Research Highlights

Research News
Friday, February 24, 2017
The effects of alcohol use during pregnancy on an unborn child are well known. However, a recent NIAAA-funded study in rats has shown that a mother’s alcohol use before conception also could have negative effects on her child’s health and response to stress during adulthood.
To study the effects of preconception alcohol use, the research team, led by Dipak Sarkar, Ph.D., at Rutgers University, gave female rats 4 weeks of access to a diet containing 6.7 percent alcohol, which raised their blood alcohol levels similar to that of binge drinking in humans. Alcohol was then removed from the rats’ diet, and they were bred 3 weeks later. After the rats’ offspring reached adulthood, the researchers used standard laboratory techniques to evaluate their response to stress, anxiety-like behaviors, changes in levels of stress regulatory genes and protein hormones, as well as epigenetic changes—chemical modifications to DNA that occur in the absence of changes in sequence and can alter gene function.
The team found that offspring of rats that were exposed to alcohol before conception had increased levels of stress hormones in their blood in response to an immune challenge and changes in the expression and epigenetic profiles of genes that play a role in regulating stress responses in their brains. However, the researchers observed changes in anxiety-like behaviors only in the male offspring.
Previous research has indicated that epigenetic mutations may be passed from parent to child and also that epigenetic mutations may play a role in the expression of anxiety-linked behaviors and response to stress. Alcohol problems are known to run in families, and increased alcohol consumption in humans has been associated with increased anxiety.
Taken together, these findings suggest that epigenetic changes in the mother as a result of alcohol misuse before conception may be passed on to her offspring. These changes could have lifelong effects on a child’s response to stress.
Jabbar, S.; Chastain, L.G.; Gangisetty, O.; Cabrera, M.A.; Sochacki, K.; and Sarkar, D.K. Preconception alcohol increases offspring vulnerability to stress. Neuropsychopharmacology 41(11):2782–2793, 2016. PMID: 27296153

Reprinted from the NIAAA Spectrum, Volume 9, Issue 1, February 2017.

Spectrum Cover
Research News
Monday, February 13, 2017
Liver fibrosis is a consequence of chronic liver injury associated with alcoholic or nonalcoholic fatty liver disease, viral hepatitis, or metabolic diseases, and can lead to cirrhosis and even cancer. While there are no effective treatments for liver fibrosis, previous research has shown that compounds that block receptors for molecules similar to those found in the marijuana plant (endocannabinoids) can interfere with the development of liver fibrosis. However, the development of therapies based on these cannabinoid-1 receptor (CB1R)-blocking compounds was halted, because they have unwanted neuropsychiatric side effects of CB1R-blocking agents acting in the brain.
In a new study, NIAAA-supported researchers have developed a CB1R-blocking compound that could avoid those side effects, because it accumulates in the liver without penetrating the brain. An added benefit of the new compound is that it also targets an enzyme called inducible nitric oxide synthase (iNOS), which also promotes the development of liver fibrosis. In studies that used mouse models of liver fibrosis, the researchers found that the new compound surpassed the antifibrotic ability of other CB1R blockers or iNOS inhibitors without inducing anxiety-like behaviors or CB1R blockade in the central nervous system.
The researchers note that the dual targeting of peripheral CB1R and iNOS exemplifies the therapeutic advantage of simultaneously hitting more than one molecule involved in a pathogenic process, particularly in light of emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases. They therefore conclude that the approach illustrated by their study shows promise as an effective anti-fibrotic strategy.
Cinar, R.; Iyer, M.R.; Liu, Z.; Cao, Z.; Jourdan, T.; Erdelyi, K.; Godlewski, G.; Szanda, G.; Liu, J.; Park, J.K.; Mukhopadhyay, B.; Rosenberg, A.Z.; Liow, J.S.; Lorenz, R.G.; Pacher, P.; Innis, R.B.; and Kunos, G. Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis. JCI Insight 1(11):e87336, 2016. PMID: 27525312

Spectrum Cover Reprinted from the NIAAA Spectrum, Volume 9, Issue 1, February 2017.

Research News
Thursday, February 19, 2015

According to the results of a recent NIAAA-funded animal study, carrying a gene variant that affects the release of a specific brain protein may increase the risk of developing an alcohol use disorder. The protein, brain-derived neurotrophic factor (BDNF), affects the survival of existing neurons and the growth of new neurons and synapses, the junctures through which cell-to-cell communication occurs.

In the study, researchers tested the role of BDNF in alcohol addiction by creating a “knock-in” mouse carrying a gene that reduces activity-dependent BDNF release. These “knock-in” mice drank more alcohol, even when the alcohol was treated with bitter-tasting quinine. This suggests carriers of the variant gene compulsively drink alcohol despite negative results. The effect of the genetic mutation seemed to be specific to alcohol consumption because the mice’s consumption of other fluids did not change, nor was there any difference in their levels of anxiety or compulsive behaviors.

By increasing levels of BDNF in the ventromedial portion of the prefrontal cortex, a brain region involved in compulsive drug and alcohol seeking, the researchers were able to return the mice to moderate levels of alcohol intake. In addition, by administering a pharmaceutical compound (LM22A-4) developed to mimic the action of BDNF, researchers were able to put a stop to compulsive drinking behaviors. LM22A-4 appears to reduce compulsive alcohol-drinking without a generalized effect on motivation and may have potential as a therapeutic for humans.


Warnault, V.; Darcq, E.; Morisot, N.; Phamluong, K.; Wilbrecht, L.; Massa, S.M.; Longo, F.M.; and Ron, D. The BDNF valine 68 to methionine polymorphism increases compulsive alcohol drinking in mice that is reversed by tropomyosin receptor kinase B activation. Biological Psychiatry, June 12, 2015. [Epub ahead of print]. PMID: 26204799



Reprinted from the NIAAA Spectrum, Volume 7, Issue 3, September 2015.

Research News
Sunday, September 20, 2015

 In a commentary published in April in the journal Alcoholism: Clinical and Experimental Research, Raye Litten, Ph.D., and other NIAAA scientists describe the evolution of our understanding of the heterogeneity of alcohol use disorder (AUD), and outline new treatment and research regimes that follow from the recognition that alcohol problems are manifested along a continuum of severity, ranging from the occasional binge drinker to the chronic relapsing heavy drinker.

“Each patient develops an AUD based on his or her unique neurobiological makeup and lifetime experiences—a complex interaction of underlying genetic and environmental mechanisms,” write Dr. Litten and his colleagues. “This heterogeneity can be understood as a number of subphenotypes, each having its own unique profile of drinking pattern, motivation for drinking, alcohol-related consequences, and neurobiological underpinnings.”

“Not surprisingly,” they note, “a wide variety of clinically acceptable treatment outcomes are possible with AUD, including not only abstinence, but also low-risk drinking, and even some less-conservative forms of moderate drinking.”

A menu of effective treatment options is available today, including three FDA-approved medications to treat alcohol dependence—disulfiram, oral and injectable naltrexone, and acamprosate. A variety of behavioral therapies have also been shown to be effective. However, the authors note that due to the complex heterogeneity of AUD, no single treatment will work for every person with AUD. However, ongoing research progress in both the neurobiology and pharmacogenetics of AUD holds the promise of identifying biologically based AUD subtypes and the selection of treatments to target those subtypes.

“Neurobiological researchers have identified more than 30 molecular targets that appear to alter people’s craving or drinking behaviors,” they write, “and emerging knowledge of the neurobiology and neurocircuitry of AUD provides a framework for organizing targets.”

Dr. Litten and his colleagues say that current evidence allows alcohol addiction, in general, to be broken down into a three-stage cycle: binge–intoxication, withdrawal–negative affect, and preoccupation–anticipation.

“These three stages interact with and build on one another, becoming more intense, and ultimately leading to the pathological state known as addiction. Within this concept, AUD can be conceptualized as a disorder that involves elements of both impulsivity and compulsivity. As an individual moves from impulsivity to compulsivity, a shift occurs from positive rein-forcement to negative reinforcement driving the motivated behavior.”

To promote systematic research discovery efforts based on current knowledge, the NIAAA scientists propose a new framework, called Alcohol Addiction Research Domain Criteria, modeled after a program in use at the National Institute of Mental Health (NIMH). Such a system, they say, enables researchers to “drill down” to the core mechanisms underlying dysfunction, and link behavior and mood to their brain function, neural circuitry, neurotransmitters, and genes.

“The development of an alcohol addiction domain criteria-based framework to conceptualize research on AUD that probes the sources of the disorder could serve to organize and advance our understanding of alcohol addiction,” the authors conclude. “Identifying the major domains underlying AUD and how the profile of vulnerability to each domain varies among individuals, and over time, not only will be vital to understand the heterogeneity of the disorder, but will also enable us to tailor treatment effectively to the individual. This will substantially advance the field of personalized medicine, and foster the translation of findings from basic research into practical, clinical applications.”


Litten, R.Z.; Ryan, M.L.; Falk, D.E.; Reilly, M.; Fertig, J.B.; and Koob, G.F. Heterogeneity of alcohol use disorder: Understanding mechanisms to advance personalized treatment. Alcoholism: Clinical and Experimental Research 39(4):579–584, 2015. PMID: 25833016



Reprinted from the NIAAA Spectrum, Volume 7, Issue 3, September 2015.

Research News
Wednesday, February 17, 2016

Two to three brief training sessions can significantly increase pediatricians’ use of screening and brief interventions to help their patients with substance use and mental health problems, according to a large, 2-year trial supported by NIAAA. The study also found that pediatric practices can increase delivery of these services by adding behavioral health clinicians to their teams.

Mounting evidence supports the use of screening, brief intervention, and referral to treatment (SBIRT) in pediatric practices to reduce underage drinking and its harmful consequences. Pediatricians often report barriers to conducting SBIRT, however, including time constraints and a lack of training.

Researchers at Kaiser Permanente Northern California compared two practical ways to overcome these barriers and increase the delivery of SBIRT services in a trial involving about 50 pediatricians and 1,900 adolescents. One group of pediatricians was offered three 60-minute SBIRT training sessions then encouraged to conduct assessments and brief interventions when needed. A second group had one 60-minute training session, then was encouraged to assess and refer patients as needed for interventions by clinical psychologists “embedded” in their practices. For comparison, a third, “usual care” group had access to the same clinical guidelines and tools but no SBIRT training or psychologists in their practices.

The researchers found that, following SBIRT training, the pediatrician-only group was about 10 times more likely to conduct brief interventions with patients deemed at risk, compared with usual care pediatricians (16 percent for the trained group vs. 1.5 percent for usual care). In the pediatrician-plus-psychologist group, 24 percent of at-risk patients received brief interventions.

Although overall pediatrician attention to behavioral health concerns was still low following training, the researchers indicated that embedding behavioral health clinicians in primary care could be a cost-effective way to increase SBIRT delivery. Future analyses will examine patient outcomes and the cost-effectiveness of the two SBIRT delivery options.


Sterling, S.; Kline-Simon, A.H.; Satre, D.D.; Jones, A.; Mertens, J.; Wong, A.; and Weisner, C. Implementation of screening, brief intervention, and referral to treatment for adolescents in pediatric primary care: A cluster randomized trial. JAMA Pediatrics 169(11):e153145, 2015. PMID: 26523821


Reprinted from the NIAAA Spectrum, Volume 8, Issue 1, February 2016.