Posts tagged alcoholism
Articles and news from the latest research reports.
Alcoholism Could Be Linked to a Hyper-Active Brain Dopamine System
Those vulnerable to alcoholism may experience an unusually large response in the brain’s reward-seeking pathway when they take a drink
Research from McGill University suggests that people who are vulnerable to developing alcoholism exhibit a distinctive brain response when drinking alcohol, according to a new study by Prof. Marco Leyton, of McGill University’s Department of Psychiatry. Compared to people at low risk for alcohol-use problems, those at high risk showed a greater dopamine response in a brain pathway that increases desire for rewards. These findings, published in the journal Alcoholism: Clinical & Experimental Research, could help shed light on why some people are more at risk of suffering from alcoholism and could mark an important step toward the development of treatment options.
“There is accumulating evidence that there are multiple pathways to alcoholism, each associated with a distinct set of personality traits and neurobiological features”, said Prof. Leyton, a researcher in the Mental Illness and Addiction axis at the Research Institute of the McGill University Health Centre (RI-MUHC). “These individual differences likely influence a wide range of behaviors, both positive and problematic. Our study suggests that a tendency to experience a large dopamine response when drinking alcohol might contribute to one (or more) of these pathways.”
For the study, researchers recruited 26 healthy social drinkers (18 men, 8 women), 18 to 30 years of age, from the Montreal area. The higher-risk subjects were then identified based on personality traits and having a lower intoxication response to alcohol (they did not feel as drunk despite having drunk the same amount). Finally, each participant underwent two positron emission tomography (PET) brain scan exams after drinking either juice or alcohol (about 3 drinks in 15 minutes).
“We found that people vulnerable to developing alcoholism experienced an unusually large brain dopamine response when they took a drink,” said Leyton. “This large response might energize reward-seeking behaviors and counteract the sedative effects of alcohol. Conversely, people who experience minimal dopamine release when they drink might find the sedative effects of alcohol especially pronounced.”
“Although preliminary, the results are compelling,” said Dr. Leyton. “A much larger body of research has identified a role for dopamine in reward-seeking behaviors in general. For example, in both laboratory animals and people, increased dopamine transmission seems to enhance the attractiveness of reward-related stimuli. This effect likely contributes to why having one drink increases the probability of getting a second one – the alcohol-induced dopamine response makes the second drink look all the more desirable. If some people are experiencing unusually large dopamine responses to alcohol, this might put them at risk.”
“People with loved ones struggling with alcoholism often want to know two things: How did they develop this problem? And what can be done to help? Our study helps us answer the first question by furthering our understanding of the causes of addictions. This is an important step toward developing treatments and preventing the disorder in others.”
(Source: newswise.com)
Scientists Identify Key Brain Circuits that Control Compulsive Drinking in Rats
Gallo Center Research Could Have Direct Application For Treating Human Drinking Problems
A research team led by scientists from the Ernest Gallo Clinic and Research Center at UC San Francisco has identified circuitry in the brain that drives compulsive drinking in rats, and likely plays a similar role in humans.
The scientists found they could reduce compulsive drinking in rats by inhibiting key neural pathways that run between the prefrontal cortex, which is involved with higher functions such as critical thinking and risk assessment, and the nucleus accumbens, a critical area for reward and motivation.
The authors noted that there are already several FDA-approved medications that target activity in these pathways, thus potentially opening an accelerated track to new treatments for compulsive drinking.
The study describing their finding was published online on June 30 in Nature Neuroscience.
The study was conducted on rats that regularly drank 20 percent alcohol. The rats drank both unmixed alcohol and alcohol mixed with extremely bitter quinine, said senior investigator F. Woodward Hopf, PhD, an assistant adjunct professor of neurology at UCSF.
Hopf explained that this alcohol-quinine solution, which he described as “like a vodka tonic without the sugar,” is often used as a rodent model of compulsive drinking, or “drinking in the face of negative consequences.” In rats, he said, the negative consequence is the bitter taste, while in humans who drink compulsively, “the negative consequences are profound: people continue to drink despite the potential loss of jobs, marriages, freedom, even their lives.”
In the United States, alcoholism is estimated to cost $224 billion per year – almost $2 per drink – mostly from lost productivity and crime, and leads to 100,000 preventable deaths per year.
The drinking rats showed a notable increase in the NMDA receptor (NMDAR), which lead author Taban Seif, PhD, a Gallo Center researcher, called “a molecule that excites the brain.” When the rats were injected with an NMDAR blocker, their consumption of quinine-laced alcohol dropped significantly, while regular alcohol use was unaffected. “In other words, only the compulsive drinking was affected,” said Seif.
Focus on Two Regions of the Prefrontal Cortex
The team then focused its research on connections from two specific regions of the rats’ prefrontal cortex where they had discovered the presence of unusual types of NMDARs: the medial prefrontal cortex, which mediates conflict during decision-making, and the insula, which is critical for self-awareness and feelings.
“In a non-addict, these brain areas tell you when something is potentially harmful and bad, and to run away as fast as possible,” said Hopf. “But if you’re a compulsive drinker, it seems instead that they give you a comforting pat on the back, in effect telling you it’s OK to have another drink, nothing to worry about.”
Using a technique called optogenetics, the scientists inserted halorhodopsin, a light-sensitive protein, into these areas. They then used fiber-optic cables implanted in the rats’ brains to send pulses of laser light that activated the halorhodopsin, which in turn inhibited the regions’ connections to the nucleus accumbens. The researchers found that rats inhibited in this way drank significantly less quinine-laced alcohol, while their intake of regular alcohol solution remained unaffected.
“The fact that we reduced the rats’ compulsive drinking using two different methods – an NMDAR blocker and direct inhibition of connections – tells us that we have probably identified the right areas,” said Hopf.
Potential Treatments for Humans
The next logical step for the research team, said Hopf, would be to work with clinical researchers on an NMDAR blocker trial in human subjects.
“What is interesting is that we have a new drug which could perhaps treat compulsive aspects of drinking,” said Hopf, “but only if you are in conflict about your drinking – if you care. Any therapy with NMDAR blockers would need a strong behavioral and cognitive component to make sure the patient stayed mentally engaged.”
Seif and Hopf also plan further experimental studies focusing on how the insula drives behavior and connects to other areas of the brain.
The brain’s response to sweets may indicate risk for development of alcoholism
Several human and animal studies have shown a relationship between a preference for highly sweet tastes and alcohol use disorders. Furthermore, the brain mechanisms of sweet-taste responses may share common neural pathways with responses to alcohol and other drugs. A new study using functional magnetic resonance imaging (fMRI) has found that recent drinking is related to the orbitofrontal-region brain response to an intensely sweet stimulus, a brain response that may serve as an important phenotype, or observable characteristic, of alcoholism risk.
Results will be published in the December 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"It has long-been known that animals bred to prefer alcohol also drink considerably greater quantities of sweetened water than do animals without this selective breeding for alcohol preference," explained David A. Kareken, deputy director of the Indiana Alcohol Research Center, a professor in the department of neurology at Indiana University School of Medicine, and corresponding author for the study. "More recently, it has become clear that animals bred to prefer the artificial sweetener, saccharin, also drink more alcohol. Although the data in humans are somewhat more variable, some studies do show that alcoholics, or even non-alcoholics with a family history of alcoholism, have a preference for unusually sweet tastes. Thus, while the precise reasons remain unclear, there does seem to be significant evidence suggesting some link between the rewarding properties of both sweet tastes and alcohol."
Kareken added that this is the first study to examine the extent to which regions of the brain’s reward system, as they respond to an intensely sweet taste, are related to human drinking patterns.
Kareken and his colleagues recruited 16 (12 males, 4 females) right-handed, non-treatment seeking, healthy volunteers with a mean age of 26 years from the community. All participants underwent a taste test using a range of sucrose concentrations, and their blood oxygen dependent (BOLD) activation was measured during an fMRI scan while receiving small squirts of either water or an intensely sweet mixture of sugar in water. All were asked about their drinking patterns.
"Our study was designed to determine which brain areas responded to sweet taste – as compared to plain water – and the extent to which these brain responses were related to subjects’ binge-drinking patterns, the number of alcoholic drinks subjects consumed per day when drinking," explained Kareken.
"In addition to ‘activating’ the brain’s gustatory or taste circuits, the sugared water also activated key elements of what neuroscientists consider to be part of the brain’s reward system, including the ventral striatum, amygdala, and parts of the orbitofrontal cortex – the inferior frontal lobe surface just above the eyes – that respond to ingested rewards," Kareken said. "We refer to these as ‘primary’ rewards, being distinct from secondary rewards, like money, which can be used to obtain primary rewards."
What the researchers found was that the response to this intensely sweet taste in the left orbitofrontal area correlated significantly with subjects’ drinking patterns.
"Specifically, the trend was such that those who drank more alcohol on drinking days had stronger left orbitofrontal responses to the intensely sweet water," said Kareken. "Subjects’ subjectively rated liking of the sweetened water also contributed to this relationship, so that both the brain response itself, as well as liking of the sugared water, collectively correlated with drinking behavior."
While previous human and animal research has noted this association between preferences for both sweet tastes and alcohol intoxication, Kareken believes that this is the first study to examine the human brain mechanism behind this association.
"While much more research needs to be done to truly understand the commonalities between sweet-liking and alcoholism, and while alcoholism itself is likely the product of several mechanisms, our findings may implicate a particular brain region that is more generally involved in coding for the value of ‘primary’ rewards such as pleasures," he said. "In a more practical sense, the findings are compelling evidence that the brain response to an intensely sweet taste may be used in future research to test for differences in the reward circuits of those at risk for alcoholism. This may be particularly useful since alcohol itself is not an easy drug to work with in this kind of human imaging, and since alcohol exposure is not ethically appropriate for use in all at-risk subjects, or in subjects trying to abstain from drinking."
(Source: eurekalert.org)
Study identifies brain circuits involved in learning and decision making
Finding has implications for alcoholism and other patterns of addictive behavior
Research from the National Institutes of Health has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help to explain the brain processes that govern choice and the ability to adapt behavior based on the end results.
Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions.
“Much remains to be understood about exactly how the brain strikes the balance between learning a behavioral response that is consistently rewarded, versus retaining the flexibility to switch to a new, better response,” said Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism. “These findings give new insight into the process and how it can go awry.”
The study, published online in Nature Neuroscience, indicates that specific circuits in the forebrain play a critical role in choice and adaptive learning.
Like other addictions, alcoholism is a disease in which voluntary control of behavior progressively diminishes and unwanted actions eventually become compulsive. It is thought that the normal brain processes involved in completing everyday activities become redirected toward finding and abusing alcohol.
The research, conducted by investigators from NIAAA, with support from the National Institute of Mental Health and the University of Cambridge, England, used a variety of approaches to study choice.
Researchers used a simple choice task in which mice viewed images on a computer touchscreen and learned to touch a specific image with their nose to get a food reward. Using various techniques to visualize and record neural activity, researchers found that as the mice learned to consistently make a choice, the brain’s dorsal striatum was activated. The dorsal striatum is thought to play an important role in motivation, decision-making, and reward.
Conversely, when the mice later had to shift to a new choice to receive a reward, the dorsal striatum quieted while regions in the prefrontal cortex, an area involved in decision-making and complex cognitive processes, became active.
Building upon these findings, the authors next deleted or pharmacologically blocked a component of nerve cells which normally binds the neurochemical glutamate (specifically, the GluN2B subunit of the NMDA receptor) within two different areas of the brain, the striatum and the frontal cortex. Previous studies have shown that GluN2B plays a role in memory, spatial reference, and attention. Researchers found that making dorsal striatal GluN2B inactive markedly slowed learning, while shutting down GluN2B in the prefrontal cortex made the mice less able to relearn the touchscreen reward task after the reward image was changed.
“These data add to what we understand about the neural control of behavioral flexibility and striatal learning by identifying GluN2B as a critical molecular substrate to both processes,” said the study’s senior author, Andrew Holmes, Ph.D., Laboratory Chief and Principal Investigator of the NIAAA Laboratory of Behavioral and Genomic Neuroscience.
“This is particularly intriguing for future studies because NMDA receptors are a major target for alcohol and contribute to important features of alcoholism, such as withdrawal. These new findings suggest that GluN2B in corticostriatal circuits may also play a key role in driving the transition from controlled drinking to compulsive abuse that characterizes alcoholism.”
(Source: niaaa.nih.gov)
It’s About Time: Disrupted Internal Clocks Play Role in Disease
Study uncovers circadian disruption as risk factor in alcoholic liver disease
Thirty percent of severe alcoholics develop liver disease, but scientists have not been able to explain why only a subset is at risk. A research team from Northwestern University and Rush University Medical Center now has a possible explanation: disrupted sleep and circadian rhythms can push those vulnerable over the edge to disease.
The team studied mice that essentially were experiencing what shift workers or people with jet lag suffer: their internal clocks were out of sync with the natural light-dark cycle. Another group of mice had circadian disruption due to a faulty gene. Both groups were fed a diet without alcohol and next with alcohol, and the team then examined the physiological effects.
The researchers found the combination of circadian rhythm disruption and alcohol is a destructive double hit that can lead to alcoholic liver disease.
The study was published last month by the journal PLOS ONE.
“Circadian disruption appears to be a previously unrecognized risk factor underlying the susceptibility to or development of alcoholic liver disease,” said Fred W. Turek, the Charles E. and Emma H. Morrison Professor of Biology at Northwestern’s Weinberg College of Arts and Sciences and one of the senior authors of the paper.
“What we and many other investigators are doing is bringing time to medicine for the diagnosis and treatment of disease,” Turek said. “We call it circadian medicine, and it will be transformative. Medicine will change a great deal, similar to the way physics changed when Einstein brought time to physics.”
A number of years ago, Ali Keshavarzian, M.D., a gastroenterologist at Rush University Medical Center who has worked with and studied patients with gastrointestinal and liver diseases, had a hunch disrupted circadian rhythms could be a contributing factor to the disease.
Keshavarzian had noticed that some patients with inflammatory bowel disease (inflammation in the intestine and/or colon) had flare-ups of symptoms when working nights, but they could control the disease when working the day shift. He sought out Turek, director of Northwestern’s Center for Sleep and Circadian Biology, to help investigate the relationship between circadian rhythms and the disease.
The two investigators and their groups first studied the effect of circadian rhythm disruption in an animal model of colitis and noted that disruption of sleep and circadian rhythms (caused by modeling shift work and chronic jet lag in the animals) caused more severe colitis in mice.
Keshavarzian has been studying the effect of “gut leakiness” (the intestinal lining becomes weak and causes dangerous endotoxins to get into the blood stream) to bacterial products in gastrointestinal diseases for two decades. Because the mouse model of colitis is associated with leaky gut, he proposed that disruption of circadian rhythms from shift work could make the intestine more susceptible to leakiness. He wanted to test its effect in an animal model of alcoholic liver disease — where a subset of alcoholics develop gut leakiness and liver disease — in order to find out whether shift work is the susceptibility factor that promotes liver injury.
“Non-pathogen-mediated chronic inflammation is a major cause of many chronic diseases common in Western societies and developing countries that have adopted a Western lifestyle,” said Keshavarzian, one of the senior authors of the paper. He is director of the Division of Digestive Diseases and the Josephine M. Dyrenforth Chair of Gastroenterology.
Crohn’s and ulcerative colitis, Parkinson’s disease, diabetes, multiple sclerosis, autoimmune disease and cardiovascular disease are examples of these diseases, to name just a few.
“Recent studies have shown that intestinal bacteria are the primary trigger for this inflammation, and gut leakiness is one of the major causes,” Keshavarzian said. “The factor leading to gut leakiness is not known, however. Our study suggests that disruption of circadian rhythms and sleep, which is part of life in industrial societies, can promote it and explain the susceptibility.”
In the study, the Northwestern and Rush researchers used two independent approaches, studying both genetic and environmental animal models. The circadian rhythms of one group of mice were disrupted genetically: Each animal had a mutant CLOCK gene, which regulates circadian rhythms. The second group’s circadian rhythms were disrupted environmentally: The animals’ light-dark cycle was changed periodically, leading to a state similar to chronic jet lag.
Mice in both groups, prior to ingesting alcohol, showed an increase in gut leakiness.
Next, both groups of mice were fed alcohol. After only one week, animals in both groups showed a significant additional increase in gut leakiness, compared to control mice on an alcohol-free diet. At the end of the three-month study, mice in both groups were in the early stages of alcoholic liver disease.
“We have clearly shown that circadian rhythm disruption can trigger gut leakiness, which drives the more severe pathology in the liver,” said Keith Summa, a co-first author of the study and an M.D./Ph.D. candidate working in Turek’s lab.
“For humans, circadian rhythm disruption typically is environmental, not genetic, so individuals have some control over the behaviors that cause trouble, be it a poor sleep schedule, shift work or exposure to light at night,” he said.
Sleep and circadian rhythms are an integral part of biology and should be part of the discussion between medical doctors and their patients, the researchers believe.
“We want to personalize medicine from a time perspective,” Turek said. “Our bodies are organized temporally on a 24-hour basis, and this needs to be brought into the equation for understanding health and disease.”
Alcoholic fly larvae need fix for learning
Fly larvae fed on alcohol-spiked food for a period of days grow dependent on those spirits for learning. The findings, reported in Current Biology, a Cell Press publication, on November 29th, show how overuse of alcohol can produce lasting changes in the brain, even after alcohol abuse stops.
The report also provides evidence that the very human experience of alcoholism can be explored in part with studies conducted in fruit flies and other animals, the researchers say.
"Our evidence supports the long-ago proposed idea that functional ethanol tolerance is produced by adaptations that counter the effects of ethanol, and that these adaptations help the nervous system function more normally when ethanol is present," says Brooks Robinson of The University of Texas at Austin. "However, when ethanol is withheld, the adaptations persist to give the nervous system abnormal properties that manifest themselves as symptoms of withdrawal."
Robinson and his colleagues found that alcohol consumption, at a level equivalent to mild intoxication in humans, at first impeded learning by fly larvae. More specifically, those larvae had some trouble in associating an unpleasant heat pulse with an otherwise attractive odor in comparison to larvae that had not been drinking alcohol.
After a six-day drinking binge, however, those larvae adapted and could learn as well as normal larvae could. In fact, the alcohol-adapted animals learned poorly when their ethanol was taken away from them. And, when given alcohol back, their learning deficit was erased.
Robinson says that the findings are the first proof of cognitive ethanol dependence in an invertebrate, suggesting that some of ethanol’s ability to change behavior must begin at the cellular level. After all, flies and humans share many of the same features at the level of individual neurons, and not so much in terms of the way those neurons are put together into working circuits.
Doctors have long recognized a link between alcoholism and anxiety disorders such as post-traumatic stress disorder (PTSD). Those who drink heavily are at increased risk for traumatic events like car accidents and domestic violence, but that only partially explains the connection. New research using mice reveals heavy alcohol use actually rewires brain circuitry, making it harder for alcoholics to recover psychologically following a traumatic experience.
“There’s a whole spectrum to how people react to a traumatic event,” said study author Thomas Kash, PhD, assistant professor of pharmacology at the University of North Carolina School of Medicine. “It’s the recovery that we’re looking at — the ability to say ‘this is not dangerous anymore.’ Basically, our research shows that chronic exposure to alcohol can cause a deficit with regard to how our cognitive brain centers control our emotional brain centers.”
The study, which was published online on Sept. 2, 2012 by the journal Nature Neuroscience, was conducted by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and UNC’s Bowles Center for Alcohol Studies.
Behavioral test shows promise in predicting future problems with alcohol
By administering a simple behavioral test, Yale researchers were able to predict which mice would later exhibit alcoholism-related behaviors such as the inability to stop seeking alcohol and a tendency to relapse, the scientists report in the Aug. 26 issue of the journal Nature Neuroscience.
"We are trying to understand the neurobiology underlying familial risk for alcoholism," said Jane Taylor, the Charles B.G. Murphy Professor of Psychiatry and professor of psychology at the Yale School of Medicine and senior author of the study. "What is encouraging about this study is that we have identified both a behavioral indicator and a molecule that explains that risk."