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.
“We know that CB1 in this brain region is involved in habit learning, but we have very little idea about how CB1 acts to sculpt this neural circuitry to ultimately result in the expression of habits,” said first author Brian Mathur, Ph.D.He explained that direct and indirect pathways originating in the striatum are composed of medium-sized spiny neurons (MSNs) have opposing effects on movement.The relative activation of the direct pathway over the indirect pathway, known as a“go signal,” is believed to encode for reinforcement of an action. A Change in a neural pathway associated with learning a behavior is called neuroplasticity.
The researchers examined the role of CB1 in a form of neuroplasticity known as long-term depression of synaptic transmission (LTD). LTD refers to the long-lasting decrease in the strength of signal transmission at a synapse, where signals pass from one neuron to another. A synapse that has undergone LTD is less able to influence the activity of the postsynaptic neuron.“We hypothesized that because CB1 is necessary for this long lasting form of the cellular substrate for learning and memory known as LTD, that this neuroplasticity allows for ‘go signal’ generation,” continued Mathur.
Using a novel combination of brain slice electrophysiology and optogenetics, a technique allowing for the activation of specific neural circuits with light, the investigators were able to determine the specific contribution of different inputs onto direct and indirect pathway MSNs to LTD. They found that MSNs express two forms of CB1-dependent LTD depending upon whether the MSN membrane voltage is in an excited “up state” or a more refractory “down state” These two different forms of LTD are each mediated by a separate signaling molecule capable of activating CB1: 2-AG and anandamide. The down state, anandamide-mediated form of LTD occurred only at inhibitory synapses onto direct pathway MSNs, offering a mechanism for go signal generation.
“This is a big step forward in understanding the possible molecular and circuit dynamics underlying habit formation,” said Mathur. The research team hopes their research will help uncover novel therapeutic strategies for the treatment of alcohol use disorders. A report of the study was published online in Nature Neuroscience on July 28, 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. Previous research has found that the mammalian target of rapamycin complex 1 (mTORC1), a group of proteins found in cells throughout the body, is involved in memory processes in the brain, and also plays an important role in alcohol-seeking behavior. In a study published online in Nature Neuroscience, researchers from the University of California San Francisco examined whether inhibiting mTORC1 could disrupt memories of alcohol cues—and thus diminish alcohol relapses in rats that had been trained to binge drink. After a period of alcohol abstinence, researchers exposed the rats to a small amount of alcohol to provide an odor and taste cue to the animals. The researchers then administered a dose of rapamycin, an mTORC1 inhibitor. Compared with a control group that did not receive rapamycin, rats that received the rapamycin sought and consumed less alcohol for the duration of the experiment. Researchers found that by disrupting memories of alcohol cues, rats were less likely to relapse to drinking than those whose memories were intact.
The researchers note memory disruption has shown success in humans who are addicted to heroin and suggest that it may prove helpful in developing new relapse-prevention strategies in alcoholics as well.
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.
“This important work could help pediatricians and clinicians make earlier identification of children at high risk for cognitive deficits due to prenatal alcohol exposure, especially those heavily exposed individuals who lack the classic facial characteristics of fetal alcohol syndrome (FAS),” said NIAAA acting director Kenneth R. Warren, Ph.D.
Prenatal alcohol exposure causes a continuum of effects. FAS is the most serious consequence of heavy drinking during pregnancy and involves a specific pattern of facial abnormalities, including small eye width, smoothing of the ridges between the base of the nose and the upper lip, and a thin upper lip border, as well as growth deficits, and neurocognitive problems.
Collaborating with other CIFASD investigators and additional researchers in South Africa, lead investigator Peter Hammond, Ph.D., of the University College London identified novel strategies for detecting facial effects of prenatal alcohol exposure among a sample of children from a community clinic in Cape Town, South Africa, where the incidence of heavy alcohol use during pregnancy and FAS are among the highest in the world.
Using three-dimensional photography and computerized image analysis techniques, the researchers examined facial characteristics of children either not exposed or heavily exposed to alcohol and compared their observations with clinically-determined FASD categorizations. They found that 3-D facial image analyses substantially enhanced the ability to detect a broad range of alcohol-induced facial changes in children. Importantly, their computer-based approach should help identify affected children who have cognitive impairments but lack facial features necessary for a FAS diagnosis. They note that more substantial testing of these techniques is planned in South Africa, the United States, and the Ukraine. For more information on the CIFASD consortium, visit http://www.cifasd.org.
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.”