A new study provides evidence that endocannabinoids, natural compounds that are chemically similar to the active ingredient in marijuana, play a role in the development of Fetal Alcohol Spectrum Disorders (FASD). Researchers led by Balapal S. Basavarajappa (aka: Basavaraj S. Balapal), Ph.D., of the Nathan Kline Institute for Psychiatric Research and New York State Psychiatric Institute, investigated the effect of alcohol on the endocannabinoid system and how those effects influence brain development in mice. The molecules and receptors that comprise the body’s endocannabinoid system work together to affect physiological processes such as brain development, appetite, pain, mood, and memory – the very processes also affected by using marijuana.
In this study, published in the April 10, 2013 issue of the Journal of Neuroscience, researchers exposed 7-day-old mice to binge-like amounts of alcohol to examine the resulting changes in the brain’s structure and functions. In terms of brain development, this is comparable to exposing a human in the third trimester of fetal development to alcohol. What they found is that the endocannabinoid anandamide (AEA) and its receptor, CB1, both increase in response to alcohol. Elevated AEA and CB1 receptor causes the extracellular signal-regulated kinases (ERK 1/2) to change from its active, or phosphorylated, form to its inactive or dephosphorylated form. The authors hypothesized that it is this change in ERK 1/2 that causes neurodegeneration in neonates and deficits in synaptic plasticity and cognitive function in adults that are characteristic of FASD.
The researchers further tested this hypothesis by blocking CB1 receptors in two ways. One was to pharmacologically block CB1 activity with an antagonist. The other was by using mice that were genetically engineered to have no CB1 receptor. Both of these manipulations prevented alcohol-induced neurodegeneration in neonates and long-lasting synaptic and memory deficits in adult mice.
Dr. Shivakumar Subbanna, the study’s first author explains that “elevated AEA/CB1 receptor signaling occurred through transcriptional activation of genes responsible for AEA biosynthetic enzymes and CB1 receptor protein.”
Dr. Balapal, who is also a faculty at Department of Psychiatry, College of Physicians and Surgeons, Columbia University, NY, and his colleagues note that AEA/CB1 receptor/pERK1/2 signaling molecules that regulate the formation of proper synaptic connections in the developing brain might be directly responsible for the synaptic and memory deficits associated with FASD.
Dr. Antonio Noronha, director of NIAAA’s Division of Neuroscience and Behavior, believes the study’s findings have important implications for the prevention of FASD.
“Understanding the mechanism leading to the neurodegeneration that underlies the development of FASD is a critical step in developing novel treatments to block alcohol-induced neurotoxicity in the developing brain. Potentially, these data can lead to the development of drugs or other tools that target the endocannabinoid/CB1 receptor-ERK 1/2 signaling pathways, and avoid or reverse brain damages,” said Dr. Noronha.
Time course and metabolism are important factors
According to National Institute on Alcohol Abuse and Alcoholism (NIAAA) scientists, existing epidemiologic evidence supporting the relationship between moderate alcohol consumption and breast cancer risk needs further study.
“Understanding how and when alcohol consumption increases breast cancer risk is important for a full understanding of how moderate alcohol drinking impacts women’s overall health,” says first author Philip J. Brooks, Ph.D., program officer in the NIAAA Division of Metabolism and Health Effects.
To help women understand alcohol’s health effects, scientists at NIAAA analyzed recent epidemiologic studies of alcohol and breast cancer, in the context of the current understanding of the time course and molecular basis of human carcinogenesis. Their analysis, which underscores the importance of accounting for time and drinking patterns when considering alcohol’s health effects, appears as an online commentary in Alcoholism: Clinical and Experimental Research.
Recent epidemiologic evidence has associated even moderate alcohol consumption by women – no more than one drink per day -- with a 10 percent increase in breast cancer risk compared with non-drinking women. Other epidemiology and laboratory studies have consistently associated low to moderate alcohol intake with reduced risk for cardiovascular problems and other health benefits.
“This commentary is an important contribution to ongoing discussions about the health effects of moderate alcohol consumption,” says Kenneth R. Warren, Ph.D., NIAAA acting director.
Research into consistent low-level drinking may not account for the effects of large amounts of alcohol consumed at any one time.
Some of the largest epidemiologic studies of alcohol and breast cancer risk involved asking middle-age postmenopausal women about their current alcohol consumption, then assessing breast cancer diagnoses over the next five to 10 years.
Since in most cases it takes roughly 20 years or more to go from a normal cell to a clinical diagnosis of cancer, Dr. Brooks maintains that the breast cancers diagnosed in these women could not have been caused by the alcohol they reported drinking at the beginning of the study.
“One possible explanation is that lifetime drinking, including heavy drinking earlier in life, increases breast cancer risk, consistent with several earlier epidemiologic studies,” says Dr. Brooks. “Another possible explanation is that some of the women had undiagnosed breast cancers at the time that the study began, and that alcohol drinking increased the probability of breast cancer diagnosis, perhaps by making the tumors grow faster.”
A significant problem with alcohol and breast cancer studies, he says, has been that people tend to report less alcohol than they actually consume. As a result, such studies can overestimate the effect of a given amount of alcohol on breast cancer risk. Another limitation of these studies is the lack of information about drinking patterns.
“There is a major difference between having several drinks on a single day and nothing on others versus consistently having one drink per day,” says Dr. Brooks. “Binge-type drinking -- four or more drinks per occasion – on some days and not drinking on others does not average out to moderate drinking. Having multiple drinks in the same sitting will result in higher blood alcohol levels than from a single drink, which can trigger a different type of alcohol metabolism leading to DNA damage. Notably, a recent epidemiologic study from Harvard found that women who reported binge-type drinking had higher breast cancer risk than those who did not. More studies of this type would be valuable, since binge drinking by young women is on the rise.”
The most important point, says Dr. Brooks, is that we need to consider both time course and drinking pattern in relating alcohol drinking to breast cancer risk.
“In view of our lack of understanding of how and when alcohol consumption impacts breast cancer risk, and the documented health benefits of moderate alcohol consumption, it is not clear that stopping drinking would benefit the overall health of postmenopausal women who are moderate drinkers,’’ Dr. Brooks says. ``In contrast, based on our understanding of alcohol metabolism, as well as recent epidemiologic data, binge drinking by younger women could increase the risk of breast cancer later in life. Binge drinking is unhealthy for anyone, and the possibility of increasing breast cancer risk is another reason for women in particular to avoid binge drinking.”
The American Journal of Drug and Alcohol Abuse recently published a special edition devoted to NIH-funded research in American Indian/Alaska Native (AI/AN) communities. The driving force behind this collection of 24 articles was a 2010 conference that brought together experts and stakeholders from across academic institutions, native communities and government to discuss research findings and research opportunities in AI/AN substance abuse research. The conference was hosted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA), in collaboration with the NIH Office of Behavioral and Social Sciences Research and the National Cancer Institute.
For a commentary by NIAAA director Dr. Kenneth R. Warren and NIDA director Dr. Nora D. Volkow, go to http://informahealthcare.com/doi/full/10.3109/00952990.2012.712174. For current science and future directions in substance abuse research in AI/AN communities, go to http://informahealthcare.com/doi/full/10.3109/00952990.2012.712173. The special edition can be found in its entirety at http://informahealthcare.com/toc/ada/38/5.
For more information, contact the NIAAA press office at NIAAAPressOffice@mail.nih.gov or 301-443-2857.
Research suggests that chronic alcohol use may increase the risk for post-traumatic stress disorder (PTSD) by altering the brain’s ability to recover from a traumatic experience. While alcoholism is often linked with PTSD, few studies have explored how chronic drinking may subsequently make a person more prone to such anxiety disorders. In a new study, researchers at the NIAAA observed that chronic alcohol exposure altered neurons in the medial prefrontal cortex (mPFC) of mice, making them slower to suppress a conditioned fear response.
“Excessive drinking has been shown to increase the likelihood that someone will experience a traumatic event, including car accidents and episodes of domestic violence. The findings from this study suggest that chronic alcohol use may also increase a person’s risk for an anxiety disorder such as PTSD after experiencing such an incident,” said lead author Andrew Holmes, Ph.D., of the NIAAA Laboratory of Behavioral and Genomic Neuroscience.
To study the potential relationship between alcoholism and PTSD, researchers examined how quickly mice learned to inhibit a fear response after a traumatic event, also known as “fear extinction.” Mice used in the study were given several rounds of vaporized alcohol to mimic a pattern of heavy use typical of alcoholism. Two days later, they were conditioned to associate a specific tone with a shock to the foot. Researchers studied how quickly the mice stopped displaying fear (indicated by freezing) when the tone was played without a resulting shock.
Mice that had undergone chronic alcohol exposure took longer to lose their fear of the tone, freezing more frequently than other mice after the second round of extinction testing. They also had poorer retention, freezing more often when the testing was done again after time had elapsed. Examining the brains of the alcohol-exposed mice revealed changes to neurons in the medial prefrontal cortex, with certain neurons displaying longer dendrites (the branching projections that carry neural signals to the cell body). Testing in live mice showed that neural functioning related to fear extinction was also affected.
These results indicate that chronic drinking may impair fear extinction and alter neural circuits that mediate recovery from trauma, increasing the risk for PTSD. The findings were published online on Sept. 2, 2012 by the journal Nature Neuroscience.
Chronic drinking rewires brain circuits that are involved in recovery from traumatic events. Researchers observed changes to neurons in the medial prefrontal cortex of the brain, suggesting that alcoholism could increase the risk for post-traumatic stress disorder and related conditions.
Brain activity patterns may provide clues about a young person’s risk for initiating harmful alcohol use, according to new research supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
NIAAA-funded scientists led by Susan Tapert, Ph.D., and Lindsay Squeglia, Ph.D., of the University of California, San Diego, School of Medicine, and VA San Diego Healthcare, used magnetic resonance imaging (MRI) scans to measure brain activity patterns among 12- to 16-year-old non-drinkers who performed a memory task while being scanned. The researchers repeated the MRI scans three years later, after some of the study subjects had begun to drink heavily.
As reported online in the Journal of Studies on Alcohol and Drugs on August 8, the researchers found that the initial MRI scans of teens who became heavy drinkers had shown less activity in brain regions involved in performing the memory task. They suggest that the decreased brain activity indicates a possible pre-existing vulnerability to harmful drinking—a signal that youth with less activity were more likely to become heavy drinkers.
Three years later, the heavy-drinking teens showed more activity in the same brain regions compared to teens who remained nondrinkers, an indication that the brains of the heavy drinking teens were processing information less efficiently than the nondrinkers’ brains. Researchers explained that, as brains get older, and more efficient, they normally require less effort to accomplish a task, the opposite of what was seen in the heavy drinkers.
“These preliminary findings suggest that we may be able to find neural markers that signal a teen’s risk for heavy drinking even before they start drinking,” notes Ellen Witt, Ph.D., deputy director of the NIAAA division of neuroscience and behavior. “This study points to the need for larger, long-term studies to differentiate the effects of pre-existing neural factors from alcohol’s specific effects on cognition and brain function during adolescence.”