Researchers find epigenetic tie to neuropsychiatric disorders

Dysfunction in dopamine signaling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioral and physiological functions regulated in the prefrontal cortex.

The study, led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics, appears online in the journal Molecular Psychiatry.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signaling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signaling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviors in the mutant mice and that prolonged treatment with a dopamine activator restored regular signaling, pointing to one possible therapeutic approach.

The researchers are continuing their work to gain more insights into the genes altered by this dysfunctional dopamine signaling.

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201467a.html

This post brought to you in part by

AmeriGlide.com

New approach for those with Tourette Syndrome being tested in clinical trials

Medical researchers are hopeful that a new investigational drug being tested in clinical trials will prove to be an effective treatment for Tourette Syndrome – an inherited, misdiagnosed, misunderstood neurological disorder that presents in childhood and causes involuntary motor and vocal tics.

The new drug, AZD5213, targets the human histamine H3 receptor.  In the brain, this receptor regulates neurotransmitters associated with Tourette Syndrome – including dopamine and histamine.A mutation that affects histamine synthesis was recently confirmed to be the cause of TS in a father and all eight of his children, a finding supported by research in mice.

If approved for treatment of Tourette, AZD5213 might represent an alternative to antipsychotics, which don’t work well in all patients and can cause serious negative side effects.  Discovered by AstraZeneca, AZD5213 has been shown to have a favorable safety profile, with no serious drug-related side effects reported in Phase 1 and Phase 2 clinical trials completed at the time of this report.

“AZD5213 represents an exciting new approach to the treatment of Tourette Syndrome, and we are currently recruiting teenagers suffering from the disorder to participate in the clinical trial,” says Dr. Roger Kurlan, Director of the Movement Disorders Program at Overlook Medical Center’s Atlantic Neuroscience Institute in Summit, N.J.

Dr. Kurlan, who frequently collaborates with the NJ Center for Tourette Syndrome & Associated Disorders (NJCTS) in Somerville, N.J., is a leading expert in the treatment of Tourette and is one of approximately six medical researchers involved in the clinical trial.

AZD5213 already has been studied in other clinical trials, including those for Alzheimer’s disease. With Tourette Syndrome, which is associated with changes in brain chemistry that appear to cause the characteristic symptoms of the disorder, AZD5213 might be able to counteract these changes – with the potential to provide symptomatic relief with less of the negative side effects associated with existing treatments.  More than 200 human subjects have already received single or multiple doses of AZD5213, with no serious drug-related adverse side effects.

The clinical trial is a 6-month, multicenter, randomized, safety, tolerability, pharmacokinetic, and preliminary efficacy study of AZD5213 in adolescents 12 to 17 years of age with Tourette Syndrome. The trial includes an up to 21-day screening period, 6 months of once-daily treatment with placebo or AZD5213, and a 3-week follow-up period.

Because of the crossover design of the trial, all enrolled patients will receive AZD5213 for at least part of the trial. Approximately 24 subjects will be treated in this study.  Safety will be carefully ensured by a battery of safety tests administered at visits throughout the study, and efficacy will be determined by means of questionnaires designed to assess the severity of symptoms associated with Tourette Syndrome.

According to the Centers for Disease Control and Prevention (CDC), 1 in 100 children show signs of Tourette Syndrome. The disorder is three times as likely in boys as in girls, and most patients experience their worst symptoms in their early teen years. There is no cure, and symptoms can persist throughout life – although most patients see improvement as they approach and enter adulthood.

Exaggerated portrayals of Tourette Syndrome have been used for comic relief in films and TV shows, usually featuring characters who shout obscenities involuntarily. In reality, this type of verbal tic – known as coprolalia – is present in only 10 to 15 percent of those with TS.

“In real life, Tourette’s is no laughing matter,” Dr. Kurlan says. “These patients often struggle with self-esteem and socialization issues, which generally arise at a crucial time in their social development. Sadly, many are victims of bullying and the ridicule of their peers.”

Tourette’s is most often present in combination with other neurological disorders, such as attention deficit-hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD), and Tourette’s patients are commonly troubled by depression, anxiety and developmental delays.

This post brought to you in part by republicwireless.com

Brain activity changes in Tourette syndrome

Kevin Black

Scientists have known for years that abnormal activity involving a brain chemical called dopamine is somehow connected to the movements and vocalizations, or tics, associated with Tourette syndrome.

Now University neuroscience researchers have found that brain activity in these patients is abnormal during memory tasks as well.

The researchers also found that giving Tourette syndrome patients the drug levodopa, which is used to treat abnormal dopamine activity in conditions such as Parkinson’s disease, normalized brain activity during memory tasks.

“We’ve observed in the living brain a dopamine-sensitive abnormality in people with tics,” said principal investigator Kevin J. Black, M.D., assistant professor of psychiatry, of neurology and of radiology.

“That’s been hypothesized for 40 years, but this is the first time it’s been demonstrated. We actually have a direct demonstration of abnormal brain activation in people with Tourette syndrome that is corrected when they are given a dopamine-type medicine.”

The study is published online and will appear in the May issue of the journal Biological Psychiatry.

Using functional magnetic resonance imaging (fMRI), the researchers compared eight adults with Tourette syndrome to 10 healthy adults the same age and gender.

Brain scans were taken while participants performed a memory task that involved remembering and identifying letters on a computer screen.

The task measures working memory, a type of short-term memory that involves concentration on several things at once.

“We chose to look at the brain’s response to a working memory task because past research has shown that working memory could be affected by dopamine levels in the brain,” said first author Tamara Hershey, Ph.D., assistant professor of psychiatry and neurology.

“We also know dopamine is involved in tics, but if we had studied a task that involved movement, for example, the fact that some tics involve movement could have made it harder to interpret the differences in brain activity.”

In terms of speed and accuracy during the memory task, there were no differences between the two groups, but fMRI scans revealed that several brain areas were more active in Tourette syndrome patients than in healthy participants.

The clearest differences were in a brain region called the parietal cortex, at the top of the brain roughly in between the front and back of the head.

Tourette syndrome patients also had increased activity in the medial frontal gyrus and in the thalamus, which acts as the brain’s relay station between the outer layer, or cortex, and the rest of the nervous system.

“People with tics performed this task just as well as people without, so it’s not something that involves a difference in output,” Black said.

“Therefore, we believe any differences we saw in the fMRI scans reflect changes in the way the brain is working.”

To determine whether the results were related to dopamine abnormalities, Hershey, Black and their colleagues gave all participants an intravenous infusion of the drug levodopa.

When the two groups repeated the original working memory task, brain activity in healthy participants was unchanged.

In Tourette patients, however, the areas that had been abnormally overactive were substantially less active after treatment.

“Levodopa seems to normalize the excess activity we had seen in the parietal cortex in the group with tics,” Hershey said. “There were changes in activity in the other structures, too, but the changes in the parietal cortex were the most dramatic.”

Before decoding which brain scans belonged to which participants, Black looked at the patients’ medical histories and used a standard method of rating the severity of their illness.

He found that those with the most severe history of Tourette syndrome had the largest post-levodopa decreases in brain activity during the working memory task.

Black and Hershey plan to look at brain activity during different tasks to see whether they can find more dopamine-related differences.

Black is also finalizing a treatment study to determine if levodopa helps control tics in Tourette syndrome patients.

Source

Tourette's Syndrome, Dopamine and Serotonin

Photo Caption Dopamine and serotonin imbalances are linked to Tourette's syndrome. Photo Credit Kernspintomographie image by Marem from Fotolia.com

Tourette's syndrome is a condition that causes involuntary behavior movements or vocal expressions known as tics. It is related to an imbalance of the brain chemicals called serotonin and dopamine. Certain drugs may interact with these brain chemicals and worsen the condition. Consult with your doctor before trying to prevent, treat or cure Tourette's syndrome.

Dopamine Release

There is evidence showing that a release of dopamine worsens symptoms in patients with Tourette's syndrome. A study published in 2009 in the "Journal of Nuclear Medicine" found that adults with Tourette's syndrome had an increased release of dopamine in the brain when given amphetamines. This led to an increase of psychiatric symptoms, specifically, the patients had attention deficit problems.

Frontal Cortex

The frontal cortex of the brain is responsible for regulating higher-order functions such as decision-making and the suppression of socially unacceptable behaviors. Dopamine-related abnormalities have been identified in this portion of the brain, according to a study published in April 2007 in the "Journal of the Neurological Sciences." Specifically, postmortem brain tissue from frontal and occipital regions from all three TS patients examined in the study had increased dopamine release and a greater density of dopamine receptors within the frontal lobes.

Dopaminergic and Serotonergic Interaction

Serotonin is another neurotransmitter, or brain chemical, that is involved in the pathogenesis of Tourette's syndrome. Serotonin is responsible for producing feelings of well-being. Interactions between dopamine and serotonin have been found in neuroimaging studies to produce abnormalities in the brain, according to an article published in 2008 in "Progress in Brain Research."

Dietary Considerations

Certain foods may affect the brain neurochemicals with regards to Tourette's syndrome. For example, caffeine-containing beverages such as coffee may worsen symptoms in patients with the disorder. A study published in April 2008 in "Acta Paediatrica" found that coffee and soda led to an increase in tics in patients with Tourette's syndrome. Therefore, caffeine likely worsens the overstimulation of the dopaminergic system, according to the researchers.

Source