Missing Enzyme Linked to Drug Addiction
A missing brain enzyme increases concentrations of a protein related to pain-killer addiction, according to an animal study. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.
Opioids are pain-killing drugs, derived from the opium plant, which block signals of pain between nerves in the body. They are manufactured in prescription medications like morphine and codeine, and also are found in some illegal drugs, like heroin. Both legal and illegal opioids can be highly addictive.
In addition to the synthetic opioids, natural opioids are produced by the body. Most people have heard of the so-called feel-good endorphins, which are opioid-like proteins produced by various organs in the body in response to certain activities, like exercise.
Drug addiction occurs, in part, because opioid-containing drugs alter the brain’s biochemical balance of naturally produced opioids. Nationwide, drug abuse of opioid-containing prescription drugs is skyrocketing, and researchers are trying to identify the risk factors that differentiate people who get addicted from those who do not.
In this particular animal model, researchers eliminated an enzyme called prohormone convertase 2, or PC2, which normally converts pre-hormonal substances into active hormones in certain parts of the brain. Previous research by this team demonstrated that PC2 levels increase after long-term morphine treatment, according to study lead author Theodore C. Friedman, MD, PhD, chairman of the internal medicine department at Charles R. Drew University of Medicine and Science in Los Angeles.
“This raises the possibility that PC2-derived peptides may be involved in some of the addiction parameters related to morphine,” Friedman said.
For this study, Friedman and his co-researchers analyzed the effects of morphine on the brain after knocking out the PC2 enzyme in mice. Morphine normally binds to a protein on cells known as the mu opioid receptor, or MOR. They found that MOR concentrations were higher in mice lacking PC2, compared to other mice.
To analyze the effects of PC2 elimination, the researchers examined MOR levels in specific parts of the brain that are related to pain relief, as well as to behaviors associated with reward and addiction. They measured these levels using a scientific test called immunohistochemistry, which uses specific antibodies to identify the cells in which proteins are expressed.
“In this study, we found that PC2 knockout mice have higher levels of MOR in brain regions related to drug addiction,” Friedman said. “We conclude that PC2 regulates endogenous opioids involved in the addiction response and in its absence, up-regulation of MOR expression occurs in key brain areas related to drug addiction.”
Nature Photography: Good or Bad for the Environment?: Scientific American
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It’s a wonderful way to share the beauty and wonder of the natural world with others, but not if landscapes are trampled and wildlife is frightened
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Is nature photography good or bad for the environment?—Cal Moss, Camden, Maine
Nature photography is a wonderful way to share the beauty and wonder of the natural world with others who don’t have the opportunity to see a given subject first-hand. An obvious benefit of the art is raising awareness about and generating empathy for special landscapes and species. But too much love can be a bad thing if landscapes are trampled and wildlife is frightened—all in the name of leaving only footprints.
The use of photography as a conservation tool dates back as far as photography itself. William Henry Jackson’s photos from his travels with the Hayden Expedition of the 1860s to survey the American West helped convince Congress to create Yellowstone National Park in 1872—and as such played a role in the birth of the worldwide movement to set aside special places as national parks. Ansel Adams carried this torch forward a century later; opening up millions of viewers’ eyes to the splendor of many an iconic western landscape. And more recently wildlife photographers have gotten up close and personal to wild animals large and small so the rest of us can appreciate their beauty out of harm’s way.But some say there is a dark side to all this exposure of the wild and the natural. In a provocative essay in the Fall 1997 issue of DoubleTake magazine, activist and author Bill McKibben argued that the world has enough wildlife photography and that continuing to invade the lives of animal subjects—given the vast oversupply of images already available—is counterproductive to the goals of preserving biodiversity. He also decried the idealized view of the world that wildlife photography portrays. “How can there really be a shortage of whooping cranes when you’ve seen a thousand images of them—seen ten times more images than there are actually whooping cranes left in the wild?” he asked.
Most wildlife photographers bristle at McKibben’s stance. “The real problem with wildlife photography is not that there is too much of it but that photographers…are failing to reflect natural diversity,” argues UK-based nature photographer Niall Benvie. “Far from inhibiting productivity, it needs to be expanded greatly, telling the story of species and locations unknown to readers and viewers.”
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Optogenetics for treating obsessive-compulsive disorders | KurzweilAI
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Obsessive-compulsive mice exhibit a defective grooming response during a conditioning task (credit: Eric Burguière et al./Science) By applying
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By applying optogenetics (light stimulation) to specific neurons in the brain, researchers at INSERM (Institut national de la santé et de la recherche médicale) have re-established normal behavior in mice with pathological repetitive behavior similar to that observed in human patients suffering from obsessive-compulsive disorders.
Repetitive obsessive-compulsive disorders can become a real handicap to daily life (for example, washing hands up to 30 times a day; or checking excessively that a door is locked, etc.). Obsessive-compulsive disorders affect 2 to 3% of the population and in France, it is estimated that over one million persons are affected by this disorder.
The usual treatment for obsessive-compulsive disorders is to use pharmacological treatments (anti-depressants, neuroleptics) and/or behavioral psychotherapy. They don’t work in around one third of patients.
So it is necessary to gain better understanding of the cerebral mechanisms that cause these repetitive behavior patterns in order to provide better treatment.
Previous neuroimaging studies allowed the INSERM scientists to identify dysfunctional neuron circuits located between the front of the brain (the orbitofrontal cortex) and more deep-seated cerebral structures (ganglions at the base on the brain), in certain persons suffering from obsessive-compulsive disorders.
In this new study, Eric Burguière and his co-workers (in the laboratory of Prof. Ann Graybiel in MIT) concentrated their research on this neuron circuit to examine its function in detail and also to develop an approach to treating obsessive-compulsive disorders in a mutant mouse model.
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Decoding Rett syndrome: New pieces to the puzzle
Rett Syndrome is a neurological disorder that affects about 1 in 10,000 girls. Back in 1992, University of Edinburgh researcher Adrian Bird discovered that the protein, MeCP2, plays a major role in the disease. The story of MeCP2 is in many ways a microcosm of human genetics. It has become the showcase gene for many complex epi-genetic phenomena including X-linked inactivation, DNA methylation, and genomic imprinting. These gender-specific bargaining chips provide compatibility in an evolutionary system where sex-chromosome provisioning is inherently assymetric. In two new papers, one in Nature and the the other in Nature Neuroscience, Bird and collaborator Michael Greenberg, show how mutations found in Rett Syndrome affect the interaction of MeCP2 with a key regulatory protein known as NCoR.
Nearly all cases of Rett Syndrome are caused by mutations at various postions in the MeCP2 gene. Bird and Greenberg analyzed the locations of these mutations using the RettBase MeCp2 database, and found they cluster to two primary locations—the well-known methyl-CpG binding domain, and a new hotspot within a transcriptional repressor domain (TRD). When they compared these locations with mutations found in the general population by using the Exome Variant Server, they found no overlap. This suggests the that the MeCP2 and TRD regions are the primary regions involved in Rett’s.
The researchers hypothesized that the newly found TRD region must act through a unknown regulator of MeCP2 function. Using mass spectrometry, they were able to identify several factors which they had purified from Mecp2-EGFP “knock-in” mice. Most of these factors turned out to be subunits of the co-repressor, NCoR, which was previously known to interact with MeCP2. This is the first identified example of a protein-protein interaction known to be disrupted in Rett’s.
In the Nature paper, the researchers further report that activity-dependent phosphorylation of MeCP2 mediates its interaction with NCoR. They used a technique known as phosphotryptic mapping to identify three sites that are directly phosphorylated in MeCP2 as a result of elevation in cAMP or BDNF. More generally, they showed that membrane depolarization, and therefore activity, results in the phosporylation.
One confounding factor in trying to pinpoint the mechanisms underlying Rett Syndrome is that both loss of MeCP2, and overexpression of MeCP2, can lead to the disease. In mouse models of the disease, this could be accounted for by the observation that both loss of NCoR binding, and constitutive binding of NCoR can lead to disease symptoms. While not a complete explanation of the role of MeCP2 in the disease, it provides some clues to help dissect the involvement of the many different kinds of mutations involved.
Despite the rarity of Rett’s syndrome, its impact on our understanding of human genetics and neural development should not be underestimated. As one of the autistic spectrum disorders, research on Rett’s helps connect molecular mechanics to behavior. For example, when MeCP2 is bound to DNA it can cause condensation of the chromatin structure, and also form complexes with histone deacetylaces. In demostrating that neural activity, and subsequent signal tranduction pathways, lead to modifications of MeCP2, the researchers have revealed a path from the environment directly to the genes.
The X-linked inactivation of one copy of the MeCP2 gene in females adds another layer of complexity to the disease. The celluar mosiac formed by the pattern of inactivation, particularly in the brain, needs more study to be undersatood. The fact that Rett’s symptoms can be “rescued” in mice by the expression of MeCP2 in postmitotic neurons is encouraging. In humans, Rett’s is frequently not observed untill the first or second year of life. As MeCP2 activation correlates with this period of rapid neural maturation, Rett’s is generally considered to be neurodevelopmental disease, as opposed to a neurodegenerative disease.
Rett’s is hardly ever observed in males for the simple reason that they fail to thrive long before birth. In those rare cases that a presumably XXY male child is rescued by the additional X chromsome, as in Klinefelder’s disease, rare opportunity to study the disease etiology is afforded. The efforts of these researchers, and the larger Rett’s community, together with the insights afforded by massive data collation have turned a rare disease into a primary source of knowledge about how evolution proceeds through the interplay of the sexes at the genetic and epigenetic levels.
