Occupancy of Brain Dopamine D3 Receptors and Drug Craving: A Translational Approach

Selective dopamine D3 receptor (D3R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D3R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D3Rs (OD3R) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) autoradiography and [11C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and OD3R at every time point, and 100% effect at OD3R values greater than or equal to 72%. In humans, a single dose of GSK598809, giving submaximal levels (72–89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher OD3R is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D3R antagonist for the treatment of substance-use disorders.

Recent findings by an international collaboration including IRCM researchers hold new implications for the pathogenesis of myotonic dystrophy.

An important breakthrough could help in the fight against myotonic dystrophy. The discovery, recently published in the prestigious scientific journal Cell, results from an international collaboration between researchers at the IRCM, the Massachusetts Institute of Technology (MIT), the University of Southern California and Illumina. Their findings could lead to a better understanding of the causes of this disease.

Myotonic dystrophy (DM), also known as Steinert’s disease, is the most common form of muscular dystrophies seen in adults. This disorder is characterized by muscle weakness and myotonia (difficulty in relaxing muscles following contraction). It is a multi-system disease, typically involving a wide range of tissues and muscle.

“We studied a specific family of proteins called muscleblind-like proteins (Mbnl), which were first discovered in the fruit fly Drosophila melanogaster,” says Dr. Éric Lécuyer, Director of the RNA Biology research unit at the IRCM. “These RNA-binding proteins are known to play important functions in muscle and eye development, as well as in the pathogenesis of DM in humans.”

Because of the extreme heterogeneity of clinical symptoms, DM has been described as one of the most variable and complicated disorders known in medicine. The systems affected, the severity of symptoms, and the age of onset of those symptoms greatly vary between individuals, even within the same family.

“In patients with DM, levels of Mbnl proteins are depleted to different extents in various tissues,” explains Dr. Neal A.L. Cody, postdoctoral fellow in Dr. Lécuyer’s laboratory. “These alterations in levels and functions of Mbnl proteins are thought to play an important role in causing the disease.”

“The global transcriptome analyses conducted in this study yielded several insights into Mbnl function and established genomic resources for future functional, modeling, and clinical studies,” add Drs. Christopher B. Burge and Eric T. Wang from MIT, the researchers who headed the study. “This knowledge will be invaluable in reconstructing the order of events that occur during DM pathogenesis, and could lead to the development of diagnostic tools for monitoring disease progression and response to therapy.”

According to Muscular Dystrophy Canada, myotonic dystrophy is the most common form of muscle disease, affecting approximately one person in 8,000 worldwide. However, in Quebec’s region of Charlevoix / Saguenay-Lac-Saint-Jean, the prevalence is exceptionally high, with one person in 500 affected by the disease. There is no cure for myotonic dystrophy at the present time. Treatment is symptomatic, meaning that problems associated with myotonic dystrophy are treated individually.

Researchers have taken a key step towards recovering specific brain functions in sufferers of brain disease and injuries by successfully restoring the decision-making processes in monkeys.

By placing a neural device onto the front part of the monkeys’ brains, the researchers, from Wake Forest Baptist Medical Centre, University of Kentucky and University of Southern California, were able to recover, and even improve, the monkeys’ ability to make decisions when their normal cognitive functioning was disrupted.

The study, which has been published today (Sept. 14) in IOP Publishing’s Journal of Neural Engineering, involved the use of a neural prosthesis, which consisted of an array of electrodes measuring the signals from neurons in the brain to calculate how the monkeys’ ability to perform a memory task could be restored.

Worth a Thousand Words: Handedness in Fish

If you look closely at the image above, you’ll see that the mouths of these cichlid fish, Perissodus microlepis, curve in opposite directions. Similar to left or right handedness in humans, many animals exhibit handedness in behavior or morphology. Whether handed behavior is expressed early in development and produces mouth asymmetry or the opposite, that mouth asymmetry produces handed behavior, however, is not well known. The authors of the study “Handed Foraging Behavior in Scale-Eating Cichlid Fish: Its Potential Role in Shaping Morphological Asymmetry” set out to investigate this question and more.

A simple blood test for Creutzfeldt-Jakob Disease and Mad Cow disease is a step closer, following a breakthrough by medical researchers at the University of Melbourne.

Using newly available genetic sequencing scientists discovered cells infected with prions (the infectious agent responsible for these diseases) release particles which contain easily recognized ‘signature genes’.

Associate Professor Andrew Hill — from the Department of Biochemistry and Molecular Biology at the Bio21 Institute — said these particles travel in the blood stream, making a diagnostic blood test a possibility.

“This might provide a way to screen people who have spent time in the UK, who currently face restrictions on their ability to donate blood,” he said.

“With a simple blood test nurses could deem a prospective donor’s blood as healthy, with the potential to significantly boost critical blood stocks.”

Mad Cow disease was linked to the deaths of nearly 200 people in Great Britain who consumed meat from infected animals in the late 1980s.

Since 2000, the Australia Red Cross Blood Service has not accepted blood from anybody who lived in the UK for more than six months between 1980 and 1996, or who received a blood transfusion in the UK after 1980.

(Photo by Peter Cade via Getty Images)

New formula predicts if scientists will be stars

A new Northwestern Medicine study offers the first formula that accurately predicts a young scientist’s success up to 10 years into the future and could be useful for hiring and funding decisions.

Currently, hiring decisions are made using the instincts and research of search committees. Universities are increasingly complementing this with a measure of the quality and quantity of papers published, called the h index.

But the new formula is more than twice as accurate as the h index for predicting future success for researchers in the life sciences. It considers other important factors that contribute to a scientist’s trajectory including the number of articles written, the current h index, the years since publishing the first article, the number of distinct journals one has published in and the number of articles in high impact journals.

New research from the Hebrew University of Jerusalem shows that a carefully scheduled high-fat diet can lead to a reduction in body weight and a unique metabolism in which ingested fats are not stored, but rather used for energy at times when no food is available.

The results were published in FASEB Journal under the title ‘Timed high-fat diet resets circadian metabolism and prevents obesity.’

Previous research has established that disrupting mammals’ daily rhythms, or feeding them a high-fat diet, disrupts metabolism and leads to obesity. The researchers wanted to determine the effect of combining a high-fat diet with long-term feeding on a fixed schedule. They hypothesized that careful scheduling of meals would regulate the biological clock and reduce the effects of a high-fat diet that, under normal circumstances, would lead to obesity.

Stem Cells Turn Hearing Back On

Scientists have enabled deaf gerbils to hear again—with the help of transplanted cells that develop into nerves that can transmit auditory information from the ears to the brain. The advance, reported in Nature, could be the basis for a therapy to treat various kinds of hearing loss.

In humans, deafness is most often caused by damage to inner ear hair cells—so named because they sport hairlike cilia that bend when they encounter vibrations from sound waves—or by damage to the neurons that transmit that information to the brain. When the hair cells are damaged, those associated spiral ganglion neurons often begin to degenerate from lack of use. Implants can work in place of the hair cells, but if the sensory neurons are damaged, hearing is still limited.

"Obviously the ultimate aim is to replace both cell types," says Marcelo Rivolta of the University of Sheffield in the United Kingdom, who led the new work. "But we already have cochlear implants to replace hair cells, so we decided the first priority was to start by targeting the neurons."

In the past, scientists have tried to isolate so-called auditory stem cells from embryoid bodie—aggregates of stem cells that have begun to differentiate into different types. But such stem cells can only divide about 25 times, making it impossible to produce them in the quantity needed for a neuron transplant.

Rivolta and his colleagues knew that during embryonic development, a handful of proteins, including fibroblast growth factor (FGF) 3 and 10, are required for ears to form. So they exposed human embryonic stem cells to FGF3 and FGF10. Multiple types of cells formed, including precursor inner-ear hair cells, but they were also able to identify and isolate the cells beginning to differentiate into the desired spiral ganglion neurons. Then, they implanted the neuron precursor cells into the ears of gerbils with damaged ear neurons and followed the animals for 10 weeks. The function of the neurons was restored.

"We’ve only followed the animals for a very limited time," Rivolta says. "We want to follow them long-term now"—both to assess the possibility of increased cancer risk and to observe the long-term function of the new neurons, he adds.

"It’s very exciting," says neuroscientist Mark Maconochie of Sussex University in the United Kingdom, who was not involved in the new work. "In the past, there has been work where someone makes a single hair cell or something that looks like one neuron [from stem cells], and even that gets the field excited. This is a real step change."

The question now, he says, is whether the procedure can be fine-tuned to allow more efficient production of the relay neurons—currently, fewer than 20% of the stem cells treated develop into those ear neurons. By combining growth factors other than FGF3 and FGF10 with the stem cell mix, researchers could harvest even more ear progenitor cells, he hypothesizes.

"The next big challenge will be to do something as effective as this for the hair cells," Maconochie adds.

A team of Australian researchers, led by University of Melbourne has developed a genetic test that is able to predict the risk of developing Autism Spectrum Disorder, ASD.

Lead researcher Professor Stan Skafidas, Director of the Centre for Neural Engineering at the University of Melbourne said the test could be used to assess the risk for developing the disorder.
 
“This test could assist in the early detection of the condition in babies and children and help in the early management of those who become diagnosed,” he said.
 
“It would be particularly relevant for families who have a history of Autism or related conditions such as Asperger’s Syndrome,” he said. 
 

Autism affects around one in 150 births and is characterized by abnormal social interaction, impaired communication and repetitive behaviours.

The test correctly predicted ASD with more than 70 per cent accuracy in people of central European descent. Ongoing validation tests are continuing including the development of accurate testing for other ethnic groups.