Posts tagged dopamine

To flexibly deal with our ever-changing world, we need to learn from both the negative and positive consequences of our behaviour. In other words, from punishment and reward. Hanneke den Ouden from the Donders Institute in Nijmegen demonstrated that serotonin and dopamine related genes influence how we base our choices on past punishments or rewards. This influence depends on which gene variant you inherited from your parents. These results were published in Neuron on 20 November.

The brain chemicals dopamine and serotonin partly determine our sensitivity to reward and punishment. At least, this was a common assumption. Hanneke den Ouden and Roshan Cools investigated this assumption together with colleagues from the Donders Institute and New York University. Den Ouden explains: ‘We used a simple computer game to test the genetic influence of the genes DAT1 and SERT, as these genes influence dopamine and serotonin. We discovered that the dopamine gene affects how we learn from the long-term consequences of our choices, while the serotonin gene affects our choices in the short term.’

Online game

‘In nearly 700 people we analysed which variant of the SERT and the DAT1 genes they had’, Den Ouden describes. ‘Using an online game, we investigated how well people are able to adjust their choice strategy after receiving a reward or a punishment.’ The players would repeatedly choose one of two symbols. Symbol A usually resulted in a reward whereas symbol B usually resulted in punishment. Halfway through the game, these rules were reversed. The game allowed the researchers to measure how flexible people are in adjusting their choices when the rules change. But it also showed whether people impulsively change their choice when the computer happened to give misleading feedback.

Different genes, different strategies

Den Ouden: ‘Different players use different strategies, which depend on their genetic material. People’s tendency to change their choice immediately after receiving a punishment depends on which serotonin gene variant they inherited from their parents. The dopamine gene variant, on the other hand, exerts influence on whether people can stop themselves making the choice that was previously rewarded, but no longer is.’

This study shows that dopamine and serotonin are important for different forms of flexibility associated with receiving reward and punishment. Many neuropsychiatric disorders caused by abnormal dopamine and/or serotonin levels are associated with forms of inflexibility, for example addiction, anxiety, or Parkinson’s disease. So this study not only tells us more about the heritability of our choice behaviour; a better understanding of the relationship between brain chemicals and behaviour in healthy people will ultimately help to provide us with better insight into these neuropsychiatric disorders.

(Source: ru.nl)

Studies have shown that resveratrol, a natural compound found in colored vegetables, fruits and especially grapes, may minimize the impact of Parkinson’s disease, stroke and Alzheimer’s disease in those who maintain healthy diets or who regularly take resveratrol supplements. Now, researchers at the University of Missouri have found that resveratrol may also block the effects of the highly addictive drug, methamphetamine.

(Image: Wikipedia)

Dennis Miller, associate professor in the Department of Psychological Sciences in the College of Arts & Science and an investigator with the Bond Life Sciences Center, and researchers in the Center for Translational Neuroscience at MU, study therapies for drug addiction and neurodegenerative disorders. Their research targets treatments for methamphetamine abuse and has focused on the role of the neurotransmitter dopamine in drug addiction. Dopamine levels in the brain surge after methamphetamine use; this increase is associated with the motivation to continue using the drug, despite its adverse consequences. However, with repeated methamphetamine use, dopamine neurons may degenerate causing neurological and behavioral impairments, similar to those observed in people with Parkinson’s disease.

“Dopamine is critical to the development of methamphetamine addiction—the transition from using a drug because one likes or enjoys it to using the drug because one craves or compulsively uses it,” Miller said. “Resveratrol has been shown to regulate these dopamine neurons and to be protective in Parkinson’s disease, a disorder where dopamine neurons degenerate; therefore, we sought to determine if resveratrol could affect methamphetamine-induced changes in the brain.”

Using procedures established by Parkinson’s and Alzheimer’s disease research, rats received resveratrol once a day for seven days in about the same concentration as a human would receive from a healthy diet. After a week of resveratrol, researchers measured how much dopamine was released by methamphetamine. Researchers found that resveratrol significantly diminished methamphetamine’s ability to increase dopamine levels in the brain. Furthermore, resveratrol diminished methamphetamine’s ability to increase activity in mice, a behavior that models the hyperactivity observed in people that use the stimulant.

“People are encouraged by physicians and dieticians to include resveratrol-containing products in their diet and protection against methamphetamine’s harmful effects may be an added bonus,” Miller said. “Additionally, there are no consistently effective treatments to help people who are dependent on methamphetamine. Our initial research suggests that resveratrol could be included in a treatment regimen for those addicted to methamphetamine and it has potential to decrease the craving and desire for the drug. Resveratrol is found in good, colorful foods, and has few side effects. We all ought to consume resveratrol for good brain health; our research suggests it may also prevent the changes in the brain that occur with the development of drug addiction.”

(Source: munews.missouri.edu)

A genetic defect that profoundly affects speech in humans also disrupts the ability of songbirds to sing effective courtship tunes. This defect in a gene called FoxP2 renders the brain circuitry insensitive to feel-good chemicals that serve as a reward for speaking the correct syllable or hitting the right note, a recent study shows. 

The research, which was conducted in adult zebrafinches, gives insight into how this genetic mutation impairs a network of nerve cells to cause the stuttering and stammering typical of people with FoxP2 mutations. It appears Nov. 21 in an early online edition of the journal Neuron.

"Our results integrate a lot of different observations that have accrued on the FoxP2 mutation and cast a different perspective on what this mutation is doing," said Richard Mooney, Ph.D., the George Barth Geller professor of neurobiology at Duke University School of Medicine and a member of the Duke Institute for Brain Sciences. "FoxP2 mutations do not simply result in a cognitive or learning deficit, but also produce an ongoing motor deficit. Individuals with these mutations can still learn and can still improve; it is just harder for them to reliably hit the right mark." 

About 15 years ago, researchers discovered a British family with many members suffering from severe speech and language deficits. Geneticists eventually pinned down the culprit — a gene called forkhead box transcription factor or FoxP2 — that was mutated in all the affected individuals. The discovery led many to believe FoxP2 was a “language gene” that granted humans the ability to speak. But further studies showed that the gene wasn’t unique to humans, and in fact was conserved among all vertebrates, including songbirds. 

Though the gene is present in every cell, it is “active,” or turned on, mostly in brain cells, particularly ones residing in a region deep within the brain known as the basal ganglia. This region is dysfunctional in Tourette syndrome, known for its vocal tics and outbursts, and is also shrunk in individuals with FoxP2 mutations. 

To explore the complex circuitry involved in these deficits, Mooney and his former graduate student Malavika Murugan, Ph.D., decided to replicate the human mutation in this region of the brain in songbirds. Zebrafinches start learning how to sing 30 days after they hatch, listening to a male tutor and then practicing thousands of times a day until, 60 days later, they are able to make a very good copy of the tutor’s song. As good as that copy is at day 90, the male finch’s song gets even more precise when he “directs” it to a female as part of courtship. 

To investigate the role of FoxP2 in the generation of this directed song, Murugan introduced specifically targeted sequences of RNA to suppress FoxP2 activity in the basal ganglia of male zebrafinches. The birds were placed in a glass cage that revealed a female sitting on the other side. Murugan then recorded sonograms of their song to capture the subtle vocal variations indistinguishable to the human ear when they produced directed songs at the female. 

Murugan found that though the genetically manipulated males had already learned how to sing, their ability to hit the right note repeatedly in the presence of a female — a behavior critical to attracting a mate — was subpar. This indicates that in songbirds, FoxP2 has an ongoing role in vocal control separate from a role in learning, a distinction that has not been possible to make in humans with FOXP2 mutations. 

Having deduced the behavior associated with this genetic mutation, the researchers then identified underlying neural deficits by recording brain activity in birds with normal and altered FoxP2 genes. In one set of experiments, Murugan sent an electrical signal into the input side of the basal ganglia pathway and then used an electrode on the output side to measure how quickly the signal traveled from one side to the other. Surprisingly, the signal moved more quickly through the basal ganglia of FoxP2 mutant songbirds than it did in songbirds with the functional gene. 

Murugan also found that dopamine, an important brain chemical involved in brain signaling and the reinforcement of learned behaviors like singing or playing sports, could influence how fast basal ganglia signals propagated in birds with normal but not mutant forms of FoxP2.  

"This switch between undirected and directed song is actually dependent on the influx of this neurotransmitter called dopamine," said Murugan, first author of the study. "So what we think is happening is knocking down FoxP2 makes the male incapable of reducing song variability in the presence of a female. An adult male sees the female, there is an influx of dopamine, but because the system is insensitive, the dopamine has no effect and the adult male continues to sing a variable tune." In juveniles, the inability to constrain variability and to respond to dopamine could also account for poor learning.

Though the researchers are cautious not to draw too many parallels between their findings in birds and the deficits in humans, they think their study does highlight the value of songbirds in studying human behaviors and disease.

"Birds are one of the few non-human animals that learn to vocalize," said Mooney. "They produce songs for courtship that they culturally transmit from one generation to the next. Their brains might be a thousandth the size of ours, but in this one dimension, vocal learning, they are our equal."

(Source: today.duke.edu)

Scientists at Rutgers and Emory universities have discovered that a compound often emitted by mold may be linked to symptoms of Parkinson’s disease.

Arati Inamdar and Joan Bennett, researchers in the School of Environmental and Biological Sciences at Rutgers, used fruit flies to establish the connection between the compound  – popularly known as mushroom alcohol – and the malfunction of two genes involved in the packaging and transport of dopamine, the chemical released by nerve cells to send messages to other nerve cells in the brain.

The findings were published online today in the Proceedings of the National Academy of Sciences.

“Parkinson’s has been linked to exposure to environmental toxins, but the toxins were man-made chemicals,” Inamdar said. “In this paper, we show that biologic compounds have the potential to damage dopamine and cause Parkinson’s symptoms.”

For co-author Bennett, the research was more than academic. Bennett was working at Tulane University in New Orleans when Hurricane Katrina struck the Gulf Coast in 2005. Her flooded house became infested with molds, which she collected in samples, wearing a mask, gloves and protective gear.

“I felt horrible – headaches, dizziness, nausea,” said Bennett, now a professor of plant pathology and biology at Rutgers. “I knew something about ‘sick building syndrome’ but until then I didn’t believe in it.  I didn’t think it would be possible to breathe in enough mold spores to get sick.” That is when she formed her hypothesis that volatiles might be involved.

Inamdar, who uses fruit flies in her research, and Bennett began their study shortly after Bennett arrived at Rutgers. Bennett wanted to understand the connection between molds and symptoms like those she had experienced following Katrina. 

The scientists discovered that the volatile organic compound 1-octen-3-ol, otherwise known as mushroom alcohol, can cause movement disorders in flies, similar to those observed in the presence of pesticides, such as paraquat and rotenone. Further, they discovered that it attacked two genes that deal with dopamine, degenerating the neurons and causing the Parkinson’s-like symptoms. 

Studies indicate that Parkinson’s disease – a progressive disease of the nervous system marked by tremor, muscular rigidity and slow, imprecise movement — is increasing in rural areas, where it’s usually attributed to pesticide exposure. But rural environments also have a lot of mold and mushroom exposure.

“Our work suggests that 1-octen-3-ol might also be connected to the disease, particularly for people with a genetic susceptibility to it,” Inamdar said. “We’ve given the epidemiologists some new avenues to explore.”

(Source: news.rutgers.edu)

A pilot study by a multi-disciplinary team of investigators at Georgetown University suggests that a simple dot test could help doctors gauge the extent of dopamine loss in individuals with Parkinson’s disease (PD). Their study is being presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience.

“It is very difficult now to assess the extent of dopamine loss — a hallmark of Parkinson’s disease — in people with the disease,” says lead author Katherine R. Gamble, a psychology PhD student working with two Georgetown psychologists, a psychiatrist and a neurologist. “Use of this test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,” she adds.

Gamble works in the Cognitive Aging Laboratory, led by the study’s senior investigator, Darlene Howard, PhD, Davis Family Distinguished Professor in the department of psychology and member of the Georgetown Center for Brain Plasticity and Recovery.

The TLT tests implicit learning, a type of learning that occurs without awareness or intent, which relies on the caudate nucleus, an area of the brain affected by loss of dopamine.

The test is a sequential learning task that does not require complex motor skills, which tend to decline in people with PD. In the TLT, participants see four open circles, see two red dots appear, and are asked to respond when they see a green dot appear. Unbeknownst to them, the location of the first red dot predicts the location of the green target. Participants learn implicitly where the green target will appear, and they become faster and more accurate in their responses.

Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, PD participants implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively impact that learning compared to healthy older adults.

“Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” says Gamble.

In this study of 27 people with PD, the research team is now testing how implicit learning may differ by different PD stages and drug doses.

“This work is important in that it may be a non-invasive way to evaluate the level of dopamine deficiency in PD patients, and which may lead to future ways to improve clinical treatment of PD patients,” explains Steven E. Lo, MD, associate professor of neurology at Georgetown University Medical Center, and a co-author of the study.

They hope the TLT may one day be a tool to help determine levels of dopamine loss in PD.

(Source: explore.georgetown.edu)

Research from Oregon Health & Science University’s Vollum Institute, published in the current issue of Nature (1, 2), is giving scientists a never-before-seen view of how nerve cells communicate with each other. That new view can give scientists a better understanding of how antidepressants work in the human brain — and could lead to the development of better antidepressants with few or no side effects.

The article in today’s edition of Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist at OHSU’s Vollum Institute and a Howard Hughes Medical Institute Investigator. The article describes research that gives a better view of the structural biology of a protein that controls communication between nerve cells. The view is obtained through special structural and biochemical methods Gouaux uses to investigate these neural proteins.

The Nature article focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain. Dopamine is an essential neurotransmitter for the human body’s central nervous system; abnormal levels of dopamine are present in a range of neurological disorders, including Parkinson’s disease, drug addiction, depression and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure.

The Gouaux lab’s more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work.

The more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they’re trying to target — and not create side effects caused by a broader blast at the brain proteins.

"By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects," said Gouaux.

Gouaux’s latest dopamine transporter research is also important because it was done using the molecule from fruit flies, a dopamine transporter that is much more similar to those in humans than the bacteria models that previous studies had used.

The dopamine transporter article was one of two articles Gouaux had published in today’s edition of Nature. The other article also dealt with a modified amino acid transporter that mimics the mammalian neurotransmitter transporter proteins targeted by antidepressants. It gives new insights into the pharmacology of four different classes of widely used antidepressants that act on certain transporter proteins, including transporters for dopamine, serotonin and noradrenaline. The second paper in part was validated by findings of the first paper — in how an antidepressant bound itself to a specific transporter.

"What we ended up finding with this research was complementary and mutually reinforcing with the other work — so that was really important," Gouaux said. "And it told us a great deal about how these transporters work and how they interact with the antidepressant molecules."

(Source: ohsu.edu)

When you experience something, neurons in the brain send chemical signals called neurotransmitters across synapses to receptors on other neurons. How well that process unfolds determines how you comprehend the experience and what behaviors might follow. In people with Fragile X syndrome, a third of whom are eventually diagnosed with Autism Spectrum Disorder, that process is severely hindered, leading to intellectual impairments and abnormal behaviors.

In a study published in the online journal PLoS One, a team of UNC School of Medicine researchers led by pharmacologist C.J. Malanga, MD, PhD, describes a major reason why current medications only moderately alleviate Fragile X symptoms. Using mouse models, Malanga discovered that three specific drugs affect three different kinds of neurotransmitter receptors that all seem to play roles in Fragile X. As a result, current Fragile X drugs have limited benefit because most of them only affect one receptor.

Nearly one million people in the United States have Fragile X Syndrome, which is the result of a single mutated gene called FMR1. In people without Fragile X, the gene produces a protein that helps maintain the proper strength of synaptic communication between neurons. In people with Fragile X, FMR1 doesn’t produce the protein, the synaptic connection weakens, and there’s a decrease in synaptic input, leading to mild to severe learning disabilities and behavioral issues, such as hyperactivity, anxiety, and sensitivity to sensory stimulation, especially touch and noise.

More than two decades ago, researchers discovered that – in people with mental and behavior problems – a receptor called mGluR5 could not properly regulate the effect of the neurotransmitter, glutamate. Since then, pharmaceutical companies have been trying to develop drugs that target glutamate receptors. “It’s been a challenging goal,” Malanga said. “No one so far has made it work very well, and kids with Fragile X have been illustrative of this.”

But there are other receptors that regulate other neurotransmitters in similar ways to mGluR5. And there are drugs already available for human use that act on those receptors. So Malanga’s team checked how those drugs might affect mice in which the Fragile X gene has been knocked out.

By electrically stimulating specific brain circuits, Malanga’s team first learned how the mice perceived reward. The mice learned very quickly that if they press a lever, they get rewarded via a mild electrical stimulation. Then his team provided a drug molecule that acts on the same reward circuitry to see how the drugs affect the response patterns and other behaviors in the mice.

His team studied one drug that blocked dopamine receptors, another drug that blocked mGluR5 receptors, and another drug that blocked mAChR1, or M1, receptors. Three different types of neurotransmitters – dopamine, glutamate, and acetylcholine – act on those receptors. And there were big differences in how sensitive the mice were to each drug.

“Turns out, based on our study and a previous study we did with my UNC colleague Ben Philpot, that Fragile X mice and Angelman Syndrome mice are very different,” Malanga said. “And how the same pharmaceuticals act in these mouse models of Autism Spectrum Disorder is very different.”

Malanga’s finding suggests that not all people with Fragile X share the same biological hurdles. The same is likely true, he said, for people with other autism-related disorders, such as Rett syndrome and Angelman syndrome.

“Fragile X kids likely have very different sensitivities to prescribed drugs than do other kids with different biological causes of autism,” Malanga said.

(Source: news.unchealthcare.org)