times. Both groups exhibited a high-low-high pattern of perfusion levels in DMN regions during the rest-task-rest runs and the opposite pattern in posterior and cerebellar regions known to be associated with spatial working memory. Alcoholics showed selective differences from control subjects in the rest-task-rest CBF pattern in the anterior precuneus and CBF level in the insula, a hub of the salience network. Connectivity analysis identified activation synchrony from an insula seed to salience nodes (parietal, medial frontal, anterior cingulate cortices) in control subjects only. CONCLUSIONS: We propose that attenuated insular CBF is a mechanism underlying compromised connectivity among salience network nodes. This local perfusion deficit in alcoholics has the potential to impair ability to switch from cognitive states of interoceptive cravings to cognitive control for curbing internal urges. (Sullivan EV, Müller-Oehring E, Pitel A-L, Chanraud S, Shankaranarayanan A, Alsop DC, Rohlfing T, Pfefferbaum A.  Biological Psychiatry. 2013 Apr 12. [Epub ahead of print])

DECONSTRUCTING THE AGE-PREVALENCE CURVE OF ALCOHOL DEPENDENCE: WHY "MATURING OUT" IS ONLY A SMALL PIECE OF THE PUZZLE 

Significance: These results increase our understanding of differences in alcohol dependence trajectories among individuals, according to age and gender, and provide implications for timing and tailoring of prevention and treatment interventions for phenotypic subgroups. 

Epidemiological studies have consistently demonstrated that heavy alcohol use and alcohol dependence (AD) tend to increase in adolescence and emerging adulthood and then show a large decline in the late 20s, a phenomenon called maturing out. This decline has been explained as an effect of "role incompatibility" in which involvement in new roles and activities interferes with a heavy drinking lifestyle. However, maturing out has been conceived mostly as a decrease in offset, with little attention paid to reductions in new onset or recurrence across decades of life. Moreover, although role incompatibility processes have been studied with young samples, little is known about the effect of life transitions (e.g., marriage, parenthood, changes in employment status) on AD later in life and whether similar effects are observed. Using longitudinal data from the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative epidemiologic survey, we examined the patterns of stability and change in AD across the life span and the differential effect of life transitions on AD across different age strata. Results showed that persistence of AD tended to increase with age, although not dramatically, and that onset and recurrence tended to decrease with age. Moreover, the effects of life transitions on the course of AD varied across the life span and were different for men and women. These results indicate that life transitions differentially affect the patterns of stability and change in younger versus older people, have a different impact for men and women, and highlight the need to consider the unique aspects of each stage of adult development on the course of AD. (Vergés A, Jackson KM, Bucholz KK, Grant JD, Trull TJ, Wood PK, Sher KJ.  J Abnorm Psychol. 2012 May;121(2):511-23.)

REHABILITATION TRAINING USING COMPLEX MOTOR LEARNING RESCUES DEFICITS IN EYEBLINK CLASSICAL CONDITIONING IN FEMALE RATS INDUCED BY BINGE-LIKE NEONATAL ALCOHOL EXPOSURE

Significance: A number of studies have demonstrated both structural and functional cerebellar deficits in prenatal alcohol-exposed children as well as in animal models of fetal alcohol spectrum disorders (FASD).  This study examines the potential of complex motor training (CMT) to reduce impairment of eyeblink classical conditioning (ECC) in a rat model of third trimester alcohol exposure.  This study shows that CMT nearly completely restores ECC in females but is only partially effective in rehabilitating male animals.  These findings suggest that CMT may be a beneficial therapy for children but may require further optimization if similar gender effects are observed. 

Effective treatments for the behavioral and cognitive deficits in children with fetal alcohol spectrum disorders (FASD) are lacking, and translational approaches using animal models can help develop rational interventions. One such model, binge-like alcohol exposure in neonatal rats during the period of brain development comparable with that of the human third trimester, causes structural and functional damage to the cerebellum and disrupts cerebellar-dependent eyeblink classical conditioning. The eyeblink conditioning deficits first demonstrated in this rat model predicted the similar deficits subsequently demonstrated in children with FASD.  Methods: The current study extends this translational approach by testing the hypothesis that rehabilitation training involving 20 days of training on traversal of an obstacle course (complex motor learning) would ameliorate the deficits on classical conditioning of eyeblink responses produced by the neonatal alcohol exposure. We have previously shown that this training stimulates cerebellar synaptic plasticity and improves alcohol-induced deficits on motor coordination tasks.  Results: The current studies found that rehabilitation training significantly attenuated alcohol-induced deficits in acquisition of eyeblink conditioning in females but not in males. These results are consistent with normalization of cerebellar-dependent learning, at least in alcohol-exposed females.  Conclusions: These findings extend previous studies in this model suggesting that rehabilitation of adolescents with FASD using training with complex motor learning tasks could be effective in ameliorating functional impairments associated with cerebellar damage. Eyeblink classical conditioning deficits are now well documented in children with FASD and could serve as an evaluation measure to continue to develop therapeutic interventions such as complex motor learning. (Wagner JL, Klintsova AY, Greenough WT, Goodlett CR. Alcohol Clin Exp Res. 2013 May 3. [Epub ahead of print])

THE GOOD, THE BAD, AND THE UGLY WITH ALCOHOL USE AND ABUSE ON THE HEART

Significance: This report of a novel mechanism provides a coherent explanation for the beneficial effects of low to moderate drinking on cardiovascular health as well as the deleterious influence of heavy drinking leading to cardiomyopathy.  A J- or U-shaped curve frequently depicts the dose-response for coronary heart disease.  In this paper, the role of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/NRF2) as well as AKT that act as regulators of oxidative balance during oxidative stress responses are explored and used to provide the basis for alcohol consumption conferring a cardioprotective effect when used in moderation through an AKT/NRF2-dependent mechanism. 

Since its advent, alcohol has been utilized throughout history socially, for rituals, worship, and for its therapeutic, antibacterial, and analgesic properties. In moderation, alcohol consumption and its use are generally viewed as clinically beneficial. Excessive alcohol consumption on the other hand has been recognized as having several adverse implications. Excessive use increases the risk of liver and heart disease, metabolic disturbances, nutritional deficiencies, certain cancers, brain damage, dementia, neuropathy, as well as other facets of morbidity and mortality. This review targets the sequelae of alcohol consumption on the heart, specifically on myocardial contractility, calcium channel signaling, and intracellular signaling pathways. With the incidence of alcohol-induced cardiac abnormalities being higher than previously thought, it is of increasing importance to elucidate the mechanisms behind them. Here, the cardiac effects of alcohol were not discussed in isolation but in conjunction with other important factors, such as high- and low-density lipoprotein levels and vascular dilatory influences. We explore these mechanisms, in particular, the oxidative stress as the major contributor, as well as pathways that may prove to be cardioprotective. As such, we demonstrate the involvement of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/NRF2) as well as AKT that act as regulators of oxidative balance during oxidative stress responses. Thus, alcohol consumption may confer a cardioprotective effect when used in moderation through an AKT/NRF2-dependent mechanism. (Walker RK, Cousins VM, Umoh NA, Jeffress MA, Taghipour D, Al-Rubaiee M, Haddad GE. Alcohol Clin Exp Res. 2013 Aug;37(8):1253-60.)

DISSOCIABLE EFFECTS OF KAPPA-OPIOID RECEPTOR ACTIVATION ON IMPULSIVE PHENOTYPES IN WISTAR RATS

Significance: This study shows, for the first time, that kappa opioid receptor (KOR) activation and dysregulation of this system observed in alcohol dependence may contribute to impulsivity in ways that initiate and sustain excessive alcohol drinking in dependent individuals.

The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN), and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect, and decision-making. Alterations in extended amygdala DYNs and KOR function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control. Given that DYN and KOR expressions are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcohol-dependent humans and rodents, and have been shown to modify multiple neurotransmitter systems associated with impulse-control disorders, we hypothesized that KOR activation could contribute to impulsive phenotypes. To test this hypothesis, separate cohorts of male Wistar rats were trained in one of the two animal models of impulsivity: delay-discounting (DD) or stop-signal reaction time (SSRT) tasks, and once stable responding was observed, received intracerebroventricular (ICV) infusions of the KOR agonist U50,488 (0-50 μg) according to a within-subject dosing regimen. The results demonstrated a dissociable effect of U50,488 on impulsive phenotypes related to intolerance to delay or response inhibition, with selective effects in the SSRT. Furthermore, the pro-impulsive effects of KOR activation were rescued by pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-sensitive. Dysregulation of impulsive behavior by increased DYN/KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders. (Walker BM, Kissler JL. Neuropsychopharmacology. 2013 May 21. [Epub ahead of print])

TAX POLICY, ADULT BINGE DRINKING, AND YOUTH ALCOHOL CONSUMPTION IN THE UNITED STATES

Significance: This study demonstrates a critical link between the prevalence of binge drinking among adults and various measures of youth drinking and binge drinking.

Prior research attributed youth alcohol consumption to the attitudes and drinking patterns among adults. Yet at a population level, few have examined the relationship between state-level adult binge drinking prevalence and youth drinking behaviors, or whether tax policy plays a role in this relationship. METHODS: We analyzed 6 biennial surveys (1999 to 2009) of individual-level youth alcohol use and related behaviors from state-based Youth Risk Behavior Surveys and corresponding years of state-level adult binge drinking prevalence from the Behavioral Risk Factor Surveillance System. We employed logistic regression with generalized estimating equations method to assess the extent to which state adult binge drinking predicted individual-level youth drinking outcomes and examined the role of alcohol taxes in that relationship. RESULTS: Population-aggregate analyses based on 194 state-year strata showed a positive correlation between state adult binge drinking and youth binge drinking (Pearson r = 0.40, p < 0.01). For individual-level youth drinking outcomes, a 5 percentage point increase in binge drinking prevalence among adults was associated with a 12% relative increase in the odds of alcohol use (adjusted OR = 1.12, 95% CI: 1.08, 1.16). Taxes were strongly inversely related with adult and youth drinking measures, and the effect of tax on youth drinking was attenuated after controlling for adult binge drinking. CONCLUSIONS: Both tax and adult binge drinking are strong predictors of youth drinking. Tax may affect youth drinking through its effect on adult alcohol consumption. Implementing effective alcohol policies to reduce excessive drinking in the general population is an important strategy to reduce youth drinking. (Xuan Z, Nelson TF, Heeren T, Blanchette J, Nelson DE, Gruenewald P, Naimi TS. (2013). Alcoholism: Clinical and Experimental Research. 2013 May 24. [Epub ahead of print])

INSIGHT INTO MECHANISMS OF 3'-5' EXONUCLEASE ACTIVITY AND REMOVAL OF BULKY 8,5'-CYCLOPURINE ADDUCTS BY APURINIC/APYRIMIDINIC ENDONUCLEASES

Significance: Oxidative DNA damage is thought to play an important role in human neurodegenerative disorders and cancer. 8,5′-cyclo-2′-deoxyadenosine (cdA) is generated in DNA by hydroxyl radical attack and strongly blocks DNA replication and transcription. Here the researchers demonstrate that cdA adducts at 3′ termini of DNA can be removed by 3′-5′ exonuclease activity of the apurinic/apyrimidinic (AP) endonucleases: Escherichia coli Xth and human APE1. The crystal structure of bacterial AP endonuclease in complex with DNA duplex provides insight into the mechanism of this activity. This new repair function provides an alternative pathway to counteract genotoxic effect of helix-distorting DNA lesions.

8,5'-cyclo-2'-deoxyadenosine (cdA) and 8,5'-cyclo-2'-deoxyguanosine generated in DNA by both endogenous oxidative stress and ionizing radiation are helix-distorting lesions and strong blocks for DNA replication and transcription. In duplex DNA, these lesions are repaired in the nucleotide excision repair (NER) pathway. However, lesions at DNA strand breaks are most likely poor substrates for NER. Here we report that the apurinic/apyrimidinic(AP) endonucleases-Escherichia coli Xth and human APE1-can remove 5'S cdA (S-cdA) at 3' termini of duplex DNA. In contrast, E. coli Nfo and yeast Apn1 are unable to carry out this reaction. None of these enzymes can remove S-cdA adduct located at 1 or more nt away from the 3' end. To understand the structural basis of 3' repair activity, we determined a high-resolution crystal structure of E. coli Nfo-H69A mutant bound to a duplex DNA containing an α-anomeric 2'-deoxyadenosine:T base pair. Surprisingly, the structure reveals a bound nucleotide incision repair (NIR) product with an abortive 3'-terminal dC close to the scissile position in the enzyme active site, providing insight into the mechanism for Nfo-catalyzed 3'→5' exonuclease function and its inhibition by 3'-terminal S-cdA residue. This structure was used as a template to model 3'-terminal residues in the APE1 active site and to explain biochemical data on APE1-catalyzed 3' repair activities. We propose that Xth and APE1 may act as a complementary repair pathway to NER to remove S-cdA adducts from 3' DNA termini in E. coli and human cells, respectively. (Mazouzi A, Vigouroux A, Aikeshev B, Brooks PJ, Saparbaev MK, Morera S, Ishchenko AA. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3071-80.)