Researchers Identify Key Factor in Transition from Moderate to Problem Drinking

A team of UC San Francisco researchers has found that a tiny segment of genetic material known as a microRNA plays a central role in the transition from moderate drinking to binge drinking and other alcohol use disorders.

Previous research in the UCSF laboratory of Dorit Ron, PhD, Endowed Chair of Cell Biology of Addiction in Neurology, has demonstrated that the level of a protein known as brain-derived neurotrophic factor, or BDNF, is increased in the brain when alcohol consumed in moderation. In turn, experiments in Ron’s lab have shown, BDNF prevents the development of alcohol use disorders.

In the new study, Ron and first author Emmanuel Darcq, PhD, a former postdoctoral fellow now at McGill University in Canada, found that when mice consumed excessive amounts of alcohol for a prolonged period, there was a marked decrease in the amount of BDNF in the medial prefrontal cortex (mPFC), a brain region important for decision making. As reported in the October 21, 2014 online edition of Molecular Psychiatry, this decline was associated with a corresponding increase in the level of a microRNA called miR-30a-5p.

MicroRNAs lower the levels of proteins such as BDNF by binding to messenger RNA, the molecular middleman that carries instructions from genes to the protein-making machinery of the cell, and tagging it for destruction.

Ron and colleagues then showed that if they increased the levels of miR-30a-5p in the mPFC, BDNF was reduced, and the mice consumed large amounts of alcohol. When mice were treated with an inhibitor of miR-30a-5p, however, the level of BDNF in the mPFC was restored to normal and alcohol consumption was restored to normal, moderate levels.

“Our results suggest BDNF protects against the transition from moderate to uncontrolled drinking and alcohol use disorders,” said Ron, senior author of the study and a professor in UCSF’s Department of Neurology. “When there is a breakdown in this protective pathway, however, uncontrolled excessive drinking develops, and microRNAs are a possible mechanism in this breakdown. This mechanism may be one possible explanation as to why 10 percent of the population develop alcohol use disorders and this study may be helpful for the development of future medications to treat this devastating disease.”

One reason many potential therapies for alcohol abuse have been unsuccessful is because they inhibit the brain’s reward pathways, causing an overall decline in the experience of pleasure. But in the new study, these pathways continued to function in mice in which the actions of miR-30a-5p had been tamped down—the mice retained the preference for a sweetened solution over plain water that is seen in normal mice.

This result has significant implications for future treatments, Ron said. “In searching for potential therapies for alcohol abuse, it is important that we look for future medications that target drinking without affecting the reward system in general. One problem with current alcohol abuse medications is that patients tend to stop taking them because they interfere with the sense of pleasure.”

Mutation stops worms from getting drunk

Neuroscientists at The University of Texas at Austin have generated mutant worms that do not get intoxicated by alcohol, a result that could lead to new drugs to treat the symptoms of people going through alcohol withdrawal.

The scientists accomplished this feat by inserting a modified human alcohol target into the worms, as reported this week in The Journal of Neuroscience.

"This is the first example of altering a human alcohol target to prevent intoxication in an animal," says corresponding author, Jon Pierce-Shimomura, assistant professor in the university’s College of Natural Sciences and Waggoner Center for Alcohol and Addiction Research.

An alcohol target is any neuronal molecule that binds alcohol, of which there are many.

One important aspect of this modified alcohol target, a neuronal channel called the BK channel, is that the mutation only affects its response to alcohol. The BK channel typically regulates many important functions including activity of neurons, blood vessels, the respiratory tract and bladder. The alcohol-insensitive mutation does not disrupt these functions at all.

"We got pretty lucky and found a way to make the channel insensitive to alcohol without affecting its normal function," says Pierce-Shimomura.

The scientists believe the research has potential application for treating people addicted to alcohol.

"Our findings provide exciting evidence that future pharmaceuticals might aim at this portion of the alcohol target to prevent problems in alcohol abuse disorders," says Pierce-Shimomura. "However, it remains to be seen which aspects of these disorders would benefit."

Unlike drugs such as cocaine, which have a specific target in the nervous system, the effects of alcohol on the body are complex and have many targets across the brain. The various other aspects of alcohol addiction, such as tolerance, craving and the symptoms of withdrawal, may be influenced by different alcohol targets.

The worms used in the study, Caenorhabditis elegans, model intoxication well. Alcohol causes the worms to slow their crawling with less wriggling from side to side. The intoxicated worms also stop laying eggs, which build up in their bodies and can be easily counted.

Unfortunately, C. elegans are not as ideal for studying the other areas of alcohol addiction, but mice make an excellent model. The modified human BK channel used in the study, which is based on a mutation discovered by lead author and graduate student Scott Davis, could be inserted into mice. These modified mice would allow scientists to investigate whether this particular alcohol target also affects tolerance, craving and other symptoms relevant to humans.

Pierce-Shimomura speculated that their research could even be used to develop a ‘James Bond’ drug someday, which would enable a spy to drink his opponent under the table, without getting drunk himself. Such a drug could potentially be used to treat alcoholics, since it would counteract the intoxicating and potentially addicting effects of the alcohol.

A New Target for Alcoholism Treatment: Kappa Opioid Receptors

The list of brain receptor targets for opiates reads like a fraternity: Mu Delta Kappa. The mu opioid receptor is the primary target for morphine and endogenous opioids like endorphin, whereas the delta opioid receptor shows the highest affinity for endogenous enkephalins. The kappa opioid receptor (KOR) is very interesting, but the least understood of the opiate receptor family.

Until now, the mu opioid receptor received the most attention in alcoholism research. Naltrexone, a drug approved by the U.S. Food and Drug Administration for the treatment of alcoholism, acts by blocking opiate action at brain receptors and is most potent at the mu opioid receptor. In addition, research has suggested that a variant of the gene that codes for the mu opioid receptor (OPRM1) may be associated with the risk for alcoholism and the response to naltrexone treatment.

However, naltrexone also acts at the kappa opioid receptor and it has not been clear whether this effect of naltrexone is relevant to alcoholism treatment.

A growing body of research in animals implicates the KOR in alcoholism. Stimulation of the KOR, which occurs with alcohol intake, is thought to produce unpleasant and aversive effects. This receptor is hypothesized to play a role in alcohol dependence, at least in part, by promoting negative reinforcement processes. In other words, the theory postulates that during development of alcohol dependence, the KOR system becomes overstimulated, producing dysphoria and anhedonia, which then leads to further alcohol seeking and escalation of alcohol intake that serves to self-medicate those negative symptoms.

A new study in Biological Psychiatry, led by Dr. Brendan Walker at Washington State University, used a rat model of alcohol dependence to directly investigate the KOR system following chronic alcohol exposure and withdrawal.

They found that the KOR system is dysregulated in the amygdala of alcohol-dependent rats, a vital brain region with many functions, including regulation of emotional behavior and decision-making. Chronic alcohol consumption is known to cause neuroadaptations in the amygdala. In this study specifically, they found increased dynorphin A and increased KOR signaling in the amygdala of alcohol-dependent rats.

When the rats were in acute alcohol withdrawal, the researchers administered different drugs, each of which target the KOR system in precise ways, directly into the amygdala. Using this site-specific antagonism, they observed that alcohol dependence-related KOR dysregulation directly contributes to the excessive alcohol consumption that occurs during withdrawal.

“These data provide important new support for the hypothesis that kappa opioid receptor blockers might play a role in the treatment of alcoholism,” said Dr. John Krystal, Editor of Biological Psychiatry. “This study suggests that one role might be to prevent a relapse to alcohol use among patients recently withdrawn from alcohol.”

“This dataset demonstrates the extensive nature of the neuroadaptations the brain undergoes when chronically exposed to alcohol. The implications of these results are far reaching and should help guide pharmacotherapeutic development efforts for the treatment of alcohol use disorders,” said Walker. “Pharmacological compounds that alleviate the negative emotional / mood states that accompany alcohol withdrawal, by attenuating the excessive signaling in the dynorphin / kappa-opioid receptor system, should result in enhanced treatment compliance and facilitate the transition away from alcohol dependence.”

Additional extensive research will be necessary to identify and test the effectiveness of specific drugs that act on the KOR system, but these findings provide researchers with a potentially successful path forward to developing new drugs for the treatment of alcoholism.

Researchers identify decision-making center of brain

Although choosing to do something because the perceived benefit outweighs the financial cost is something people do daily, little is known about what happens in the brain when a person makes these kinds of decisions. Studying how these cost-benefit decisions are made when choosing to consume alcohol, University of Georgia associate professor of psychology James MacKillop identified distinct profiles of brain activity that are present when making these decisions.

"We were interested in understanding how the brain makes decisions about drinking alcohol. Particularly, we wanted to clarify how the brain weighs the pros and cons of drinking," said MacKillop, who directs the Experimental and Clinical Psychopharmacology Laboratory in the UGA Franklin College of Arts and Sciences.

The study combined functional magnetic resonance imaging and a bar laboratory alcohol procedure to see how the cost of alcohol affected people’s preferences. The study group included 24 men, age 21-31, who were heavy drinkers. Participants were given a $15 bar tab and then were asked to make decisions in the fMRI scanner about how many drinks they would choose at varying prices, from very low to very high. Their choices translated into real drinks, at most eight that they received in the bar immediately after the scan. Any money not spent on drinks was theirs to keep.

The study applied a neuroeconomic approach, which integrates concepts and methods from psychology, economics and cognitive neuroscience to understand how the brain makes decisions. In this study, participants’ cost-benefit decisions were categorized into those in which drinking was perceived to have all benefit and no cost, to have both benefits and costs, and to have all costs and no benefits. In doing so, MacKillop could dissect the neural mechanisms responsible for different types of cost-benefit decision-making.

"We tried to span several levels of analysis, to think about clinical questions, like why do people choose to drink or not drink alcohol, and then unpack those choices into the underlying units of the brain that are involved," he said.

When participants decided to drink in general, activation was seen in several areas of the cerebral cortex, such as the prefrontal and parietal cortices. However, when the decision to drink was affected by the cost of alcohol, activation involved frontostriatal regions, which are important for the interplay between deliberation and reward value, suggesting suppression resulting from greater cognitive load. This is the first study of its kind to examine cost-benefit decision-making for alcohol and was the first to apply a framework from economics, called demand curve analysis, to understanding cost-benefit decision making.

"The brain activity was most differentially active during the suppressed consumption choices, suggesting that participants were experiencing the most conflict," MacKillop said. "We had speculated during the design of the study that the choices not to drink at all might require the most cognitive effort, but that didn’t seem to be the case. Once people decided that the cost of drinking was too high, they didn’t appear to experience a great deal of conflict in terms of the associated brain activity."

These conflicted decisions appeared to be represented by activity in the anterior insula, which has been linked in previous addiction studies to the motivational circuitry of the brain. Not only encoding how much people crave or value drugs, this portion of the brain is believed to be responsible for processing interceptive experiences, a person’s visceral physiological responses.

"It was interesting that the insula was sensitive to escalating alcohol costs especially when the costs of drinking outweighed the benefits," MacKillop said. "That means this could be the region of the brain at the intersection of how our rational and irrational systems work with one another. In general, we saw the choices associated with differential brain activity were those choices in the middle, where people were making choices that reflect the ambivalence between cost and benefits. Where we saw that tension, we saw the most brain activity."

While MacKillop acknowledges the impact this research could have on neuromarketing-or understanding how the brain makes decisions about what to buy-he is more interested in how this research can help people with alcohol addictions.

"These findings reveal the distinct neural signatures associated with different kinds of consumption preferences. Now that we have established a way of studying these choices, we can apply this approach to better understanding substance use disorders and improving treatment," he said, adding that comparing fMRI scans from alcoholics with those of people with normal drinking habits could potentially tease out brain patterns that show what is different between healthy and unhealthy drinkers. "In the past, we have found that behavioral indices of alcohol value predict poor treatment prognosis, but this would permit us to understand the neural basis for negative outcomes."

The research was published in the journal Neuropsychopharmacology March 3. A podcast highlighting this work is available at http://www.nature.com/multimedia/podcast/npp/npp_030314_alcohol.mp3.

Study debunks alcohol consumption assertions

ALCOHOL consumption is not a direct cause of cognitive impairment in older men later in life, a study conducted by the University of Western Australia has found. 

The study, published in the Journal of Neurology, used Mendelian randomisation to analyse the genetic data from 3,542 men between the ages of 65 and 83 years. 

The scientists measured the participants’ cognitive function three to eight years after recording their alcohol consumption. 

Lead author, Western Australian Centre for Health and Ageing Director and UWA Professor Osvaldo Almeida says the team investigated the triangular association between alcohol consumption, cognitive impairment and a genetic polymorphism that modulates the efficiency of a critical enzyme of alcohol metabolism. 

“We found a genetic variation that increases absenteeism and decreases the total amount of alcohol consumed,” Prof Almeida says.

“If alcohol were a cause of cognitive impairment, one would expect that this genetic variation would be associated with lower risk of cognitive impairment in later life [because people with this genetic variation drink less or not at all]. 

“That was not the case. Hence, we concluded that the association between alcohol use and cognitive impairment is not due to a direct effect of alcohol.”

The study also presented results that are consistent with the possibility, but do not necessarily prove, that regular moderate drinking decreases the risk of cognitive impairment in older men.

Prof Almeida says the reasons for these results were unclear.

“But evidence from a randomised trial looking at the effect of the Mediterranean diet [which includes nuts, olive oil, vegetables and wine] on health outcomes is supportive of this hypothesis,” he says. 

“One may argue that people who drink in moderation have a lifestyle where, in general, things are done in moderation. 

“This approach to life may decrease health hazards in general.”

Prof Almeida says that although the results didn’t show alcohol affecting cognitive impairment, other studies have found excessive alcohol use to be associated with worse physical health, widowhood and poor social support. 

“[These studies] led to the assumption that alcohol must directly damage the brain and cause cognitive impairment,” he says. 

“This study shows that such an assumption is wrong. 

“It also suggests that alcohol may have a small protective effect that we need to understand better in order to develop new interventions that might contribute to prevent dementia without all the bad outcomes associated with alcohol.”

Stimulating brain cells stops binge drinking, animal study finds

Researchers at the University at Buffalo have found a way to change alcohol drinking behavior in rodents, using the emerging technique of optogenetics, which uses light to stimulate neurons.

Their work could lead to powerful new ways to treat alcoholism, other addictions, and neurological and mental illnesses; it also helps explain the underlying neurochemical basis of drug addiction.

The findings, published in November in Frontiers in Neuroscience, are the first to demonstrate a causal relationship between the release of dopamine in the brain and drinking behaviors of animals. Research like this, which makes it possible to map the neuronal circuits responsible for specific behaviors, is a major focus of President Obama’s Brain Research for Advancing Innovative Neurotechnologies initiative, known as BRAIN.

In the experiments, rats were trained to drink alcohol in a way that mimics human binge-drinking behavior.

First author Caroline E. Bass, PhD, assistant professor of pharmacology and toxicology in the UB School of Medicine and Biomedical Sciences explains:  “By stimulating certain dopamine neurons in a precise pattern, resulting in low but prolonged levels of dopamine release, we could prevent the rats from binging. The rats just flat out stopped drinking,” she says.

Bass’s co-authors are at Wake Forest University, where she worked previously.

Interestingly, the rodents continued to avoid alcohol even after the stimulation of neurons ended, she adds.

“For decades, we have observed that particular brain regions light up or become more active in an alcoholic when he or she drinks or looks at pictures of people drinking, for example, but we didn’t know if those changes in brain activity actually governed the alcoholic’s behavior,” says Bass.

The researchers activated the dopamine neurons through a type of deep brain stimulation, but unlike techniques now used to treat certain neurological disorders, such as severe tremors in Parkinson’s disease patients, this new technique, called optogenetics, uses light instead of electricity to stimulate neurons.

“Electrical stimulation doesn’t discriminate,” Bass explains. “It hits all the neurons, but the brain has many different kinds of neurons, with different neurotransmitters and different functions. Optogenetics allows you to stimulate only one type of neuron at a time.”

Bass specializes in using viral vectors to study the brain in substance abuse. In this study, she used a virus to introduce a gene encoding a light-responsive protein into the animals’ brains. That protein then activated a specific subpopulation of dopamine neurons in the brain’s reward system.

“I created a virus that will make this protein only in dopaminergic neurons,” Bass says.

The neuronal pathways affected in this research are involved in many neurological disorders, she says. For that reason, the results have application not only in understanding and treating alcohol-drinking behaviors in humans, but also in many devastating mental illnesses and neurological diseases that have a dopamine component.

Bass notes that this ability to target genes to dopamine neurons could potentially lead to the use of gene therapy in the brain to mitigate many of these disorders.

“We can target dopamine neurons in a part of the brain called the nigrostriatal pathway, which is what degenerates in Parkinson’s disease,” she says. “If we could infuse a viral vector into that part of the brain, we could target potentially therapeutic genes to the dopamine neurons involved in Parkinson’s. And by infusing the virus into other areas of the brain, we could potentially deliver therapeutic genes to treat other neurological diseases and mental illnesses, including schizophrenia and depression.”

Prenatal Exposure to Alcohol Disrupts Brain Circuitry

Prenatal exposure to alcohol severely disrupts major features of brain development that potentially lead to increased anxiety and poor motor function, conditions typical in humans with Fetal Alcohol Spectrum Disorders (FASD), according to neuroscientists at the University of California, Riverside.

In a groundbreaking study, the UC Riverside team discovered that prenatal exposure to alcohol significantly altered the expression of genes and the development of a network of connections in the neocortex — the part of the brain responsible for high-level thought and cognition, vision, hearing, touch, balance, motor skills, language, and emotion — in a mouse model of FASD. Prenatal exposure caused wrong areas of the brain to be connected with each other, the researchers found.

These findings contradict the recently popular belief that consuming alcohol during pregnancy does no harm.

“If you consume alcohol when you are pregnant you can disrupt the development of your baby’s brain,” said Kelly Huffman, assistant professor of psychology at UC Riverside and lead author of the study that appears in the Nov. 27 issue of The Journal of Neuroscience, the official, peer-reviewed publication of the Society of Neuroscience. Study co-authors are UCR Ph.D. students Hani El Shawa and Charles Abbott.

“This research helps us understand how substances like alcohol impact brain development and change behavior,” Huffman explained. “It also shows how prenatal alcohol exposure generates dramatic change in the brain that leads to changes in behavior. Although this study uses a moderate- to high-dose model, others have shown that even small doses alter development of key receptors in the brain.”

Researchers have long known that ethanol exposure from a mother’s consumption of alcohol impacts brain and cognitive development in the child, but had not previously demonstrated a connection between that exposure and disruption of neural networks that potentially leads to changes in behavior.

Huffman’s team found dramatic changes in intraneocortical connections between the frontal, somatosensory and visual cortex in mice born to mothers who consumed ethanol during pregnancy. The changes were especially severe in the frontal cortex, which regulates motor skill learning, decision-making, planning, judgment, attention, risk-taking, executive function and sociality.

The neocortex region of the mammalian brain is similar in mice and humans, although human processing is more complex. In previous research, Huffman and her team created what amounts to an atlas of the neocortex, identifying the development of regions, gene expression and the cortical circuit over time. That research is foundational to understanding behavioral disorders such as autism and FASD.

Children diagnosed with FASD may have facial deformities and can exhibit cognitive, behavioral and motor deficits from ethanol-related neurobiological damage in early development. Those deficits may include learning disabilities, reduced intelligence, mental retardation and anxiety or depression, Huffman said.

Milder forms of FASD may produce no facial deformities, such as wideset eyes and smooth upper lip, but behavioral issues such as hyperactivity, hyperirritability and attention problems may appear as the child develops, she added.

Based on her earlier research, Huffman said, she expected to find some disruption of intraneocortical circuitry, but thought it would be subtle.

“I was surprised that the result of alcohol exposure was quite dramatic,” she said. “We found elevated levels of anxiety, disengaged behavior, and difficulty with fine motor coordination tasks. These are the kinds of things you see in children with FASD.”

The next phase of her research will examine whether deficits related to prenatal exposure to alcohol continue in subsequent generations.

The bottom line, Huffman said, is that women who are pregnant or who are trying to get pregnant should abstain from drinking alcohol.

“Would you put whiskey in your baby’s bottle? Drinking during pregnancy is not that much different,” she said. “If you ask me if you have three glasses of wine during pregnancy will your child have FASD, I would say probably not. If you ask if there will be changes in the brain, I would say, probably. There is no safe level of drinking during pregnancy.”