Posts tagged addiction
Posts tagged addiction
New research shows that craving drugs such as nicotine can be visualized in specific regions of the brain that are implicated in determining the value of actions, in planning actions and in motivation. Dr. Alain Dagher, from McGill University, suggests abnormal interactions between these decision-making brain regions could underlie addiction. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN).
Neuroeconomics is a field of research which seeks to explain decision making in humans based on calculating costs and likely rewards or benefits of choices individuals make. Previous studies have suggested addicted individuals place greater value on immediate rewards (cigarette smoking) over delayed rewards (health benefits). Research done by Dr. Dagher and colleagues show how the value of the drug, which is indicated by the degree of craving, varies based on drug availability, decision to quit and other factors. He also shows that this perceived value of the drug at a given time can be visualized in the brains of addicted individuals by functional Magnetic Resonance Imaging (fMRI), and that imaging results can be used to predict subsequent consumption.
Dr. Dagher showed that a specific brain region called the dorsolateral prefrontal cortex (abbreviated DLPFC) regulates cigarette craving in response to drug cues - seeing people smoke, or smelling cigarettes - and that these induced cravings could be altered by inactivating the DLPFC by Transcranial Magnetic Stimulation (TMS). He suggests addiction may result from abberrant connections between the DLFPC and other brain region in susceptible individuals. These results could provide a rational basis for novel interventions to reduce cravings in addicted individuals, such as cognitive behavioral therapy or transcranial stimulation of the DLFPC.
Concluding quote from Dr. Dagher: “Policy debates have often centred on whether addictive behaviour is a choice or a brain disease. This research allows us to view addiction as a pathology of choice. Dysfunction in brain regions that assign value to possible options may lead to choosing harmful behaviours.”
Children of parents who were addicted to drugs or alcohol are more likely to be depressed in adulthood, according to a new study by University of Toronto researchers.
“These findings underscore the intergenerational consequences of drug and alcohol addiction and reinforce the need to develop interventions that support healthy childhood development,” said the study’s lead author, Esme Fuller-Thomson, professor and Sandra Rotman Endowed Chair in the University of Toronto’s Factor-Inwentash Faculty of Social Work and the Department of Family and Community Medicine.
In a paper published online in the journal Psychiatry Research this month, investigators examined the association between parental addictions and adult depression in a representative sample of 6,268 adults, drawn from the 2005 Canadian Community Health Survey.
Of these respondents, 312 had a major depressive episode within the year preceding the survey and 877 reported that while they were under the age of 18 and still living at home that at least one parent who drank or used drugs “so often that it caused problems for the family.”
Results indicate that individuals whose parents were addicted to drugs or alcohol are more likely to develop depression than their peers. After adjusting for age, sex and race, parental addictions were associated with more than twice the odds of adult depression, says Fuller-Thomson.
“Even after adjusting for factors ranging from childhood maltreatment and parental unemployment to adult health behaviours including smoking and alcohol consumption, we found that parental addictions were associated with 69 per cent higher odds of depression in adulthood,” explains Fuller-Thomson. The study was co-authored with four graduate students at the University of Toronto: Robyn Katz, Vi Phan, Jessica Liddycoat and Sarah Brennenstuhl.
This study could not determine the cause of the relationship between parental addictions and adult depression. Co-author Robyn Katz, suggests that “It is possible that the prolonged and inescapable strain of parental addictions may permanently alter the way these children’s bodies react to stress throughout their life.
“One important avenue for future research is to investigate potential dysfunctions in cortisol production – the hormone that prepares us for ‘fight or flight’ – which may influence the later development of depression.”
“As an important first step, children who experience toxic stress at home can be greatly helped by the stable involvement of caring adults, including grandparents, teachers, coaches, neighbours and social workers,” said Fuller-Thomson. “Although more research is needed to determine if access to a responsive and loving adult decreases the likelihood of adult depression among children exposed to parental addictions, we do know that these caring relationships promote healthy development and buffer stress.”
Can Virtual Reality Treat Addiction?
Researchers are plugging in smokers, alcoholics, and even crack addicts to expose them to a relapse environment—and teach them how to deal with it. Will it work?
When the addicts enter the room, they haven’t met the people inside. They’ve never been there before, but the setting is familiar, and so is the pipe on the table, or the bottles of booze on the ground. Soon enough, someone’s offering them a hit, or a drug deal’s going down right in front of them.
They’ve been trying to get better—that’s why they’re doing this—but now they have cravings.
It’s about then that a voice instructs them to put down the joystick and look around the room without speaking, “allowing that drug craving to come and go like a wave.” The voice asks them periodically to rate their cravings as, after a couple minutes, they start to relax. The craving starts to dissipate and they hear a series of tones: beep-boop-boop.
It’s all being orchestrated by a wizard behind the virtual curtain: Zach Rosenthal, an assistant professor at Duke. For years now, with funding from the National Institute on Drug Abuse and the Department of Defense, Rosenthal has been running virtual reality trials like this with drug addicts in North Carolina (and veterans, hence the DOD funding) who are trying to recover. About 90 people, passing in and out of the NIDA study, have been coming to Rosenthal for treatment through virtual reality. They’re hooked up to a virtual reality simulator and dumped somewhere (a neighborhood, a crack house) where the researchers can slowly add cues to the environment, or change the environment itself, altering the situation to based on each patient’s history and adding paraphernalia (drugs, a crack pipe) as necessary.
The idea is that people will develop coping strategies, then take those strategies back to the real world. With coping mechanisms in their tool kits, users will get better, faster. But just because someone says no in a fake world, does that mean he’ll say no in real life?
Using a miniature electronic device implanted in the brain, scientists have tapped into the internal reward system of mice, prodding neurons to release dopamine, a chemical associated with pleasure.
The researchers, at Washington University School of Medicine in St. Louis and the University of Illinois at Urbana-Champaign, developed tiny devices, containing light emitting diodes (LEDs) the size of individual neurons. The devices activate brain cells with light. The scientists report their findings April 12 in the journal Science.
“This strategy should allow us to identify and map brain circuits involved in complex behaviors related to sleep, depression, addiction and anxiety,” says co-principal investigator Michael R. Bruchas, PhD, assistant professor of anesthesiology at Washington University. “Understanding which populations of neurons are involved in these complex behaviors may allow us to target specific brain cells that malfunction in depression, pain, addiction and other disorders.”
For the study, Washington University neuroscientists teamed with engineers at the University of Illinois to design microscale (LED) devices thinner than a human hair. This was the first application of the devices in optogenetics, an area of neuroscience that uses light to stimulate targeted pathways in the brain. The scientists implanted them into the brains of mice that had been genetically engineered so that some of their brain cells could be activated and controlled with light.
Although a number of important pathways in the brain can be studied with optogenetics, many neuroscientists have struggled with the engineering challenge of delivering light to precise locations deep in the brain. Most methods have tethered animals to lasers with fiber optic cables, limiting their movement and altering natural behaviors.
But with the new devices, the mice freely moved about and were able to explore a maze or scamper on a wheel. The electronic LEDs are housed in a tiny fiber implanted deep in the brain. That’s important to the device’s ability to activate the proper neurons, according to John A. Rogers, PhD, professor of materials science and engineering at the University of Illinois.
“You want to be able to deliver the light down into the depth of the brain,” Rogers says. “We think we’ve come up with some powerful strategies that involve ultra-miniaturized devices that can deliver light signals deep into the brain and into other organs in the future.”
Using light from the cellular-scale LEDs to stimulate dopamine-producing cells in the brain, the investigators taught the mice to poke their noses through a specific hole in a maze. Each time a mouse would poke its nose through the hole, that would trigger the system to wirelessly activate the LEDs in the implanted device, which then would emit light, causing neurons to release dopamine, a chemical related to the brain’s natural reward system.
“We used the LED devices to activate networks of brain cells that are influenced by the things you would find rewarding in life, like sex or chocolate,” says co-first author Jordan G. McCall, a neuroscience graduate student in Washington University’s Division of Biology and Biomedical Sciences. “When the brain cells were activated to release dopamine, the mice quickly learned to poke their noses through the hole even though they didn’t receive any food as a reward. They also developed an associated preference for the area near the hole, and they tended to hang around that part of the maze.”
The researchers believe the LED implants may be useful in other types of neuroscience studies or may even be applied to different organs. Related devices already are being used to stimulate peripheral nerves for pain management. Other devices with LEDs of multiple colors may be able to activate and control several neural circuits at once. In addition to the tiny LEDs, the devices also carry miniaturized sensors for detecting temperature and electrical activity within the brain.
Bruchas and his colleagues already have begun other studies of mice, using the LED devices to manipulate neural circuits that are involved in social behaviors. This could help scientists better understand what goes on in the brain in disorders such as depression and anxiety.
“We believe these devices will allow us to study complex stress and social interaction behaviors,” Bruchas explains. “This technology enables us to map neural circuits with respect to things like stress and pain much more effectively.”
The wireless, microLED implant devices represent the combined efforts of Bruchas and Rogers. Last year, along with Robert W. Gereau IV, PhD, professor of anesthesiology, they were awarded an NIH Director’s Transformative Research Project award to develop and conduct studies using novel device development and optogenetics, which involves activating or inhibiting brain cells with light.
Scientists have discovered a molecular process in the brain triggered by cocaine use that could provide a target for treatments to prevent or reverse addiction to the drug.
Reporting in the Journal of Neuroscience, Michigan State University (MSU) neuroscientist A.J. Robison and colleagues say cocaine alters the nucleus accumbens, the brain’s pleasure center that responds to stimuli such as food, sex and drugs.
“Understanding what happens molecularly to this brain region during long-term exposure to drugs might give us insight into how addiction occurs,” said Robison, assistant professor in the Department of Physiology and in the Neuroscience Program.
The researchers found that cocaine causes cells in the nucleus accumbens to boost production of two proteins, one associated with addiction and the other related to learning. The proteins have a reciprocal relationship – they increase each other’s production and stability in the cells – so the result is a snowball effect that Robison calls a feed-forward loop.
Robison and colleagues demonstrated that loop’s essential role in cocaine responses by manipulating the process in rodents. They found that raising production of the protein linked to addiction made animals behave as if they were exposed to cocaine even when they weren’t. They also were able to break the loop, disrupting rodents’ response to cocaine by preventing the function of the learning protein.
“At every level that we study, interrupting this loop disrupts the process that seems to occur with long-term exposure to drugs,” said Robison, who conducted the study as a postdoctoral fellow at Mount Sinai School of Medicine in New York City before joining the faculty at MSU.
Robison said the study was particularly compelling because it found signs of the same feed-forward loop in the brains of people who died while addicted to cocaine.
“The increased production of these proteins that we found in the animals exposed to drugs was exactly paralleled in a population of human cocaine addicts,” he said. “That makes us believe that the further experiments and manipulations we did in the animals are directly relevant to humans.”
Robison said the growing understanding of addiction at the molecular level could help pave the way for new treatments for addicts.
“This sort of molecular pathway could be interrupted using genetic medicine, which is what we did with the mice,” he said. “Many researchers think that is the future of medicine.”
Studying what makes us want to eat, could help devise approaches to prevent obesity, which is becoming widespread in Europe.
Suzanne Dickson is a Professor of physiology and neuroendocrinology at the Institute of Neuroscience and Physiology, based at the Sahlgrenska Academy at the University of Gothenburg, Sweden. She tells youris.com about her involvement in the EU funded NeuroFAST project. Her focus is on the impact of appetite-regulating gut hormones on parts of the brain that influence food preference and food reward.
This research is also driven by the huge unmet need of treating the growing group of obese patients.
What is the focus of your work relating to food and the brain?
We work on food reward, which involves neurobiological circuits linked to the addiction process. We decided to work on this because increasing evidence linked excessive over-eating to brain pathways involved in reward, including pathways known to be targets for addictive drugs. Over-eating can be influenced by genetic predisposition traits, psychiatric diseases, cues from the environment that trigger expectation of a food reward. Other factors include socio-economic pressures, stressful lifestyle including stress in the workplace or home.
What is the nature of food reward?
Our specific focus is on the property of the reward value. If animals find food rewarding, they will display altered behaviours that indicate that the reward value of the food is changed. Members of our team are working with sugars, fats and combinations of the above. We have also been working in clinical projects with foods of similar taste but with altered caloric value. By targeting brain mechanisms involved in food reward, we hope to reveal new mechanisms that will help develop new treatment strategies for obesity.
We have studied an area of the brain called ventral tegmental area (VTA) is a key node in the brain’s reward pathway. It is the home of the dopamine cells that are activated by rewards, including food rewards. Its role is very complex. Many believe that these cells are involved in food searching behaviours or food motivation, for example. However, they also can be activated simply by cues associated with foods akin to deciding to consume a chocolate bar by the sight of one at the cashier in a supermarket and novelty of the reward stimulus appears to play a role.
Did you identify the difference between the brain’s pleasure center and hunger center?
The pleasure centres are involved in food intake that is linked to its reward value. Whether we are hungry or fed, by raising the reward value of food the reward system encourages us to eat more, especially rewarding food. This system has been critical during the evolution process to ensure survival from famine. In our modern environment that generates obesity, food reward is no longer our friend as it encourages us to over-indulge in sweet and fatty food, even when we are not hungry.
By contrast, the hunger pathways can be considered more primitive. They detect and respond to nutrient deficit. If we enter negative energy balance, homeostatic pathways become activated informing higher feeding networks to initiate feeding behaviours.
What strategies have studied to try and find ways to limit over-eating?
We have recently learned from the field of bariatric—weight loss—surgery that it is possible to change reward behaviour towards food. This involves unknown mechanisms that are likely linked to the brain’s food reward system. We focus particularly on a hormone called ghrelin whose secretion is altered after bariatric surgery. We hope to reveal new information that is of clinical and therapeutic relevance for future drug strategies for this disease area.
So far, in the laboratory, we have learned a lot about the basic brain mechanisms controlling food reward and the role played by gut hormones in regulating these. We therefore know a lot more about mechanisms—namely about the brain systems and circuits underpinning over-eating—especially for calorie dense foods.
(Image credit: Zorrilla Laboratory, The Scripps Research Institute)
All too often, stress turns addiction recovery into relapse, but years of basic brain research have provided scientists with insight that might allow them develop a medicine to help. A new study in the journal Neuron pinpoints the neural basis for stress-related relapse in rat models to an unprecedented degree. The advance could accelerate progress toward a medicine that prevents stress from undermining addiction recovery.
In the paper published March 6, researchers at Brown University and the University of Pennsylvania demonstrated specific steps in the sequence of neural events underlying stress-related drug relapse and showed that they take place within a brain region called the ventral tegmental area (VTA), which helps reinforce behaviors related to fulfilling basic needs. They also showed that a closely related neural process believed to be crucial to stress-related relapse may not be involved after all.
Moreover, this new understanding allowed the researchers to prevent relapse to drug seeking in the animal model. When they treated rats that had recovered from cocaine addiction with a chemical that blocks the “kappa opioid receptors” that stress activates in the VTA, the rats did not relapse to cocaine use under stress. Untreated rats who had also recovered from addiction did relapse after the same stress.
The chemical that helped the rats, “nor-BNI,” may be one that would someday be tried in humans, said study senior author Julie Kauer, professor of biology in Brown’s Department of Molecular Pharmacology, Physiology, and Biotechnology. By deepening scientists’ understanding of the stress-related relapse mechanism, she and her co-authors hope to identify multiple possible targets for eventual patient treatments.
“If we understand how kappa opioid receptor antagonists are interfering with the reinstatement of drug seeking we can target that process,” Kauer said. “We’re at the point of coming to understand the processes and possible therapeutic targets. Remarkably, this has worked.”
The neural crux of relapse
Exactly how stress acts in the brain to trigger relapse is a complicated sequence that is still not fully understood, but the new study focuses on and elucidates three key players at the crux of the phenomenon in the VTA: GABA-releasing neurons, dopamine-releasing neurons, and the kappa opioid receptors that affect their connections.
Fulfilling natural needs such as hunger or thirst results in a rewarding release of dopamine from the VTA’s dopamine neurons, Kauer said. Unfortunately, so does using drugs of abuse.
In normal brain function, GABA applies the brakes on the rewarding dopamine release, slowing it back to a normal level. It achieves this by forging and then strengthening the connections, called synapses, with the dopamine neuron. The strengthening process is called long-term potentiation (LTP).
In the first of their experiments, the team at Brown, including lead author Nicholas Graziane, showed that stress interrupts the LTP process, hindering GABA’s ability to slam the brakes on dopamine release.
Previous research implicated kappa opioid receptors as one of many neural entities that could have a role in stress-related relapse. Kauer, Graziane, and co-author Abigail Polter investigated that directly by blocking the receptors in some rats with a treatment of nor-BNI in the VTA and leaving others untreated. Then they subjected the rats to a standardized five-minute stress exercise. After 24 hours they looked at the cells in the VTA and found that LTP was hindered in the untreated rats but still present and underway in the rats whose receptors had been blocked with nor-BNI.
With the role of stress and the receptors in the GABA-dopamine dynamic both confirmed and then mitigated, the question remained: Could this knowledge be used to prevent relapse?
To answer that, Penn co-authors Lisa Briand and Christopher Pierce performed the experiment demonstrating that nor-BNI delivered directly to the VTA prevented stressed rats from relapsing to cocaine seeking, while untreated rats subjected to the same stress did relapse.
“Our results indicate that the kappa receptors within the VTA critically control stress-induced drug seeking in animals,” the authors wrote in Neuron.
Along the way, the team also discovered evidence that another stress-affected synapse in the VTA – one that excites dopamine release rather than inhibits it – does not play a role in the stress-related relapse as many researchers have thought. The nor-BNI treatment that prevented stress-related relapse, for example, did not affect those synapses.
Kauer emphasized that her lab’s findings of therapeutic potential are the product of more than a decade of essential basic research on the importance of how changes in synapses relate to behaviors including addiction.
“If we can figure out how not only stress, but the whole system works, then we’ll potentially have a way to tune it down in a person who needs that,” she said.
Addiction may result from abnormal brain circuitry in the frontal cortex, the part of the brain that controls decision-making. Researchers from the RIKEN Center for Molecular Imaging Science in Japan collaborating with colleagues from the Montreal Neurological Institute of McGill University in Canada report today that the lateral and orbital regions of the frontal cortex interact during the response to a drug-related cue and that aberrant interaction between the two frontal regions may underlie addiction. Their results are published today in the journal Proceedings of the National Academy of Sciences of the USA.
Cues such as the sight of drugs can induce cravings and lead to drug-seeking behaviors and drug use. But cravings are also influenced by other factors, such as drug availability and self-control. To investigate the neural mechanisms involved in cue-induced cravings the researchers studied the brain activity of a group of 10 smokers, following exposure to cigarette cues under two different conditions of cigarette availability. In one experiment cigarettes were available immediately and in the other they were not. The researchers combined a technique called transcranial magnetic stimulation (TMS) with functional magnetic resonance imaging (fMRI).
The results demonstrate that in smokers the orbitofrontal cortex (OFC) tracks the level of craving while the dorsolateral prefrontal cortex (DPFC) is responsible for integrating drug cues and drug availability. Moreover, the DPFC has the ability to suppress activity in the OFC when the cigarette is unavailable. When the DPFC was inactivated using TMS, both craving and craving-related signals in the OFC became independent of drug availability.
The authors of the study conclude that the DLPFC incorporates drug cues and knowledge on drug availability to modulate the value signals it transmits to the OFC, where this information is transformed into drug-seeking action.
“We demonstrate that in smokers, cravings build up in the OFC upon processing of cigarette cues and availability by the DFPC. What is surprising is that this is a neural circuit involved in decision making and self-control, that normally guides individuals to optimal behaviors in daily life.” Explains Dr. Hayashi, from RIKEN, who designed and conducted the fMRI and TMS experiments.
“This research uncovers the brain circuitry responsible for self-control during reward-seeking choices. It is also consistent with the view that drug addiction is a pathology of decision making.” According to Dr. Alain Dagher, a neurologist at the Montreal Neurological Institute.
These findings will help understand the neural basis of addiction and may contribute to a therapeutic approach for addiction.
(Image: New Jersey Addiction Assistance)
Rats that are socially isolated during a critical period of adolescence are more vulnerable to addiction to amphetamine and alcohol, found researchers at The University of Texas at Austin. Amphetamine addiction is also harder to extinguish in the socially isolated rats.
These effects, which are described this week in the journal Neuron, persist even after the rats are reintroduced into the community of other rats.
“Basically the animals become more manipulatable,” said Hitoshi Morikawa, associate professor of neurobiology in the College of Natural Sciences. “They’re more sensitive to reward, and once conditioned the conditioning takes longer to extinguish. We’ve been able to observe this at both the behavioral and neuronal level.”
Morikawa said the negative effects of social isolation during adolescence have been well documented when it comes to traits such as anxiety, aggression, cognitive rigidity and spatial learning. What wasn’t clear until now is how social isolation affects the specific kind of behavior and brain activity that has to do with addiction.
“Isolated animals have a more aggressive profile,” said Leslie Whitaker, a former doctoral student in Morikawa’s lab and now a researcher at the National Institute on Drug Abuse. “They are more anxious. Put them in an open field and they freeze more. We also know that those areas of the brain that are more involved in conscious memory are impaired. But the kind of memory involved in addiction isn’t conscious memory. It’s an unconscious preference for the place in which you got the reward. You keep coming back to it without even knowing why. That kind of memory is enhanced by the isolation.”
The widespread belief that dopamine regulates pleasure could go down in history with the latest research results on the role of this neurotransmitter. Researchers have proved that it regulates motivation, causing individuals to initiate and persevere to obtain something either positive or negative.
The neuroscience journal Neuron publishes an article by researchers at the Universitat Jaume I of Castellón that reviews the prevailing theory on dopamine and poses a major paradigm shift with applications in diseases related to lack of motivation and mental fatigue and depression, Parkinson’s, multiple sclerosis, fibromyalgia, etc. and diseases where there is excessive motivation and persistence as in the case of addictions.
“It was believed that dopamine regulated pleasure and reward and that we release it when we obtain something that satisfies us, but in fact the latest scientific evidence shows that this neurotransmitter acts before that, it actually encourages us to act. In other words, dopamine is released in order to achieve something good or to avoid something evil”, explains Mercè Correa.
Studies had shown that dopamine is released by pleasurable sensations but also by stress, pain or loss. These research results however had been skewed to only highlight the positive influence, according to Correa. The new article is a review of the paradigm based on the data from several investigations, including those conducted over the past two decades by the Castellón group in collaboration with the John Salamone of the University of Connecticut (USA), on the role of dopamine in the motivated behaviour in animals.
The level of dopamine depends on individuals, so some people are more persistent than others to achieve a goal. “Dopamine leads to maintain the level of activity to achieve what is intended. This in principle is positive, however, it will always depend on the stimuli that are sought: whether the goal is to be a good student or to abuse of drugs” says Correa. High levels of dopamine could also explain the behaviour of the so-called sensation seekers as they are more motivated to act.
Application for depression and addiction
To know the neurobiological parameters that make people be motivated by something is important to many areas such as work, education or health. Dopamine is now seen as a core neurotransmitter to address symptoms such as the lack of energy that occurs in diseases such as depression. “Depressed people do not feel like doing anything and that’s because of low dopamine levels,” explains Correa. Lack of energy and motivation is also related to other syndromes with mental fatigue such as Parkinson’s, multiple sclerosis or fibromyalgia, among others.
In the opposite case, dopamine may be involved in addictive behaviour problems, leading to an attitude of compulsive perseverance. In this sense, Correa indicates that dopamine antagonists which have been applied so far in addiction problems probably have not worked because of inadequate treatments based on a misunderstanding of the function of dopamine.