The Dopamine Transporter

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.

This is Your Brain on Drugs

Funded by a $1 million award from the Keck Foundation, biomedical researchers at UCSB will strive to find out who could be more vulnerable to addiction

We’ve all heard the term “addictive personality,” and many of us know individuals who are consistently more likely to take the extra drink or pill that puts them over the edge. But the specific balance of neurochemicals in the brain that spurs him or her to overdo it is still something of a mystery.

“There’s not really a lot we know about specific molecules that are linked to vulnerability to addiction,” said Tod Kippin, a neuroscientist at UC Santa Barbara who studies cocaine addiction. In a general sense, it is understood that animals — humans included — take substances to derive that pleasurable rush of dopamine, the neurochemical linked with the reward center of the brain. But, according to Kippin, that dopamine rush underlies virtually any type of reward animals seek, including the kinds of urges we need to have in order to survive or propagate, such as food, sex or water. Therefore, therapies that deal with that reward system have not been particularly successful in treating addiction.

However, thanks to a collaboration between UCSB researchers Kippin; Tom Soh, professor of mechanical engineering and of materials; and Kevin Plaxco, professor of chemistry and biochemistry — and funding from a $1 million grant from the W. M. Keck Foundation — the neurochemistry of addiction could become a lot less mysterious and a lot more specific. Their study, “Continuous, Real-Time Measurement of Psychoactive Molecules in the Brain,” could, in time, lead to more effective therapies for those who are particularly inclined toward addictive behaviors.

“The main purpose is to try to identify individuals that would be vulnerable to drug addiction based on their initial neurochemistry,” said Kippin. “The idea is that if we can identify phenotypes — observable characteristics — that are vulnerable to addiction and then understand how drugs change the neurochemistry related to that phenotype, we’ll be in a better position to develop therapeutics to help people with that addiction.”

To identify these addiction-prone neurochemical profiles, the researchers will rely on technology they recently developed, a biosensor that can track the concentration of specific molecules in vivo, in real time. One early incarnation of this device was called MEDIC (Microfluidic Electrochemical Detector for In vivo Concentrations). Through artificial DNA strands called aptamers, MEDIC could indicate the concentration of target molecules in the bloodstream. 

“Specifically, the DNA molecules are modified so that when they bind their specific target molecule they begin to transfer electrons to an underlying electrode, producing an easily measurable current,” said Plaxco. Prior to the Keck award, the team had shown that this technology could be used to measure specific drugs continuously and in real time in blood drawn from a subject via a catheter. With Keck funding, “the team is hoping to make the leap to measurements performed directly in vivo. That is, directly in the brains of test subjects,” said Plaxco.

For this study, the technology would be modified for use in the brain tissue of awake, ambulatory animals, whose neurochemical profiles would be measured continuously and in real time. The subjects would then be allowed to self-dose with cocaine, while the levels of the drug in their brain are monitored. Also monitored are concomitant changes in the animal’s neurochemistry or drug-seeking (or other) behaviors.

“The key aspect of it is understanding the timing of the neurochemical release,” said Kippin. “What are the changes in neurochemistry that causes the animals to take the drug versus those that immediately follow consumption of the drug?”

Among techniques for achieving this goal, a single existing technology allows scientists to monitor more than one target molecule at a time (e.g., a drug, a metabolite, and a neurotransmitter). However, Kippin noted, it provides an average of one data point about every 20 minutes, which is far slower than the time course of drug-taking behaviors and much less than the sub-second timescale over which the brain responds to drugs. With the implantable biosensor the team has proposed, it would be possible not only to track how the concentration of neurochemicals shift in relation to addictive behavior in real time, but also to simultaneously monitor the concentrations of several different molecules.

“One of our hypotheses about what makes someone vulnerable to addiction is the metabolism of a drug to other active molecules so that they may end up with a more powerful, more rewarding pharmacological state than someone with a different metabolic profile,” Kippin said. “It’s not enough to understand the levels of the compound that is administered; we have to understand all the other compounds that are produced and how they’re working together.”

The implantable biosensor technology also has the potential to go beyond cocaine and shed light on addictions to other substances such as methamphetamines or alcohol. It also could explore behavioral impulses behind obesity, or investigate how memory works, which could lead to further understanding of diseases such as Alzheimers.

Brain activity in sex addiction mirrors that of drug addiction

Pornography triggers brain activity in people with compulsive sexual behaviour – known commonly as sex addiction – similar to that triggered by drugs in the brains of drug addicts, according to a University of Cambridge study published in the journal PLOS ONE. However, the researchers caution that this does not necessarily mean that pornography itself is addictive.

Although precise estimates are unknown, previous studies have suggested that as many as one in 25 adults is affected by compulsive sexual behaviour, an obsession with sexual thoughts, feelings or behaviour which they are unable to control. This can have an impact on a person’s personal life and work, leading to significant distress and feelings of shame. Excessive use of pornography is one of the main features identified in many people with compulsive sexual behaviour. However, there is currently no formally accepted definition of diagnosing the condition.

In a study funded by the Wellcome Trust, researchers from the Department of Psychiatry at the University of Cambridge looked at brain activity in nineteen male patients affected by compulsive sexual behaviour and compared them to the same number of healthy volunteers. The patients started watching pornography at earlier ages and in higher proportions relative to the healthy volunteers.

“The patients in our trial were all people who had substantial difficulties controlling their sexual behaviour and this was having significant consequences for them, affecting their lives and relationships,” explains Dr Valerie Voon, a Wellcome Trust Intermediate Clinical Fellow at the University of Cambridge. “In many ways, they show similarities in their behaviour to patients with drug addictions. We wanted to see if these similarities were reflected in brain activity, too.”

The study participants were shown a series of short videos featuring either sexually explicit content or sports whilst their brain activity was monitored using functional magnetic resonance imaging (fMRI), which uses a blood oxygen level dependent (BOLD) signal to measure brain activity.

The researchers found that three regions in particular were more active in the brains of the people with compulsive sexual behaviour compared with the healthy volunteers. Significantly, these regions – the ventral striatum, dorsal anterior cingulate and amygdala – were regions that are also particularly activated in drug addicts when shown drug stimuli. The ventral striatum is involved in processing reward and motivation, whilst the dorsal anterior cingulate is implicated in anticipating rewards and drug craving. The amygdala is involved in processing the significance of events and emotions.

The researchers also asked the participants to rate the level of sexual desire that they felt whilst watching the videos, and how much they liked the videos. Drug addicts are thought to be driven to seek their drug because they want – rather than enjoy – it. This abnormal process is known as incentive motivation, a compelling theory in addiction disorders.

As anticipated, patients with compulsive sexual behaviour showed higher levels of desire towards the sexually explicit videos, but did not necessarily rate them higher on liking scores. In the patients, desire was also correlated with higher interactions between regions within the network identified – with greater cross-talk between the dorsal cingulate, ventral striatum and amygdala – for explicit compared to sports videos.

Dr Voon and colleagues also found a correlation between brain activity and age – the younger the patient, the greater the level of activity in the ventral striatum in response to pornography. Importantly, this association was strongest in individuals with compulsive sexual behaviour. The frontal control regions of the brain – essentially, the ‘brakes’ on our compulsivity – continue to develop into the mid-twenties and this imbalance may account for greater impulsivity and risk taking behaviours in younger people. The age-related findings in individuals with compulsive sexual behaviours suggest that the ventral striatum may be important in developmental aspects of compulsive sexual behaviours in a similar fashion as it is in drug addictions, although direct testing of this possibility is needed.

“There are clear differences in brain activity between patients who have compulsive sexual behaviour and healthy volunteers. These differences mirror those of drug addicts,” adds Dr Voon. “Whilst these findings are interesting, it’s important to note, however, that they could not be used to diagnose the condition. Nor does our research necessarily provide evidence that these individuals are addicted to porn – or that porn is inherently addictive. Much more research is required to understand this relationship between compulsive sexual behaviour and drug addiction.”

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, says: “Compulsive behaviours, including watching porn to excess, over-eating and gambling, are increasingly common. This study takes us a step further to finding out why we carry on repeating behaviours that we know are potentially damaging to us. Whether we are tackling sex addiction, substance abuse or eating disorders, knowing how best, and when, to intervene in order to break the cycle is an important goal of this research.”

Addiction starts with an overcorrection in the brain

The National Institutes of Health has turned to neuroscientists at the nation’s most “Stone Cold Sober” university for help finding ways to treat drug and alcohol addiction.

Brigham Young University professor Scott Steffensen and his collaborators have published three new scientific papers that detail the brain mechanisms involved with addictive substances. And the NIH thinks Steffensen’s on the right track, as evidenced by a $2-million grant that will help fund projects in his BYU lab for the next five years.

“Addiction is a brain disease that could be treated like any other disease,” Steffensen said. “I wouldn’t be as motivated to do this research, or as passionate about the work, if I didn’t think a cure was possible.” 

Steffensen’s research suggests that the process of a brain becoming addicted is similar to a driver overcorrecting a vehicle. When drugs and alcohol release unnaturally high levels of dopamine in the brain’s pleasure system, oxidative stress occurs in the brain.

Steffensen and his collaborators have found that the brain responds by generating a protein called BDNF (brain derived neurotrophic factor). This correction suppresses the brain’s normal production of dopamine long after someone comes down from a high. Not having enough dopamine is what causes the pains, distress and anxiety of withdrawal.

“The body attempts to compensate for unnatural levels of dopamine, but a pathological process occurs,” Steffensen said. “We think it all centers around a subset of neurons that ordinarily put the brakes on dopamine release.”

A group of undergraduate students work in Steffensen’s lab along with post-doctoral fellows and graduate students. Jennifer Blanchard Mabey, a graduate student in neuroscience, co-authored a paper about withdrawal that is in the current issue of The Journal of Neuroscience.

“It’s rewarding to see that your research efforts place another small piece in the enormous addiction puzzle,” said Mabey.

A separate study, co-authored by Steffensen and Ph.D. candidates Nathan Schilaty and David Hedges, explains how nicotine and alcohol interact in the brain.

“Addiction is a huge concern in our society and is very misunderstood,” Schilaty said. “Our research is helping us to formulate ideas on how we can better help these individuals through non-invasive and non-pharmacological means.”

Eun Young Jang, a post-doctoral fellow in Steffensen’s lab, authored a third paper for Addiction Biology describing the effects of cocaine addiction on the brain’s reward circuitry.

In these three research papers, dopamine is the common thread.

“I am optimistic that in the near future medical science will be able to reverse the brain changes in dopamine transmission that occur with drug dependence and return an ‘addict’ to a relatively normal state,” Steffensen said. “Then the addict will be in a better position to make rational decisions regarding their behavior and will be empowered to remain drug free.”

New insights could boost treatment for P addiction

A Kiwi researcher’s discovery of new ways methamphetamine can alter the brain could help the development of new drug-based therapies for addiction treatment.

In 2009, New Zealand had one of the highest rates of P users in the world, and today, more than 25,000 Kiwis were estimated to still be using the drug.

Now, new research by a Victoria of University of Wellington graduate has provided valuable insights into how the brain’s natural reward pathways are strongly stimulated following exposure to methamphetamine.

Read more

A Brain Region for Resisting Alcohol’s Allure

As recovering spring breakers are regretting binge drinking escapades, it may be hard for them to appreciate that there is a positive side to the nausea, sleepiness, and stumbling. University of Utah neuroscientists report that when a region of the brain called the lateral habenula is chronically inactivated in rats, they repeatedly drink to excess and are less able to learn from the experience. The study, published online in PLOS ONE on April 2, has implications for understanding behaviors that drive alcohol addiction.

While complex societal pressures contribute to alcoholism, physiological factors are also to blame. Alcohol is a drug of abuse, earning its status because it tickles the reward system in the brain, triggering the release of feel-good neurotransmitters. The dreaded outcomes of overindulging serve the beneficial purpose of countering the pull of temptation, but little is understood about how those mechanisms are controlled.

U of U professor of neurobiology and anatomy Sharif Taha, Ph.D., and colleagues, tipped the balance that reigns in addictive behaviors by inactivating in rats a brain region called the lateral habenula. When the rats were given intermittent access to a solution of 20% alcohol over several weeks, they escalated their alcohol drinking more rapidly, and drank more heavily than control rats.

“In people, escalation of intake is what eventually separates a social drinker from someone who becomes an alcoholic,” said Taha. “These rats drink amounts that are quite substantial. Legally they would be drunk if they were driving.”

The lateral habenula is activated by bad experiences, suggesting that without this region the rats may drink more because they fail to learn from the negative outcomes of overindulging. The investigators tested the idea by giving the rats a desirable, sweet juice then injecting them with a dose of alcohol large enough to cause negative effects.

“It’s the same kind of learning that mediates your response in food poisoning. You taste something and then you get sick, and then of course you avoid that food in future meals,” explained Taha.

Yet rats with an inactivated lateral habenula sought out the juice more than control animals, even though it meant a repeat of the bad experience.

“The way I look at it is the rewarding effects of drinking alcohol compete with the aversive effects,” explained Andrew Haack, who is co-first author on the study with Chandni Sheth, both neuroscience graduate students. “When you take the aversive effects away, which is what we did when we inactivated the lateral habenula, the rewarding effects gain more purchase, and so it drives up drinking behavior.”

The group’s findings may help explain results from previous clinical investigations demonstrating that men who were less sensitive to the negative effects of alcohol drank more heavily, and were more likely to become problem drinkers later in life.

The researches think the lateral habenula likely works in one of two ways. The region may regulate how badly an individual feels after over-drinking. Alternatively, it may control how well an individual learns from their bad experience. Future work will resolve between the two.

“If we can understand the brain circuits that control sensitivity to alcohol’s aversive effects, then we can start to get a handle on who may become a problem drinker,” said Taha.

Can ‘love hormone’ protect against addiction?

Researchers at the University of Adelaide say addictive behaviour such as drug and alcohol abuse could be associated with poor development of the so-called “love hormone” system in our bodies during early childhood.

The groundbreaking idea has resulted from a review of worldwide research into oxytocin, known as the “love hormone” or “bonding drug” because of its important role in enhancing social interactions, maternal behaviour and partnership.

This month’s special edition of the international journal Pharmacology, Biochemistry and Behavior deals with the current state of research linking oxytocin and addiction, and has been guest edited by Dr Femke Buisman-Pijlman from the University of Adelaide’s School of Medical Sciences.

Dr Buisman-Pijlman, who has a background in both addiction studies and family studies, says some people’s lack of resilience to addictive behaviours may be linked to poor development of their oxytocin systems.

"We know that newborn babies already have levels of oxytocin in their bodies, and this helps to create the all-important bond between a mother and her child. But our oxytocin systems aren’t fully developed when we’re born - they don’t finish developing until the age of three, which means our systems are potentially subject to a range of influences both external and internal," Dr Buisman-Pijlman says.

She says the oxytocin system develops mainly based on experiences.

"The main factors that affect our oxytocin systems are genetics, gender and environment. You can’t change the genes you’re born with, but environmental factors play a substantial role in the development of the oxytocin system until our systems are fully developed," Dr Buisman-Pijlman says.

"Previous research has shown that there is a high degree of variability in people’s oxytocin levels. We’re interested in how and why people have such differences in oxytocin, and what we can do about it to have a beneficial impact on people’s health and wellbeing," she says.

She says studies show that some risk factors for drug addiction already exist at four years of age. “And because the hardware of the oxytocin system finishes developing in our bodies at around age three, this could be a critical window to study. Oxytocin can reduce the pleasure of drugs and feeling of stress, but only if the system develops well.”

Her theory is that adversity in early life is key to the impaired development of the oxytocin system. “This adversity could take the form of a difficult birth, disturbed bonding or abuse, deprivation, or severe infection, to name just a few factors,” Dr Buisman-Pijlman says.

"Understanding what occurs with the oxytocin system during the first few years of life could help us to unravel this aspect of addictive behaviour and use that knowledge for treatment and prevention."

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.