Posts tagged dopamine
Articles and news from the latest research reports.
Genes exhibit different behaviours in different stages of development
The effect that genes have on our brain depends on our age. These are the findings of a group of researchers from the MedUni Vienna. It has been known for a number of years that particular genetic variations are of importance for the functioning of neural circuits in the brain. Just how these effects differ in the various stages of life has until recently not been fully understood. This international study has been able to demonstrate that genetic variations at different times in our lives can actually have opposite effects on the brain, which provides an explanation for the differences that clinicians observe in the psychiatric symptoms and response to medications of adolescents and adults.
The group of researchers from Vienna, in collaboration with international cooperation partners, has shown that the effect of a psychiatric risk gene on a resting state network in the forebrain depends greatly on the patient’s age.
The human forebrain is crucial for planning and action, which are closely interwoven with concentration, attention and memory functions. The nerve transmitter substance dopamine orchestrates the activity of neurons in the forebrain in order to ensure an ideal level of functioning. The amount of dopamine in the brain is not constant for life, however. Instead, it rises until adolescence and then falls by the time the individual reaches early adulthood to a much lower level. When the dopaminergic control function collapses, serious mental illnesses such as schizophrenia, depression or attention deficit / hyperactivity disorder (ADHD) can result that usually start around the period of transition to adulthood.
For a number of years, doctors have known that a risk gene involved in dopamine metabolism (COMT) can affect neuronal regulation of the forebrain in adults. Carriers of risk gene variants are more prone to dopaminergic mental illness.
The interaction of genes and stages of development
As part of the study, carried out at the MedUni Vienna’s University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team used magnetic resonance imaging data from a large random sample of over 200 test subjects to analyse the complex interaction between stages of development and genetic variations in the COMT gene and how it affects the resting state network of the forebrain.
Some of the magnetic resonance scans were performed in Vienna (Centre of Excellent, High-Field MR, Department of MR Physics, Head: Ewald Moser) and some as part of an EU project (Institute of Psychiatry, London, Head: Gunther Schumann). Gene analyses (COMT Val158Met) were carried out in Vienna (Univ. Dept. of Laboratory Medicine, Harald Esterbauer and colleagues) or as part of the EU project.
"Our age has a crucial influence on the effects of psychiatric risk genes. A gene that has positive effects during puberty can be bad for us in adulthood," says study leader Lukas Pezawas, describing the results. In the study, adolescents exhibited contrary gene effects on the brain compared to adults.
The study highlights the dynamism of gene effects on brain function throughout the various stages of life such as adolescence or adulthood. “These results are important for understanding the onset of illness in conditions such as schizophrenia, depression or ADHD, which mostly occur at the threshold of adulthood. Our results also show that there are fundamental differences in the dopamine system between adolescents and adults, which we need to take into account in future treatments”, explains Pezawas.
(Source: meduniwien.ac.at)
Researchers debunk myth about Parkinson’s disease
Using advanced computer models, neuroscience researchers at the University of Copenhagen have gained new knowledge about the complex processes that cause Parkinson’s disease. The findings have recently been published in the prestigious Journal of Neuroscience.
The defining symptoms of Parkinson’s disease are slow movements, muscular stiffness and shaking. There is currently no cure for the condition, so it is essential to conduct innovative research with the potential to shed some light on this terrible disruption to the central nervous system that affects one person in a thousand in Denmark.
Dopamine is an important neurotransmitter which affects physical and psychological functions such as motor control, learning and memory. Levels of this substance are regulated by special dopamine cells. When the level of dopamine drops, nerve cells that constitute part of the brain’s ‘stop signal’ are activated.
“This stop signal is rather like the safety lever on a motorised lawn mower: if you take your hand off the lever, the mower’s motor stops. Similarly, dopamine must always be present in the system to block the stop signal. Parkinson’s disease arises because for some reason the dopamine cells in the brain are lost, and it is known that the stop signal is being over-activated somehow or other. Many researchers have therefore considered it obvious that long-term lack of dopamine must be the cause of the distinctive symptoms that accompanies the disease. However, we can now use advanced computer simulations to challenge the existing paradigm and put forward a different theory about what actually takes place in the brain when the dopamine cells gradually die,” explains Jakob Kisbye Dreyer, Postdoc at the Department of Neuroscience and Pharmacology, University of Copenhagen.
A thorn in the side
Scanning the brain of a patient suffering from Parkinson’s disease reveals that in spite of dopamine cell death, there are no signs of a lack of dopamine – even at a comparatively late stage in the process.
“The inability to establish a lack of dopamine until advanced cases of Parkinson’s disease has been a thorn in the side of researchers for many years. On the one hand, the symptoms indicate that the stop signal is over-activated, and patients are treated accordingly with a fair degree of success. On the other hand, data prove that they are not lacking dopamine,” says Postdoc Jakob Kisbye Dreyer.
Computer models predict the progress of the disease
“Our calculations indicate that cell death only affects the level of dopamine very late in the process, but that symptoms can arise long before the level of the neurotransmitter starts to decline. The reason for this is that the fluctuations that normally make up a signal become weaker. In the computer model, the brain compensates for the shortage of signals by creating additional dopamine receptors. This has a positive effect initially, but as cell death progresses further, the correct signal may almost disappear. At this stage, the compensation becomes so overwhelming that even small variations in the level of dopamine trigger the stop signal – which can therefore cause the patient to develop the disease.”
The new research findings may pave the way for earlier diagnosis of Parkinson’s disease.
(Source: healthsciences.ku.dk)
Lipid Deficiency Linked to Neuron Degeneration
A type of lipid that naturally declines in the aging brain impacts – within laboratory models used to study Parkinson’s disease – a protein associated with the disease, according to a study co-authored by University of Alabama researchers.
The study, which published today in the Proceedings of the National Academy of Sciences, focuses on lipids, fat-like molecules that naturally occur in organisms, and their potential roles in a complex process that leads to the death of neurons that produce dopamine. When dopamine-producing neurons malfunction or die, this leads to the symptoms associated with Parkinson’s disease.
“This gets right to the heart of understanding, possibly, the mechanism by which one form of lipid is impacting the process of neuron degeneration,” said Dr. Guy Caldwell, UA professor of biological sciences and one of the study’s co-authors.
The study, led by researchers at the Louisiana State University Health Sciences Center, focused on phosphatidylethanolamine, a lipid known as PE. Today’s scholarly article details how low levels of PE lead to high-levels of alpha-synuclein, a protein previously linked to Parkinson’s. It also show the promise a second lipid, ethanolamine, or ETA, has in boosting PE levels.
To function correctly, proteins must fold properly within cells. One misfolding, as can occur when extra copies of the protein alpha-synuclein are present, can lead to others and, subsequently, to aggregation, or clumping, of proteins. Aggregation of proteins can lead to neuron malfunction or cell death.
Previous research had shown that excess alpha-synuclein can serve as an intra-cellular “roadblock,” preventing proteins, dopamine and other things cells need from being delivered to their necessary locations. This delivery disruption can lead to serious disorders.
“That situation is being applied here, but in a different way,” Caldwell said. “We’re gaining a better understanding of the importance these lipids, which are components of cellular membranes, have in maintaining proper trafficking.”
A proper link with alpha-synuclein helps “lipid rafts” in their transport of proteins.
“As the name implies, lipid rafts are like rafts of fat,” Caldwell said. “If alpha-synuclein can’t associate with those rafts, it could be a toxic situation for these cells.”
Using yeast and the tiny nematode C. elegans as laboratory models, the researchers showed they could reverse the delivery problem by adding ETA to the mix.
“This supplementation of ETA basically tells us that if we can restore the amount of PE that is being made, we can create a healthier situation in neurons, and this might help them to survive longer.”
UA’s lead author on the study is Siyuan “Alice” Zhang, a third-year UA doctoral student who works in the Caldwell lab. Dr. Kim Caldwell, UA professor of biological sciences, is also a co-author. LSU’s senior researcher on the project is Dr. Stephan Witt.
Additional study is needed in rodents and patient-derived stem cells before knowing how beneficial the discovery could eventually prove, Caldwell said.
Perhaps one day, Caldwell said, a supplement could be developed to prevent the decline of PE or possibly a drug could be developed to activate an enzyme that converts ETA to PE.
“I think it has promise as a new way of looking at alleviating toxicity,” Caldwell said. “It’s a different angle.”
(Source: uanews.ua.edu)
Eating habits, body fat related to differences in brain chemistry
People who are obese may be more susceptible to environmental food cues than their lean counterparts due to differences in brain chemistry that make eating more habitual and less rewarding, according to a National Institutes of Health study published in Molecular Psychiatry.
Researchers at the NIH Clinical Center found that, when examining 43 men and women with varying amounts of body fat, obese participants tended to have greater dopamine activity in the habit-forming region of the brain than lean counterparts, and less activity in the region controlling reward. Those differences could potentially make the obese people more drawn to overeat in response to food triggers and simultaneously making food less rewarding to them. A chemical messenger in the brain, dopamine influences reward, motivation and habit formation.
"While we cannot say whether obesity is a cause or an effect of these patterns of dopamine activity, eating based on unconscious habits rather than conscious choices could make it harder to achieve and maintain a healthy weight, especially when appetizing food cues are practically everywhere," said Kevin D. Hall, Ph.D., lead author and a senior investigator at National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of NIH. "This means that triggers such as the smell of popcorn at a movie theater or a commercial for a favorite food may have a stronger pull for an obese person – and a stronger reaction from their brain chemistry – than for a lean person exposed to the same trigger."
Study participants followed the same eating, sleeping and activity schedule. Tendency to overeat in response to triggers in the environment was determined from a detailed questionnaire. Positron emission tomography (PET) scans evaluated the sites in the brain where dopamine was able to act.
According to the Centers for Disease Control and Prevention, more than one-third of U.S. adults are obese. Obesity-related conditions include heart disease, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death.
"These findings point to the complexity of obesity and contribute to our understanding of how people with varying amounts of body fat process information about food," said NIDDK Director Griffin P. Rodgers, M.D. "Accounting for differences in brain activity and related behaviors has the potential to inform the design of effective weight-loss programs."
The study did not demonstrate cause and effect among habit formation, reward, dopamine activity, eating behavior and obesity. Future research will examine dopamine activity and eating behavior in people over time as they change their diets, physical activity, and their weight.
Dopamine Replacement Therapy Associated with Increase in Impulse Control Disorders Among Early Parkinson’s Disease Patients
New Penn Medicine research shows that neuropsychiatric symptoms such as depression, anxiety and fatigue are more common in newly diagnosed Parkinson’s disease (PD) patients compared to the general population. The study also found that initiation of dopamine replacement therapy, the most common treatment for PD, was associated with increasing frequency of impulse control disorders and excessive daytime sleepiness. The new findings, the first longitudinal study to come out of the Parkinson’s Progression Markers Initiative (PPMI), are published in the August 15, 2014, issue of Neurology®, the medical journal of the American Academy of Neurology.
The PPMI, a landmark, multicenter observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research, uses a combination of advanced imaging, biologics sampling and behavioral assessments to identify biomarkers of Parkinson’s disease progression. The Penn study, which represents neuropsychiatric and cognitive data from baseline through the first 24 months of follow up, was conducted in collaboration with the Philadelphia VA Medical Center and the University Hospital Donostia in Spain.
The study examined 423 newly diagnosed, untreated Parkinson’s patients and 196 healthy controls at baseline and 281 people with PD at six months. Of these, 261 PD patients and 145 healthy controls were evaluated at 12 months, and 96 PD patients and 83 healthy controls evaluated at 24 months.
PD patients were permitted to begin dopamine therapy at any point after their baseline evaluation.
“We hypothesized that neuropsychiatric symptoms would be common and stable in severity soon after diagnosis and that the initiation of dopamine replacement therapy would modify their natural progression in some way,” says senior author, Daniel Weintraub, MD, associate professor of Psychiatry and Neurology at the Perelman School of Medicine at the University of Pennsylvania and a fellow in Penn’s Institute on Aging.
The Penn team showed that while there was no significant difference between PD patients and healthy controls in the frequency of impulse control disorders, a neuropsychiatric symptom that can lead to compulsive gambling, sexual behavior, eating or spending, 21 percent of newly diagnosed PD patients screened positive for such symptoms at baseline. That percentage did not increase significantly over the 24-month period.
However, six patients who had been on dopamine therapy for more than a year at the 24-month evaluation showed impulse control disorders or related behavior symptoms while no impulse control incident symptoms were reported in PD patients who had not commenced dopamine therapy. Dopamine therapy did help with fatigue, with 33 percent of patients improving their fatigue test score over 24 months compared with only 11 percent of patients not on dopamine therapy.
The investigators also found evidence that depression may be undertreated in early PD patients: Two-thirds of patients who screened positive for depression at any time point were not taking an antidepressant.
PPMI follows volunteers for five years, so investigators plan to expand upon these results, which Weintraub still considers preliminary. “We will more closely look at cognitive changes over time,” he says. “Two years is not a sufficient period of follow up to really look at meaningful cognitive decline.”
The perspective of time is what makes the PPMI such an important initiative, Weintraub points out, since many patients with the disease live for 10 to 20 years following their diagnosis. “It’s really a chance to assess the frequency and characteristics of psychiatric and cognitive symptoms in PD, compare it with healthy controls, and then also look at its evolution over time,” he says. “The hope is that we will be able to continue this work so that we can obtain long-term follow up data on these patients,” says Weintraub.
(Source: uphs.upenn.edu)
(Image caption: This is the happiness equation, where t is the trial number, w0 is a constant term, other weights w capture the influence of different event types, 0 ≤ γ ≤ 1 is a forgetting factor that makes events in more recent trials more influential than those in earlier trials, CRj is the CR if chosen instead of a gamble on trial j, EVj is the EV of a gamble (average reward for the gamble) if chosen on trial j, and RPEj is the RPE on trial j contingent on choice of the gamble. The RPE is equal to the reward received minus the expectation in that trial EVj. If the CR was chosen, then EVj = 0 and RPEj = 0; if the gamble was chosen, then CRj = 0. The variables in the equation are quantities that the neuromodulator dopamine has been associated with in previous neuroscience studies. Credit: Robb Rutledge, UCL)
The happiness of over 18,000 people worldwide has been predicted by a mathematical equation developed by researchers at UCL, with results showing that moment-to-moment happiness reflects not just how well things are going, but whether things are going better than expected.
The new equation accurately predicts exactly how happy people will say they are from moment to moment based on recent events, such as the rewards they receive and the expectations they have during a decision-making task. Scientists found that overall wealth accumulated during the experiment was not a good predictor of happiness. Instead, moment-to-moment happiness depended on the recent history of rewards and expectations. These expectations depended, for example, on whether the available options could lead to good or bad outcomes.
The study, published in the Proceedings of the National Academy of Sciences, investigated the relationship between happiness and reward, and the neural processes that lead to feelings that are central to our conscious experience, such as happiness. Before now, it was known that life events affect an individual’s happiness but not exactly how happy people will be from moment to moment as they make decisions and receive outcomes resulting from those decisions, something the new equation can predict.
Scientists believe that quantifying subjective states mathematically could help doctors better understand mood disorders, by seeing how self-reported feelings fluctuate in response to events like small wins and losses in a smartphone game. A better understanding of how mood is determined by life events and circumstances, and how that differs in people suffering from mood disorders, will hopefully lead to more effective treatments.
Research examining how and why happiness changes from moment to moment in individuals could also assist governments who deploy population measures of wellbeing to inform policy, by providing quantitative insight into what the collected information means. This is especially relevant to the UK following the launch of the National Wellbeing Programme in 2010 and subsequent annual reports by the Office for National Statistics on ‘Measuring National Wellbeing’.
For the study, 26 subjects completed a decision-making task in which their choices led to monetary gains and losses, and they were repeatedly asked to answer the question ‘how happy are you right now?’. The participant’s neural activity was also measured during the task using functional MRI and from these data, scientists built a computational model in which self-reported happiness was related to recent rewards and expectations. The model was then tested on 18,420 participants in the game ‘What makes me happy?’ in a smartphone app developed at UCL called 'The Great Brain Experiment'. Scientists were surprised to find that the same equation could be used to predict how happy subjects would be while they played the smartphone game, even though subjects could win only points and not money.
Lead author of the study, Dr Robb Rutledge (UCL Wellcome Trust Centre for Neuroimaging and the new Max Planck UCL Centre for Computational Psychiatry and Ageing), said: “We expected to see that recent rewards would affect moment-to-moment happiness but were surprised to find just how important expectations are in determining happiness. In real-world situations, the rewards associated with life decisions such as starting a new job or getting married are often not realised for a long time, and our results suggest expectations related to these decisions, good and bad, have a big effect on happiness.
"Life is full of expectations - it would be difficult to make good decisions without knowing, for example, which restaurant you like better. It is often said that you will be happier if your expectations are lower. We find that there is some truth to this: lower expectations make it more likely that an outcome will exceed those expectations and have a positive impact on happiness. However, expectations also affect happiness even before we learn the outcome of a decision. If you have plans to meet a friend at your favourite restaurant, those positive expectations may increase your happiness as soon as you make the plan. The new equation captures these different effects of expectations and allows happiness to be predicted based on the combined effects of many past events.
"It’s great that the data from the large and varied population using The Great Brain Experiment smartphone app shows that the same happiness equation applies to thousands people worldwide playing our game, as with our much smaller laboratory-based experiments which demonstrate the tremendous value of this approach for studying human well-being on a large scale."
The team used functional MRI to demonstrate that neural signals during decisions and outcomes in the task in an area of the brain called the striatum can be used to predict changes in moment-to-moment happiness. The striatum has a lot of connections with dopamine neurons, and signals in this brain area are thought to depend at least partially on dopamine. These results raise the possibility that dopamine may play a role in determining happiness.
Striatal dopamine transporter binding correlates with body composition and visual attention bias for food cues in healthy young men
Research to be presented at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior, describes a way that brain chemistry may make some people notice food more easily, which can tempt overeating even in people who are not overweight. Dopamine activity in the striatum, an area of the brain sensitive to food reward, was linked to how quickly men noticed a food picture hidden among neutral pictures. In turn, the men who quickly noticed food pictures also ate more.
From rodent research it is clear that dopamine action in the striatum motivates eating, and this goes awry in obesity. “We do know that in human obesity the striatal dopamine system is affected, but interesting enough we know little about the striatal dopamine system of young, healthy individuals and how it relates to the motivation to eat” says Susanne la Fleur from the Academic Medical Center in Amsterdam, who directed the study linking dopamine, attention to food, and eating.
Ordinarily the burst of dopamine during a rewarding activity is eventually stopped when it is re-absorbed into the cells it came from. That re-uptake process requires a brain chemical called “dopamine transporter” (DAT). Lower DAT means dopamine is reabsorbed more slowly, causing it to keep acting on the brain. The researchers scanned brains of healthy, non-obese young men to determine available DAT. The men completed a computerized visual attention task to see how quickly they could detect food pictures among neutral pictures. Subjects were also asked to report food intake during 7 days.
The researchers found that the men with lower DAT, which means higher dopamine activity, showed a stronger visual attention bias towards food, detecting food pictures more quickly. “We could speculate that in healthy humans dopamine does motivate eating, however although we did observe a correlation between striatal dopamine transporter binding and the visual attention bias for food; and between visual attention bias for food and actual food intake, we did not observe a correlation between striatal dopamine transporter binding and actual food intake. Thus, a factor in addition to dopamine must be involved in going from being motivated to actual eating”, la Fleur concluded.
(Source: eurekalert.org)
The bit of your brain that signals how bad things could be
An evolutionarily ancient and tiny part of the brain tracks expectations about nasty events, finds new UCL research.
The study, published in Proceedings of the National Academy of Sciences, demonstrates for the first time that the human habenula, half the size of a pea, tracks predictions about negative events, like painful electric shocks, suggesting a role in learning from bad experiences.
Brain scans from 23 healthy volunteers showed that the habenula activates in response to pictures associated with painful electric shocks, with the opposite occurring for pictures that predicted winning money.
Previous studies in animals have found that habenula activity leads to avoidance as it suppresses dopamine, a brain chemical that drives motivation. In animals, habenula cells have been found to fire when bad things happen or are anticipated.
"The habenula tracks our experiences, responding more the worse something is expected to be," says senior author Dr Jonathan Roiser of the UCL Institute of Cognitive Neuroscience. "For example, the habenula responds much more strongly when an electric shock is almost certain than when it is unlikely. In this study we showed that the habenula doesn’t just express whether something leads to negative events or not; it signals quite how much bad outcomes are expected."
During the experiment, healthy volunteers were placed inside a functional magnetic resonance imaging (fMRI) scanner, and brain images were collected at high resolution because the habenula is so small. Volunteers were shown a random sequence of pictures each followed by a set chance of a good or bad outcome, occasionally pressing a button simply to show they were paying attention. Habenula activation tracked the changing expectation of bad and good events.
"Fascinatingly, people were slower to press the button when the picture was associated with getting shocked, even though their response had no bearing on the outcome." says lead author Dr Rebecca Lawson, also at the UCL Institute of Cognitive Neuroscience. "Furthermore, the slower people responded, the more reliably their habenula tracked associations with shocks. This demonstrates a crucial link between the habenula and motivated behaviour, which may be the result of dopamine suppression."
The habenula has previously been linked to depression, and this study shows how it could be involved in causing symptoms such low motivation, pessimism and a focus on negative experiences. A hyperactive habenula could cause people to make disproportionately negative predictions.
"Other work shows that ketamine, which has profound and immediate benefits in patients who failed to respond to standard antidepressant medication, specifically dampens down habenula activity," says Dr Roiser. "Therefore, understanding the habenula could help us to develop better treatments for treatment-resistant depression."
(Source: eurekalert.org)
Major dopamine system helps restore consciousness after general anesthesia
Researchers may be one step closer to better understanding how anesthesia works. A study in the August issue of Anesthesiology, the official medical journal of the American Society of Anesthesiologists® (ASA®), found stimulating a major dopamine-producing region in the brain, the ventral tegmental area (VTA), caused rats to wake from general anesthesia, suggesting that this region plays a key role in restoring consciousness after general anesthesia. Activating this region at the end of surgery could provide a novel approach to proactively induce consciousness from anesthesia in surgical patients, researchers say.
"While generally safe, it is well known that patients should not be under general anesthesia longer than necessary," said Ken Solt, M.D., lead author, Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine and assistant professor of anesthesia, Harvard Medical School, Boston. "Currently, there are no treatments to reverse the effects of general anesthesia. We must wait for the anesthetics to wear off. Having the ability to control the process of arousal from general anesthesia would be advantageous as it might speed recovery to normal cognition after surgery and enhance operating room (O.R.) efficiencies."
Although the brain circuits that drive the process of emerging from general anesthesia are not well understood, recent studies suggest that certain arousal pathways in the brain may be activated by certain drugs to promote consciousness. The authors previously reported that methylphenidate (Ritalin), a drug used to treat attention deficit hyperactivity disorder, awakened rats from general anesthesia by activating dopamine-releasing pathways.
In the current study, rats were given the general anesthetics isoflurane or propofol. Once unconscious, researchers performed targeted electrical stimulation, through implanted steel electrodes, on the two major regions of the rats’ brains that contain dopamine-releasing cells – the VTA (the area of the brain that controls cognition, motivation and reward in humans) and the substantia nigra, which controls movement.
Researchers found that electrical stimulation of the VTA caused the rats to regain consciousness, suggesting that dopamine released from cells in this area of the brain is likely involved in arousal. Interestingly, electrical stimulation of the VTA had an effect similar to that of the drug methylphenidate in restoring consciousness after anesthesia.
"We now have evidence that dopamine released by cells in the VTA is mainly responsible for the awakening effect seen with methylphenidate," said Dr. Solt. "Because dopamine-releasing cells in the VTA are important for cognition, we may be able to use drugs that act on this region not only to induce consciousness in anesthetized patients, but to potentially treat common postoperative emergence-related problems such as delirium and restore cognitive function."
Recent published research in the Journal of Clinical Investigation demonstrates how changes in dopamine signaling and dopamine transporter function are linked to neurological and psychiatric diseases, including early-onset Parkinsonism and attention deficit hyperactivity disorder (ADHD).
"The present findings should provide a critical basis for further exploration of how dopamine dysfunction and altered dopamine transporter function contribute to brain disorders" said Michelle Sahai, a postdoctoral associate at the Weill Cornell Medical College of Cornell University, adding "it also contributes to research efforts developing new ways to help the millions of people suffering."
Sahai is also studying the effects of cocaine, a widely abused substance with psychostimulant effects that targets the dopamine transporter. She and her colleagues expect to release these specific findings within the next year.
Losing Control
Dopamine is a neurotransmitter that plays an important role in our cognitive, emotional, and behavioral functioning. When activated from outside stimuli, nerve cells in the brain release dopamine, causing a chain reaction that releases even more of this chemical messenger.
To ensure that this doesn’t result in an infinite loop of dopamine production, a protein called the dopamine transporter reabsorbs the dopamine back into the cell to terminate the process. As dopamine binds to its transporter, it is returned to the nerve cells for future use.
However, cocaine and other drugs like amphetamine, completely hijack this well-balanced system.
"When cocaine enters the bloodstream, it does not allow dopamine to bind to its transporter, which results in a rapid increase in dopamine levels," Sahai explained.
The competitive binding and subsequent excess dopamine is what causes euphoria, increased energy, and alertness. It also contributes to drug abuse and addiction.
To further understand the effects of drug abuse, Sahai and other researchers in the Harel Weinstein Lab at Cornell are delving into drug interactions on a molecular level.
Using supercomputer resources, she is able to observe the binding of dopamine and various drugs to a 3D model of the dopamine transporter on a molecular level. According to Sahai, the work requires very long simulations in terms of microseconds and seconds to understand how drugs interact with the transporters.
Through the Extreme Science and Engineering Discovery Environment (XSEDE), a virtual cyberinfrastructure that provides researchers access to computing resources, Sahai performs these simulations on Stampede, the world’s 7th fastest supercomputer, at the Texas Advanced Computing Center (TACC).
"XSEDE-allocated resources are fundamental to helping us understand of how drugs work. There’s no way we could perform these simulations on the machines we have in house. Through TACC as an XSEDE service provider, we can also expect an exponential increase in computational results, and good customer service and feedback."
Ultimately, Sahai’s research will contribute to an existing body of work that is attempting to develop a cocaine binding inhibitor without suppressing the dopamine transporter.
"If we can understand how drugs bind to the dopamine transporter, then we can better understand drug abuse and add information on what’s really important in designing therapeutic strategies to combat addiction," Sahai said.
A Common Link in the Research
While Sahai is still working to understand drug abuse, her simulations of the dopamine transporter have contributed to published research on Parkinson’s disease and other neurological disorders.
In a collaborative study with the University of Copenhagen, Copenhagen University Hospital, and other research groups in the U.S. and Europe, researchers revealed the first known link between de novo mutations in the dopamine transporter and Parkinsonism in adults.
The study found that mutations can produce typical effects including debilitating tremors, major loss of motor control, and depression. The study also provides additional support for the idea that dopamine transporter mutations are a risk factor for attention deficit hyperactivity disorder (ADHD).
After identifying the dopamine transporter as the mutated gene linked to Parkinson’s, researchers once again turned to the Harel Weinstein Lab due to its long-standing interest and investment in studying the human dopamine transporter.
Sahai’s simulations using XSEDE and TACC’s Stampede supercomputer supported clinical trials by offering greater insight into how the dopamine transporter is involved in neurological disorders.
"This research is very important to me," Sahai said. "I was able to look at the structure of the dopamine transporter on behalf of experimentalists and understand how irregularities in this protein are harming an actual person, instead of just looking at something isolated on a computer screen."
While there is currently no cure for Parkinson’s disease, a deeper understanding of the specific mechanisms behind it will help the seven to ten million people afflicted with the disease.
"Like my work on drug abuse, the end goal is thinking about how we can help people. And it all comes back to drug design," Sahai said.