NIAAA Director's Report on Institute Activities to the 151st Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism
Table of Contents
- NIAAA BUDGET
- COLLABORATIVE RESEARCH ON ADDICTION AT NIH (CRAN) UPDATE
- DIRECTOR'S ACTIVITIES
- STAFF TRANSITIONS
- HONORS & AWARDS
- RECENTLY ISSUED NOTICE OF FUNDING OPPORTUNITIES AND NOTICES
- NOTABLE NIAAA STAFF ACTIVITIES
- WHAT'S AHEAD
- NIAAA RESEARCH HIGHLIGHTS
- NIAAA COMMUNICATIONS ACTIVITIES
Fiscal Year (FY) 2019
On September 28, 2018, the President signed H.R.6157 - Department of Defense and Labor, Health and Human Services, and Education Appropriations Act, 2019 and Continuing Appropriations Act, 2019 Public Law No. 115-245. The National Institutes of Health (NIH) received a total of $39.3 billion, $2.1 billion above the fiscal year 2018 enacted level. This funding includes allocations for the HEAL Initiative, the 21st Century Cures Act, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and research on influenza. The bill provides a general increase to NIH Institutes and Centers and it continues to support for the Gabriella Miller Kids First Act pediatric research initiative.
The FY 2019 appropriation for NIAAA provides $525.6 million. This represents a $16 million or a 3.1 percent increase over the FY 2018 budget level. NIAAA estimates it will support a total of 793 RPGs in FY 2019.
The President released his FY 2020 budget in March, requesting $34.4 billion for NIH, a $4.9 billion decrease from FY 2019, and $452.4 million for NIAAA, a $73.2 million decrease from FY 2019
|Research Project Grants||769||298,807||793||305,638|
|Res. Centers in Minority Instit.||-||-||-||-|
|Cooperative Clinical Research||1||7,344||1||7,391|
|Biomedical Research Support||-||-||-||-|
|Minority Biomed. Research Support||2||500||2||500|
|Subtotal, Other Research||175||43,083||189||44,216|
|Total Research Grants||964||371,918||1,003||381,431|
|Research & Develop. Contracts||34,424||38,766|
|Res. Management & Support||$34,569
|Total, NIAAA Budget Authority||$508,398||$525,316|
*FY 2019 Enacted Total: Mandatory transfer amount accounts for the difference of -$275K
Adolescent Brain Cognitive Development (ABCD) Study
The NIMH Data Archive (NDA; https://data-archive.nimh.nih.gov/) is the repository for public access to the data collected from the ABCD Study. Individuals can request access to the ABCD Study data through this site.
The ABCD Curated Annual Release 2.0 (April 2, 2019) included baseline data from 11,874 research participants, including minimally processed structural MRI, diffusion MRI, resting-state fMRI and task fMRI results, as well as data from the genetic, mental health, physical health, neurocognition, substance use, mobile technology, and culture and environment domains. All personally identifiable information is removed to ensure participant confidentiality and anonymity. Also available on the NDA website is the Data Exploration and Analysis Portal (DEAP), which provides users with appropriate statistical models to investigate the ABCD Study data.
NIAAA Director Dr. George F. Koob made the following presentations between January 1, 2019, and March 31, 2019:
- “Dynorphin-Kappa System in the Dark Side of Drug Dependence” at the Winter Conference on Brain Research in Snowmass, Colorado, on January 31, 2019
- “Neurobiology of Addiction: The Gain in the Brain is in the Pain” for the Duke Law-Miami University National Townhall Meeting in Miami, Florida, on February 28, 2019
- “Drug Addiction: The Gain in the Brain is in the Pain” at the Walter Reed Army Institute of Research Distinguished Speaker Event in Bethesda, Maryland, on March 4, 2019
- “Alcohol and Drug Addiction: The Gain in the Brain is in the Pain” at the 2019 Luttge Lecture in Gainesville, Florida, on March 11, 2019
- “Emerging Research on Alcohol and Women’s Health: What We Know and Where Do We Go From Here?” at the meeting of the NIH Coordinating Committee on Research on Women’s Health in Bethesda, Maryland, on March 13, 2019
- “A Heuristic Domain Framework for Understanding the Prevention, Diagnosis, and Treatment of Alcohol Use Disorder” at the 2019 UCLA Luskin Thought Leadership Meeting on Translational Science of Alcoholism in Los Angeles, California, on March 19, 2019
Dr. Yoo Sun Kim, joined the Laboratory of Molecular Signaling (LMS) as a Visiting Fellow in February 2019. Dr. Kim received her Ph.D. in Nutritional Science from Ewha Woman's University, in Seoul, Republic of Korea, where she studied molecular mechanisms of tumor metastasis. She has also researched microenvironments of tumor cells and nutrigenetic effects on cancer stem cells and metastasis. Before joining LMS, Dr. Kim was a postdoctoral fellow in Clinical Nutrition and Nutrigenomics in the Department of Nutritional Science and Food Management at Ewha Woman's University.
Nyamer Koat joined the Division of Medications Development (DMD) as a Health Research Associate. Ms. Koat completed her B.S. in Biology from Iowa State University. She has six years of experience performing public health research and data analysis. In her most recent position as a Research Assistant at Iowa State University, she was responsible for conducting searches of the literature, research databases, and publicly available statistics, as well as compiling and organizing data into user-friendly formats for inclusion in presentations and reports, and drafting and producing reports, briefings and visual aids. In addition, Ms. Koat has experience with data analysis, including both qualitative and quantitative analysis, as well as a variety of statistical and scientific software applications, including SAS and Sigma Plot
Dr. Ralph Hingson received an Albert Nelson Marquis Who’s Who Lifetime Achievement Award, featured in the Wall Street Journal on May 1, 2019.
Notice of Funding Opportunities (NOFO) and Notices (NOT) Issued by NIAAA:
Mechanistic studies on chronic alcohol use and sleep homeostasis (R01 Clinical Trial Optional): This NOFO, issued by NIAAA, encourages Research Project Grant (R01) applications proposing to conduct mechanistic studies on the relationships between sleep problems and alcohol dependence. RFA-AA-19-006
Alcohol and Other Substance Use Research Education Programs for Health Professionals (R25 Clinical Trial Not Allowed): The over-arching goal of the NIAAA and National Institute on Drug Abuse (NIDA) R25 program is to support educational activities that complement and/or foster a better understanding of biomedical, behavioral, and clinical research and its implications. PAR-19-207
Notice of Special Interest on Methodological Advances to Improve Alcohol Measurement and its Consequences for People Living with HIV who have Comorbidities, Coinfections, and Complications: The primary goal of this notice is to support studies that accurately assess, through improved measurement and analysis, the impact of HIV infection and alcohol use on health outcomes related to associated comorbidities, coinfections, and complications (CCC). NOT-AA-19-006
Notice of Special Interest in Supporting Administrative Supplements for Fetal Alcohol Spectrum Disorders (FASD): This notice supports studies on children with neurodevelopmental deficits resulting from prenatal alcohol exposure. NIAAA is interested in supporting applications that focus on, but are not limited to, how essential nutrients naturally present in some foods (e.g., choline) mitigate these neurocognitive and behavioral deficits when administered as either a prenatal or postnatal supplement. NOT-AA-19-009
Notice of Special Interest on Development and Dissemination of Behavioral Treatments for Alcohol Use Disorder: This Notice signals NIAAA’s continuing interest in research on behavioral treatments for AUD. NIAAA invites applications for research that develop novel behavioral therapies, adapt existing treatments to new formats or populations, and enhance the broader dissemination of effective behavioral treatments for those with an AUD or significant drinking problems. Such research considers behavioral treatments; developing, disseminating and implementing mechanisms of behavior change evidence-based processes; the organizational, cost-effectiveness, and environmental factors that facilitate or inhibit the delivery of evidence-based services for AUD; and enhancing clinical and supervision processes among clinical researchers and treatment providers. NOT-AA-19-010
NIH-Wide NOFOs and NOT with NIAAA Participation:
BRAIN Initiative: Secondary Analysis and Archiving of BRAIN Initiative Data (R01 Clinical Trial Not Allowed) RFA-MH-20-120
BRAIN Initiative: Tools to Facilitate High-Throughput Microconnectivity Analysis (R01 Clinical Trial Not Allowed) RFA-MH-20-135
Building Interdisciplinary Research Careers in Women's Health (BIRCWH) (K12 Clinical Trial Optional) RFA-OD-19-020
Limited Competition for Adolescent Brain Cognitive Development (ABCD) Study - Data Analysis, Informatics and Resource Center (U24 Clinical Trial Not Allowed) RFA-DA-20-003
Limited Competition for Adolescent Brain Cognitive Development (ABCD) Study - Linked Research Project Sites (Collaborative U01 Clinical Trial Not Allowed) RFA-DA-20-002
Limited Competition for Adolescent Brain Cognitive Development (ABCD) Study - Coordinating Center (U24 Clinical Trial Not Allowed) RFA-DA-20-004
U.S.-South Africa Program for Collaborative Biomedical Research - Phase 2 (HIV/AIDS) (R01 Clinical Trial Optional) RFA-AI-19-022
Administrative Supplement for Research on Bioethical Issues (Clinical Trial Optional) PA-19-217
Summer Research Education Experience Program (R25 Clinical Trial Not Allowed) PAR-19-197
Limited Competition for a Connectome Coordination Facility (R24 Clinical Trial Not Allowed) RFA-MH-20-210
Notice of Interest in Long-term Maintenance of Behavior Change Research NOT-OD-19-040
Dr. Changhai Cui moderated a Research Highlight Session on Cells and Circuits at the 5th BRAIN Initiative Investigators Meeting held April 11-13, 2019, in Washington, D.C.
Dr. Changhai Cui was a co-organizer for the NIH Blueprint Workshop on The Science of Interoception and Its Role in Nervous System Disorders, April 16-17, 2019, in Bethesda, Maryland. Dr. Cui co-chaired a session on Modeling Disease, Alterations in Interoceptive Processes, and Comorbidities; Dr. Lorenzo Leggio gave a presentation on The Gut in the Brain: Potential Novel Targets for the Treatment of Addictions.
Dr. Bill Dunty served as a member of the expert planning committee for the 8th International Conference on Fetal Alcohol Spectrum Disorder: Research, Results and Relevance held on March 6-9, 2019 in Vancouver, Canada. At the meeting, Dr. Dunty co-chaired a plenary session on Prenatal Alcohol Exposure and the Microbiome.
Dr. Bill Dunty participated in the symposium titled “Child Development Research Priorities and Opportunities for Young Investigators at the National Institutes of Health” at the Society for Research in Child Development (SRCD) 2019 Biennial Meeting held on March 23, 2019, in Baltimore, Maryland.
Dr. Ralph Hingson presented a talk to the Friends of NIAAA titled “Division of Epidemiology and Prevention Research Priorities: Including Focus on Trends and Interventions that work to Prevent Underage Drinking” on March 19, 2019.
Dr. Lorenzo Leggio was Keynote Speaker (title: “Medication development for addiction via translational investigations of the gut-brain axis”) at the First Annual Substance Use Research Day at the University of Kentucky in Lexington on March 7, 2019.
Dr. Lorenzo Leggio was Keynote Speaker (title: “Developing novel treatments for addiction via gut-brain pathways: recent translational efforts” at the North Central Florida Society for Neuroscience (SfN) Chapter Conference, University of Florida in Gainesville on January 25, 2019. Dr. Leggio also served as a Panelist for a professional development session that was part of the same event.
Dr. Lorenzo Leggio was among the 12 ‘Experts’ invited to The 2019 UCLA Luskin Thought Leadership Meeting on Translational Science of Alcoholism, University of California Los Angeles on March 19, 2019.
Dr. Gary Murray represented NIAAA at the Cancer Moonshot Immuno-Oncology Translational Network Face to Face Meeting 2019 on March 27-28, 2019, at the National Cancer Institute at Shady Grove in Rockville, Maryland.
Dr. Abbas Parsian co-organized the NIDA and NIAAA Genetics and Epigenetics Research Meeting that took place January 14-15, 2019, in Rockville, Maryland. Dr. Parsian gave a short presentation and chaired two session.
Dr. Soundar Regunathan presented NIAAA efforts on alcohol and sleep research at the American Academy of Sleep Medicine Foundation 11th annual Young Investigators Research Forum held on April 11, 2019. He also participated in two group sessions with young investigators and answered questions about the sleep research activities and funding opportunities available at NIAAA and gave feedback on questions regarding research proposals of young investigators.
Dr. Deidra Roach organized a symposium titled “Problem Drinking Among Medically Underserved Women: New Horizons in Treatment” for the 2019 American Society of Addiction Medicine Annual Meeting held April 4-7, 2019, in Orlando, Florida.
Multiple NIAAA staff members participated in the Gordon Research Conference (GRC) on “Alcohol-Induced End Organ Diseases” that was held March 24-29, 2019, in Ventura, California:
- Dr. Li Lin served on a discussion panel on the topic of “Mentorship Component: What Can You Learn from Successful Scientists?”
- Dr. Andras Orosz served as discussion leader of a scientific session titled “Protein and Organelle Homeostasis: Novel Mechanisms of Alcohol-Induced Organ Injury.”
- Drs. Bin Gao and Pal Pacher were invited participants in a session titled “Genetic Factors, Post-Metabolic Signaling and Stress Pathways.”
The 42nd Annual Meeting of the Research Society on Alcoholism will take place June 22-26, 2019, in Minneapolis, Minnesota.
NIAAA and NIDA will again sponsor the Frontiers in Addiction Research Mini-Convention on Friday, October 18, 2019, as a satellite event to the Society for Neuroscience annual meeting in Chicago. In addition to scientific sessions on emerging areas in addiction research, the program will also feature the Jacob Waletzky Memorial Award lecture and Early Career Investigator Showcase. Dr. John Matochik is the program contact.
Significance: The Model for End-Stage Liver Disease (MELD) score is a combined index of lab test results for liver and renal functions and has been the gold standard for prognostic evaluation of severe liver disease conditions. However, the MELD score is a poor mortality predictor for patients with alcoholic hepatitis. This study assessed novel candidate biomolecules, focusing on a panel of recently identified potential biomarkers of tissue injury and immune cell activation. Among these, plasma levels of soluble cluster of differentiation 14 (sCD14), soluble cluster of differentiation 163 (sCD163), and osteopontin (OPN) show promise in predicting not only 90-day alcoholic hepatitis mortality, but also infection and organ failure. Prior to application of any of the potential biomarkers in clinical settings, validation in additional cohorts will be required.
Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, new biomarkers are critically needed to manage this disease. An increase in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically-diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S rDNA) and host response indicators (soluble (s)CD14 and lipopolysaccharide binding protein, LBP) compared to controls. Patient MELD and Glasgow Alcoholic Hepatitis scores (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in High Mobility Group Protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD scores and GAHS and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD and GAHS scores. These findings indicate a connection between microbial translocation, immune cell activation and AH severity. Plasma sCD14, OPN, sCD163 and sCD206 levels were significantly higher in non-survivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Thus, our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are new biomarkers to indicate severity and predict clinical outcomes in AH. (Saha B, Tornai D, Kodys K, Adejumo A, Lowe P, McClain C, Mitchell M, McCullough A, Srinivasan D, Kroll-Desrosiers A, Barton B, Radaeva S, and Szabo G. Hepatology. Epub 2019 Mar 19. doi: 10.1002/hep.30617)
Significance: Previous animal research has demonstrated that paternal chronic alcohol exposure prior to conception has developmental consequences for offspring, including sex-specific growth restriction and placental dysfunction during gestation. This study examined the long-term effects of chronic preconception paternal alcohol exposure on offspring growth and metabolic programming. Results indicated that paternal alcohol exposure is associated with prolonged fetal gestation and increased intrauterine growth restriction, which affected male offspring more than females. Male growth deficits persisted into adult life and were associated with insulin hypersensitivity, increased markers of hepatic fibrosis, and alterations in immune signaling. These abnormalities may suggest alterations in a sperm-inherited epigenetic program that influences the formation and function of the placenta. Importantly, these findings suggest that preconception lifestyle choices of biological fathers may impact offspring.
Background: Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. Results: Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-β signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. Conclusions: The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm. (Chang RC, Wang H, Bedi Y, and Golding MC. Epigenetics Chromatin. 2019 Jan 22;12(1):9. doi: 10.1186/s13072-019-0254-0)
Significance: Previous research has strongly implicated the central nucleus of the amygdala (CeA) in stress and alcohol withdrawal-related effects, including elevated consumption. The current study identifies a population of corticotropin-releasing factor (CRF) neurons projecting from the CeA to the bed nucleus of the stria terminalis (BNST) that are activated by withdrawal from chronic alcohol exposure in rats. Inactivation of these CRF neurons decreased the intensity of somatic withdrawal signs and attenuated the escalation of alcohol drinking. These results suggest that drugs or gene therapies targeting this neural pathway may effectively treat symptoms of AUD.
The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder. (de Guglielmo G, Kallupi M, Pomrenze MB, Crawford E, Simpson S, Schweitzer P, Koob GF, Messing RO, and George O. Nat Commun. 2019 Mar 18;10(1):1238. doi: 10.1038/s41467-019-09183-0)
Significance: Alcohol misuse during late adolescence and early adulthood is a risk factor for the development of alcohol use disorder. This longitudinal study used a macaque model of daily alcohol self-administration and in vivo imaging to quantify the impact of chronic alcohol exposure on neural alterations that occur during this developmental period. Heavy alcohol self-administration during late adolescence was associated with reduced growth rates of the subcortical thalamus, cerebral white matter, and overall brain volume. These results demonstrate that heavy alcohol exposure during the transition to young adulthood significantly impacts brain development in macaques, an insult that may lead to the continuation of heavy drinking throughout later adult life.
The transition from adolescence to adulthood is associated with brain remodeling in the final stages of developmental growth. It is also a period when a large proportion of this age group engages in binge alcohol drinking (occasional consumption of four to five drinks leading to intoxication) and heavy alcohol drinking (binge drinking on 5 d in a month). Here we report on magnetic resonance imaging of developmental changes in the brain occurring during late adolescence and early adulthood (3.5–7.5 years of age) in a rhesus macaque model of alcohol self-administration. Monkeys were imaged prior to alcohol exposure, and following 6 and 12 months of daily (22 h/d) access to ethanol and water. The results revealed that the brain volume increases by 1ml/1.87 years throughout the late adolescence and early adulthood in controls. Heavy alcohol drinking reduced the rate of brain growth by 0.25 ml/year per 1 g/kg daily ethanol. Cortical volume increased throughout this period with no significant effect of alcohol drinking on the cortical growth rate. In subcortical regions, age-dependent increases in the volumes of globus pallidus, thalamus, brainstem, and cerebellum were observed. Heavy drinking attenuated the growth rate of the thalamus. Thus, developmental brain volume changes in the span of late adolescence to young adulthood in macaques is altered by excessive alcohol, an insult that may be linked to the continuation of heavy drinking throughout later adult life. (Shnitko TA, Liu Z, Wang X, Grant KA, and Kroenke CD. eNeuro. 2019 Apr 9;6(2). pii: ENEURO.0044-19.2019. doi: 10.1523/ENEURO.0044-19.2019)
Significance: Evidence for distinct functional roles of hippocampal subregions suggests that the dorsal hippocampus (dHC) primarily mediates spatial learning and memory whereas the ventral hippocampus (vHC) regulates anxiety- and depressive-like behaviors. Previous research has implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD), but the discrete effects of chronic alcohol on synaptic transmission in the vHC compared to the dHC have not been characterized. This study demonstrated that withdrawal from chronic intermittent alcohol exposure enhances synaptic excitability specifically in the vHC, providing insight into a neural mechanism that may contribute to the negative affect observed during abstinence in AUD.
Abstract: Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety- and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long–Evans rats were exposed to CIE or AIR for 10 days (12 h/day; targeting blood ethanol levels of 175–225 mg%) and recordings were made 24 h into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze and successive alleys test. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, were dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal. (Ewin SE*, Morgan JW, Niere F, McMullen NP, Barth SH, Almonte AG, Raab-Graham KF, and Weiner JL. Neuroscience. 2019 Feb 1;398:144-157. doi: 10.1016/j.neuroscience.2018.11.028)
*denotes NIAAA trainee
Significance: Negative affect during alcohol abstinence is a feature of alcohol use disorder (AUD) that may promote relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence, this study demonstrates that the endocannabinoid-sensitive projection from the insular cortex to the dorsal bed nucleus of the stria terminalis (dBNST) plays a key role in regulating negative affective behavior. These results establish the insula-dBNST neurocircuit as a promising target for endocannabinoid-based pharmacotherapy to alleviate negative affective symptoms associated with abstinence in AUD.
Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a Gq-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders. (Centanni SW, Morris BD, Luchsinger JR, Bedse G, Fetterly TL, Patel S, and Winder DG. Neuropsychopharmacology. 2019 Feb; 44(3): 526-537. doi: 10.1038/s41386-018-0257-8)
Significance: Long non-coding RNAs (lncRNA), which regulate gene expression and chromatin structure, play an important role in normal brain development. Brain-derived neurotropic factor (BDNF) is a critical molecular player in alcohol use disorder (AUD), and BDNF antisense (BDNF-AS) is a lncRNA that negatively regulates BDNF. The current study compared BDNF-AS expression and associated epigenetic mechanisms in the postmortem human amygdala in individuals with AUD who began drinking either before (“early onset”) or after (“late onset”) age 21 to age-matched control samples. Increased BDNF-AS expression in the amygdala was observed in the early onset AUD group, suggesting a possible role for developmentally-sensitive lncRNAs in early onset AUD. These results suggest that regulation of BDNF may prove useful in the treatment of adult psychopathology after adolescent alcohol drinking.
Objective: Previous work has found that individuals with alcohol dependence have decreased circulating BDNF in blood. Also, transgenic mice harboring a homolog of a common human polymorphism of BDNF (Val66Met) compulsively consume more alcohol than wild-type mice. However, the role of BDNF in the molecular mechanisms of AUD is unknown. Design: This study evaluated the expression and functional role of BDNF-AS in postmortem amygdala of either early onset or late onset alcoholics (individuals who began drinking before or after 21 years of age, respectively) and age-matched control subjects. ChIP assay evaluated the epigenetic modifications at several different BDNF loci. Conclusions: BDNF-AS expression is increased in early onset but not in late onset AUD amygdala and appears to be regulated epitranscriptomically via decreased N6-methyladenosine on BDNF-AS. Early onset AUD individuals show repressive chromatin remodeling at several different BDNF gene loci. Also, the early immediate gene ARC, which is a downstream target of BDNF and involved in synaptic plasticity, is decreased in the amygdala of early onset AUDs through interactions with the synaptic activity response element (SARE) in the ARC promoter. Conclusions: These findings taken together with previous studies suggest that disruptions to BDNF expression and ARC signaling are likely to increase the risk for alcohol dependence, and the risk is greater if these changes occur at a critical period of brain development, such as adolescence, due to enduring effects on epigenetic programming. (Bohnsack JP, Teppen T, Kyzar EJ, Dzitoyeva S, and Pandey SC. Transl Psychiatry. 2019 Feb 6;9(1):34. doi: 10.1038/s41398-019-0367-z)
Significance: Loss of control over drinking and impulsivity, among other behaviors, are key features of alcohol use disorder (AUD). This study examined the relationship between impaired control over drinking and alcohol consumption and the modulation of this relationship by impulsive personality traits in drinkers without AUD. Impaired control, measured by self-report, was associated with higher alcohol self-administration in a human laboratory paradigm. Impaired control was also found to be a significant mediator of the relationship between the tendency to act rashly during positive mood states (“positive urgency”) and alcohol self-administration. These findings highlight the critical role of impaired control over drinking on alcohol consumption and subjective responses in drinkers without AUD.
Impaired control over drinking is a significant marker of alcohol use disorder (AUD), and a potential target of intervention (Heather, Tebbutt, Mattick, & Zamir, 1993; Leeman, Toll, Taylor, & Volpicelli, 2009). Impaired control may be related to, but conceptually distinct from, impulsivity (Leeman, Patock-Peckham, & Potenza, 2012; Leeman, Ralevski, et al., 2014). However, the relationship between impaired control, impulsivity, and alcohol consumption, particularly in nondependent drinkers is less clear. This study aimed to characterize these relationships using a free-access intravenous alcohol self-administration (IV-ASA) paradigm in nondependent drinkers (N = 48). Results showed individuals with higher self-reported impaired control achieved higher blood alcohol concentrations (BAC) during the IV-ASA session and reported greater hedonic subjective responses to alcohol. Higher impaired control was also associated with greater positive urgency and reward sensitivity. Moderated-mediation analysis showed that the relationship between positive urgency and peak BAC was mediated by impaired control, and partially moderated by subjective alcohol response. These findings highlight the critical role of impaired control over drinking on alcohol consumption and subjective responses in nondependent drinkers. (Vaughan CL, Stangl BL, Schwandt ML, Corey KM, Hendershot CS, and Ramchandani VA. Exp Clin Psychopharmacol. Epub 2019 Jan 28. doi: 10.1037/pha0000247)
Significance: Previous research has established the validity of NIAAA’s two-question alcohol risk youth Screening Guide, which aids primary care providers in identifying 9- to 18-year-olds at risk for alcohol-related problems, across multiple settings and underage populations. This study, conducted across a large network of pediatric emergency departments, tests the Screening Guide for its ability to accurately assess longer-term risky drinking and alcohol use disorder (AUD) in youth. Results indicated that youth showing at least “low risk” or higher on the Screening Guide at baseline were significantly more likely to report risky drinking or meet criteria for AUD, when interviewed one, two, and three years later. The Screening Guide’s brevity; ability to detect the risk of alcohol use, alcohol use, and AUD early; and ease of use should facilitate its routine use in busy clinical practice settings.
Background: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) 2-question screen is a valid adolescent alcohol screening tool. No studies have examined if this tool predicts future alcohol problems. We conducted a study at 16 pediatric emergency departments to determine the tool's predictive validity for alcohol misuse and alcohol use disorders (AUDs). Methods: Participants (N = 4834) completed a baseline assessment battery. A subsample of participants completed the battery at 1, 2, and 3 years follow up. Results: Of the 2209 participants assigned to follow-up, 1611 (73%) completed a 1-year follow-up, 1591 (72%) completed a 2-year follow-up, and 1377 (62%) completed a 3-year follow-up. The differences in AUDs between baseline NIAAA screen nondrinkers and lower-risk drinkers were statistically significant at 1 year (P = .0002), 2 years (P <.0001), and 3 years (P = .0005), as were the differences between moderate- and highest-risk drinkers at 1 and 2 years (P < .0001 and P = .0088, respectively) but not at 3 years (P = .0758). The best combined score for sensitivity (86.2% at 1 year, 75.6% at 2 years, and 60.0% at 3 years) and specificity (78.1% at 1 year, 79.2% at 2 years, and 80.0% at 3 years) was achieved by using "lower risk" and higher as a cutoff for the prediction of a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis. Conclusions: The NIAAA 2-question screen can accurately characterize adolescent risk for future AUDs. Future studies are needed to determine optimaluse of the screen. (Linakis JG, Bromberg JR, Casper TC, Chun TH, Mello MJ, Richards R, Mull CC, Shenoi RP, Vance C, Ahmad F, Bajaj L, Brown KM, Chernick LS, Cohen DM, Fein J, Horeczko T, Levas MN, McAninch B, Monuteaux MC, Grupp-Phelan J, Powell EC, Rogers A, Suffoletto B, Dean JM, Spirito A, and Pediatric Emergency Care Applied Research Network. Pediatrics. 2019 Mar; 143(3). doi: 10.1542/peds.2018-2001)
Significance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Although both outcomes are clinically intuitive, neither considers the magnitude of reduction in drinking or the potential benefits of reductions in drinking short of total abstinence or no heavy drinking. This study conducted secondary analyses of data from three multi-site AUD pharmacotherapy trials to evaluate reduction in World Health Organization (WHO) drinking risk level as a treatment outcome. This measure captures reduction in drinking, an outcome which is more often achieved by subjects than total abstinence or no heavy drinking days. Results suggest that WHO drinking risk level reduction is equally or more sensitive to treatment compared to total abstinence and no heavy drinking days, demonstrating that this measure is an indicator of treatment efficacy that could be included as an additional outcome for AUD pharmacotherapy trials.
Objective: To compare 2 drinking reduction outcomes with total abstinence and no heavy drinking outcomes. Design, Setting, and Participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. Main Outcomes and Measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h).Results: Across the 3 trials (N = 1169; mean [SD] age, 45  years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]).Conclusions and Relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. (Falk DE, O'Malley SS, Witkiewitz K, Anton RF, Litten RZ, Slater M, Kranzler HR, Mann KF, Hasin DS, Johnson B, Meulien D, Ryan M, and Fertig J; Alcohol Clinical Trials Initiative [ACTIVE] Workgroup. JAMA Psychiatry. Epub 2019 Mar 13. doi: 10.1001/jamapsychiatry.2018.3079)
Significance: The Institute of Medicine’s 2011 report on the health of sexual and gender minorities emphasized that the absence of explanatory frameworks hampers the ability to effectively prevent, mitigate, or treat alcohol use disorder (AUD) in high‐risk vulnerable populations. This study examined the association between DSM‐5 AUD severity and sexual orientation discrimination using a nationally representative sample. Sexual minorities who experienced higher levels of sexual orientation discrimination had significantly higher levels of AUD severity than sexual minorities who experienced lower levels or no discrimination, with proximal experiences of discrimination more salient than distal experiences. These findings provide new evidence that sexual minorities who experience high levels of sexual orientation discrimination are at substantially increased risk of severe AUD.
Background: Sexual minorities are more likely than their heterosexual counterparts to develop alcohol use disorder (AUD), and understanding the underlying reasons for this heightened risk is a public health priority. This study examined relationships between sexual orientation discrimination and DSM-5 AUD severity. Methods: The 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions III conducted in-person interviews with a nationally representative sample of U.S. adults (N = 36,309). Approximately 2.8% of the target population self-identified as lesbian, gay, or bisexual, 3.1% had at least 1 past-year same-sex sexual partner, and 8.3% reported same-sex sexual attraction. Results: Adults who identified as lesbian, gay, bisexual, heterosexual with same-sex attraction and/or current same-sex sexual partners, and those not sure of their sexual identity, had higher rates of individual DSM-5 AUD criteria than heterosexual-identified adults with only opposite-sex attraction and sexual partners. Respondents who were bisexual or unsure of their sexual identity consistently had the highest probabilities of endorsing each of these AUD criteria relative to the other subgroups. Differences in AUD severity across sexual orientation subgroups were much larger among women than among men. Sexual minorities who experienced higher levels of sexual orientation discrimination had significantly higher levels of AUD severity than sexual minorities who experienced lower levels or no discrimination. In particular, greater levels of sexual orientation discrimination increased the odds of impaired control criteria and pharmacologic criteria. Associations between prior-to-past-year sexual orientation discrimination and AUD severity were not as robust as those involving past-year discrimination. Conclusions: Sexual minorities are at substantially greater risk of severe DSM-5 AUD, and this is particularly true among those who experience high levels of sexual orientation discrimination. Findings indicate that proximal experiences of discrimination are more salient than distal experiences. AUD treatment should address recent sexual orientation discrimination given that such experiences are associated with more severe AUD. (McCabe SE, Hughes TL, West BT, Veliz P, and Boyd CJ. Alcohol Clin Exp Res. 2019 Mar;43(3):497-508. doi: 10.1111/acer.13960)
Press and Publications Activities:
Recent News Media Interviews: Dr. Koob continues to speak with a variety of national and international news outlets on timely topics related to NIAAA’s research and its impact on treatment and prevention of alcohol misuse and AUD. Notable interviews by Dr. Koob and other staff since January 2019 including TIME Magazine, Self Magazine, AARP.com, Consumer Reports and The Washington Post.
- NIH study of brain energy patterns provides new insights into alcohol effects (March 4, 2019)
- NIH-funded rodent study finds molecular link between adolescent alcohol use and adult anxiety (March 11, 2019)
Publication Statistics: In the month of March 2019, NIAAA filled orders for 16,937 copies of print publications. As of April 8, 2019, there were 30,019 Granicus/GovDelivery listserv subscribers to Alcohol Research: Current Reviews; 23,424 to the NIAAA Spectrum; 745 to News Alerts; and 22,622 to receive general information.
New and Updated Publications:
Hangovers fact sheet: https://pubs.niaaa.nih.gov/publications/hangoversfactsheet/hangovers.htm
Social Media Highlights
Twitter: The NIAAA Twitter account (@NIAAAnews) currently has more than 23,000 followers and averages about 100,000 impressions (number of times users saw the tweet on Twitter) per month. NIAAA co-hosted two Twitter chats in recognition of Alcohol Awareness Month – see below.
Instagram: NIAAA’s Instagram account (@niaaanews) continues to grow. Recent posts include messages about seasonal alcohol awareness (the Super Bowl, Valentine’s Day, and St. Patrick’s Day), alcohol’s effects on the brain, women and alcohol, postbaccalaureate research at NIAAA, funding opportunities, research on adolescent brain development, and the NIAAA Alcohol Treatment Navigator.
#ThisIsNIH social media takeover: During the week of April 15-19, NIAAA participated in a takeover of NIH’s social media accounts (Twitter, Instagram, and Facebook), posting alcohol-related messages on the main NIH accounts. April was chosen for NIAAA’s takeover in recognition of Alcohol Awareness Month. The expanded audience (NIH’s Twitter account has 897K followers; Instagram has 67K followers) resulted in increased reach for NIAAA’s messages, with the most popular Instagram post receiving more than 1,200 likes. A video about the Alcohol Treatment Navigator was viewed more than 1,300 times in one day.
NIAAA Seasonal Outreach:
St. Patrick’s Day Safety Awareness: NIAAA tweeted St. Patrick’s Day safety messages on March 15 and 16, 2019. Other stakeholder groups were also encouraged to disseminate the message on their social media channels--the Sun-Gazette, Self Magazine, and The Fix ran related stories..
Valentine’s Day Health Message: NIAAA tweeted a Valentine’s Day health message to “Love Your Liver” on February 14, 2019. Overall, the total potential audience for the social media outreach effort was 6,700 followers..
Super Bowl Safety Awareness: NIAAA tweeted several Super Bowl safety messages on January 28 and on February 1 and 3, 2019, resulting in an estimated reach of 12,400 followers. Forbes.com, Cleveland.com, and Thrillest.com ran related stories. Forbes.com also promoted the NIAAA’s Director’s Blog.
Alcohol Awareness Month:
To recognize Alcohol Awareness Month, NIAAA implemented a multi-faceted outreach strategy, which included social media messages, carousel images, and a Director’s Blog post.
Social media messages: Throughout the month, @NIAAAnews tweeted informational messages and graphics using the #AlcoholAwarenessMonth hashtag. Tweets included facts about AUD prevalence, treatment options, and health effects, and linked to resources like Rethinking Drinking and the NIAAA Alcohol Treatment Navigator.
Twitter chats: NIAAA partnered with the American Society of Addiction Medicine (ASAM) and the American College of Obstetricians and Gynecologists (ACOG) for two separate chats during the month. The chats covered alcohol screening and fetal alcohol spectrum disorders, respectively.
Carousel graphics: Staff worked with the NIH Office of the Director to develop a carousel for NIH.gov, linked to the NIAAA Alcohol Treatment Navigator.
NIAAA Director’s Blog: Dr. Koob updated his blog with a new entry recognizing Alcohol Awareness Month. The post can be read here: https://www.niaaa.nih.gov/directors-blog.
Partnerships, Outreach, and Public Liaison Activities:
Community Anti-Drug Coalitions of America (CADCA): At the 2019 CADCA Leadership Forum on February 5, NIAAA Director Dr. George F. Koob presented the “NIAAA Power Session: Giving You Information and Tools for Addressing Alcohol Problems in Your Communities.” Dr. Ralph Hingson lectured on “Trends and Interventions That Work to Prevent Underage Drinking,” and Dr. Aaron White presented “Alcohol and Opioids—A Deadly Combination.”
In addition, NIAAA together with NIDA and SAMHSA received CADCA’s 2019 National Leadership Award. The distinguished award recognizes organizations that have been instrumental in the prevention movement and work to ensure progress is being made in addressing serious public health issues in the United States. On behalf of NIAAA, Dr. Koob accepted the award from CADCA Chairman and CEO General Arthur T. Dean (right).
Brain Awareness Week: NIAAA staff participated in Brain Awareness Week (BAW) events hosted by the National Museum of Health and Medicine in Silver Spring, Maryland. On March 14, 2019, Drs. Mohammed Akbar, Ivana Grakalic, Soundar Regunathan, and Rachel Anderson presented a slideshow on alcohol and adolescent brain development. Students learned about alcohol’s effects on the developing brain and the consequences of underage drinking. Teens also engaged in a bean-bag toss game while wearing Fatal Vision goggles to simulate being under the influence of alcohol. BAW is an annual program founded by the Dana Alliance for Brain Initiatives and serves as a global campaign to increase public awareness of the progress and benefits of brain research.
ScienceBlog.com: Continuing its relationship with NIAAA Communications, in February and March 2019 ScienceBlog.com posted content written by NIAAA staff. The stories spotlighted an imaging study on brain energy patterns (right); a rodent model of anxiety; and research on alcoholic hepatitis, underage drinking, and prenatal alcohol exposure.
NAADAC, the Association for Addiction Professionals: Recently, NAADAC published an article written by NIAAA on “Alcohol and the Aging Brain” (right) in its quarterly magazine, Advances in Addiction & Recovery. The feature, written by John Bowersox, first appeared in the Fall 2018 issue of NIAAA Spectrum.
NBC Health and Fitness Expo
On January 12 and 13, NIAAA exhibited at the NBC4 Health and Fitness Expo in Washington, D.C. An estimated 85,000 people attend this annual event. The NIAAA exhibit booth offered general information about alcohol, as well as promoting the NIAAA Treatment Navigator, which booth visitors could “test drive” at interactive touchscreen kiosks. Leading up to the event, NIAAA’s Treatment Navigator booth was promoted through banner advertisements for two weeks on the NBC4 homepage, which generated about 300,000 impressions and over 1000 clicks. These advertisements can be viewed at https://vimeo.com/307718655/191e1bf40b (link is external). In addition, the program booklet for the expo included a quarter-page color advertisement about the NIAAA Treatment Navigator.