Ecstasy Component May Help Researchers Measure Brain Damage From The Drug

Researchers in Spain have isolated for the first time a by-product of the illicit drug Ecstasy that is believed to cause some of the brain damage associated with the drug. They believe their finding will help them measure, with greater precision, the long-term neurotoxicity of Ecstasy in human users.

The report will be published in the September issue of Chemical Research in Toxicology, a peer-reviewed journal of the American Chemical Society, the world’s largest scientific society.

The findings may corroborate speculation that HHMA (3,4 dihydroxymethamphetamine), is at least partially responsible for Ecstasy’s harm to the human brain, according to lead researcher Rafael de la Torre, D.Pharm., of the Municipal Institute of Medical Research in Barcelona. Previous study had linked HHMA to many of Ecstasy’s known side effects, but until now researchers had not been able to accurately measure the amounts of HHMA in users.

HHMA is created when Ecstasy (known chemically as MDMA, or 3,4- methylenedioxymethamphetamine) is metabolized through the liver. Animal studies have shown Ecstasy to damage the brain’s thought and memory function, but research has indicated that such side effects don’t develop until the drug is metabolized. Accurately measuring the amount and concentration of HHMA in a person’s body can provide new insight into the drug’s effects, including how it is metabolized, and possibly determine its long-term effects, de la Torre said. HHMA does not occur naturally in the body and thus would not be found in a non-user of Ecstasy, he noted.

“This observation concerns not only Ecstasy’s acute effects, but more interestingly, its mid- and long-term neurotoxicity,” de la Torre said. “The detection of HHMA was hampered up to now by problems measuring it in humans, which we have solved.”

The research represents the first validated method for measuring HHMA in body fluids, according to de la Torre. It involved four men who each volunteered to take a 100-milligram dose of Ecstasy and submit blood and urine samples regularly for the following 24 hours. All were described as regular users of the drug. The researchers found nearly identical concentrations of HHMA and MDMA in the samples, establishing HHMA as a likely contributor to conditions associated with Ecstasy use, de la Torre said.

In widespread use since the 1980s, Ecstasy is a stimulant with effects similar to the short-term euphoria and increased alertness claimed by cocaine users, according to the National Institute on Drug Abuse. It is considered dangerous, however, since it has been shown to damage nerve cells in the brain critical for thought and memory, NIDA reports. Other experiments show that people who take MDMA score lower on memory tests and that animals have persistent effects from the drug six to seven years after exposure.

The research cited above was funded by the Spanish government and the Spanish National Plan on Drugs in Madrid.

Rafael de la Torre, D. Pharm., is a researcher in the pharmacology research unit at the Municipal Institute of Medical Research in Barcelona and a professor of toxicology and pharmacology at the Autonomous University in Barcelona.

Mother's Drug Use Increases Risks For Male Offspring

Exposure before birth to methamphetamine, an increasingly popular "club" drug, renders males, even as adults, much more susceptible to the drug's brain-damaging effects, reveals a study performed in mice by researchers at the University of Chicago.

If males who were prenatally exposed to methamphetamine take the drug themselves as teens or adults, the increased toxicity could hasten the onset of brain disorders such as Parkinson's disease, warn the authors in the August issue of the Journal of Pharmacology and Experimental Therapeutics, published electronically on July 13.

"No one who values his or her brain should take this drug," cautions neurotoxicologist Alfred Heller, M.D., Ph.D., professor of neurobiology, pharmacology and physiology at the University of Chicago and director of the study. "If you're male, and if your mother took methamphetamine — and it's difficult to be certain she didn't — you should not go near this drug."

Methamphetamine — also known as "meth" or "chalk," or when smoked as "crystal," "crank" or "ice" — is the world's second most widely used illicit drug, according to the World Health Organization, and is rapidly gaining popularity. After claiming a foothold in the Southwest in the early 1990s, it has spread across much of the United States.

"We now are seeing high levels of methamphetamine abuse in many areas of the Midwest," notes an alert on the National Institute of Drug Abuse (NIDA) web site, "in both urban and rural settings, and by very diverse segments of the population."

Cheap, long-lasting, easy to make, easy to take and perceived as relatively safe, this stimulant is widely used by young women because it elevates mood, boosts energy, suppresses appetite and helps with weight loss.

Researchers have long known that methamphetamine has multiple side effects. It damages neurons that use the neurotransmitter dopamine to relay signals. Women who abuse the drug during pregnancy have increased risk of premature delivery. Their newborns are often unusually irritable. But because the drug has only recently become so popular, there is limited information about its long-term effects on users' offspring.

Last spring, recognition of methamphetamine's blossoming popularity among young women, and the uncertainty about its effects on an exposed fetus, provoked NIDA to call for research on how the drug affects brain development for those exposed in utero.

Heller's group at the University of Chicago had already developed a mouse model of prenatal methamphetamine exposure. They determined the dose that exposed the mouse fetal brain to similar concentrations of methamphetamine as in human infants and then studied its effects on the exposed mice and their offspring.

The key finding was that male mice who were exposed to the drug before birth and then exposed again as adults (at 11 weeks old), were significantly more vulnerable to methamphetamine's neurotoxic effects. These males suffered damage to the dopamine-using neurons, particularly in areas of the brain known as the substantia nigra and the striatum, the system that is damaged in Parkinson's disease.

Why the effect was so much greater in males than females is unclear. It may be connected with the rise in body temperature associated with use of the drug. The amount of brain damage was closely associated with this increase in body temperature in exposed mice. Methamphetamine increases core temperatures more in males than in females.

The researchers also suggest that a likely mechanism for the increase in brain damage is that fetal exposure to methamphetamine increases the release of dopamine from adult brain cells by methamphetamine.

When stimulated later in life by this drug, these preconditioned nerve cells release abnormal amounts of dopamine, which accumulates outside the cells, where it can be chemically altered or oxidized. Heat exacerbates this dopamine secretion. When the altered neurotransmitters are taken back up into these nerve cells, they can be toxic. In fact, drugs that block re-uptake can prevent this toxicity.

The enhanced neurotoxicity in response to methamphetamine in male animals exposed in utero "may be an additional risk factor in the development of parkinsonism," note the authors. "With age, the persistent damage to the dopaminergic system may predispose these individuals to brain disorders."

Although Parkinson's disease doesn't immediately appear in these animals, or in most human drug users, the drug may be setting the stage for early disease onset. People begin to exhibit symptoms, such as slowed movements, rigidity and tremors, only after losing more than 80 percent of the dopamine-producing cells in the substantia nigra.

"Regular methamphetamine users, or those at increased risk because of prenatal exposure, may have a head start on this process," suggests Heller.

Additional authors of the study include Nancy Bubula, Robert Lew and Lisa Won of the University of Chicago, and statistician Barbara Heller, from the Illinois Institute of Technology.

Stress Delays Puberty, Dutch Researchers Find

NWO research at Utrecht University has shown that when carp are subjected to stress, the development of their genital organs is delayed, so that they reach puberty later. It is likely that the stress hormone cortisol plays a major role in delaying puberty.

Changes in water temperature produce stress in fish. Dimitri Consten of Utrecht University subjected carp to a rapid reduction in water temperature three times a week from 25°C down to 14°C. This led to delayed development of their reproductive cells and the fish reached puberty later than normal. The researchers assumed that the hormone cortisol, which is released when an animal is under stress, plays a major role in this. This assumption was confirmed by means of two tests. In one of them, the biologists ‘switched off’ the cortisol in the stressed fish. These animals then developed to puberty in the normal manner. In a second test, cortisol was administered to fish which were not subjected to stress. In these fish, puberty was delayed.

Cortisol would seem to affect the testes. It directly delays the development of reproductive cells into sperm cells. This slows the growth of the sexual organs and also the supply of steroids to the blood. During puberty, steroids from the testes ensure that the brain, the pituitary gland and testes develop properly. Because the cortisol produced under stress reduces the supply of steroids, communication to the brain and the pituitary (a gland under the brain) is reduced. This means that, like the testes, these organs develop more slowly, thus slowing down overall development.

The whole complex of hormones involved in puberty is self-regulatory. The brain produces the gonadotropin-releasing hormone, which stimulates cells in the pituitary. On order, the pituitary then excretes the gonadotropins, the luteinising hormone and the hormone which stimulates the follicles. In the testes, the gonadotropins promote the production of reproductive cells and steroid hormones. The steroid hormones contribute to the production of the reproductive cells and ensure communication between the brain and the pituitary gland, thus completing the cycle.

Researchers Document Brain Damage, Reduction In Motor And Cognitive Function From Methamphetamine Abuse

UPTON, NY — Two studies by researchers at the U.S. Department of Energy's Brookhaven National Laboratory provide evidence for the first time that abuse of methamphetamine ­ the drug commonly known as "speed" — is associated with physiological changes in two systems of the human brain. The changes are evident even for abusers who have not taken the drug for a year or more. The studies also found that methamphetamine abusers have reduced cognitive and motor functions, even at one year after quitting the drug. The findings appear in the March issue of the American Journal of Psychiatry.

"These studies provide some of the first clear evidence that methamphetamine at dose levels taken by human abusers leads to dopamine transporter reduction," said Brookhaven psychiatrist Nora Volkow, lead investigator on the study. "For the first time we can also see that this transporter reduction is associated with motor and cognitive impairment." Previously, in animal studies and two small human studies, researchers documented reductions in dopamine transporters. Past studies did not test whether these reductions were associated with changes in cognitive and motor function. "We also have the first evidence that methamphetamine affects circuits of the brain other than those regulated by dopamine, and that the drug causes changes that are consistent with inflammation throughout the brain," Volkow continued. "This is objective evidence that methamphetamine is damaging to the brain. These changes are much greater than what wehave seen with heroin, alcohol, or cocaine. We need to further study whether these changes are long-lasting and result in long-term impairment of memory and motor functions, such as motor speed and motor coordination."

Reduced Dopamine Transporters, Cognitive and Motor Function

In the first study, Volkow and colleagues tested both dopamine transporter levels and motor and cognitive function in 15 detoxified methamphetamine abusers and 18 control subjects who had not previously used methamphetamine. Dopamine transporters help transport "used" dopamine, a neurotransmitter that contributes to feelings of satisfaction and pleasure, back into the nerve cells that produce it, thus terminating the pleasure signal.

Each study volunteer was given an injection called a radiotracer, a radioactive chemical "tag" designed to bind to dopamine transporters in the brain. The researchers then scanned the subjects' brains using a positron emission tomography (PET) camera. The PET camera picks up the radioactive signal of the tracer and shows where it is bound to dopamine transporters. The strength of the signal indicates the number of transporters.

Within two weeks of the PET scans, the researchers administered a battery of neuropsychological tests. These included tests of fine and gross motor function and tests of attention and memory.Methamphetamine abusers showed a significant reduction in dopamine transporters in the caudate (27.8%) and putamen (21.1.%) ­ two areas of the striatum, a section of the brain that controls movement, attention, motivation, and other higher functions — compared with non-abusers in the study. The reduction was evident even in abusers who had been detoxified for 11 months or more. Study subjects with reduced dopamine transporters also exhibited memory impairment and slowed motor function.Increased Brain Glucose Metabolism and Inflammation

In the second study, Volkow's team looked at brain glucose metabolism in order to see if there was any functional change in regions of the brains of methamphetamine abusers other than those in which dopamine cells are active. The same 15 detoxified methamphetamine abusers who participated in the first study, and 21 non-abusers, received PET scans following administration of a radioactive tracer. The scans showed a 14% higher whole brain metabolism in abusers than in non-abusers. Differences were most accentuated in the parietal cortex ­ an area of the brain that regulates sensation and coordinates information on space and spatial relations ­ where abusers showed a 20% higher rate of metabolism.

"This finding was a complete surprise," Volkow says. "Most drug studies have shown decreased metabolism. The increased metabolism we saw is consistent with an inflammatory response. This result, taken together with our other findings, indicates that this is a very toxic drug." The presence of inflammation signals that there is a physical insult to the brain.

Long-Term Effects

"We cannot reach any definite conclusions about long-term effects, because only three of the subjects had been detoxified for an extended period. But our three primary findings — dopamine transporter loss, whole brain inflammation, and loss of motor and cognitive abilities — document the adverse effects of methamphetamine to the human brain. We believe more studies must be done to assess if there is long-term damage from this drug," says Volkow. "We can say unequivocally that methamphetamine abusers need to be watched by their physicians as they age to determine whether they begin seeing any effects of neurodegenerative diseases like Parkinson's." The reduction in brain dopamine that occurs as these subjects age, in addition to the loss they experience from use of methamphetamine, may result in symptoms similar to those seen in Parkinson's disease, a severe movement disorder that results from a loss of dopamine in the brain.

Methamphetamine is a highly addictive stimulant that dramatically affects the central nervous system. Long reported as a dominant drug problem in southern California, methamphetamine abuse has recently become a substantial problem in other areas of the West and Southwest as well. Usage has also recently increased in areas of the Midwest and South. According to a survey by the National Institute on Drug Abuse, an estimated 4.9 million Americans have tried methamphetamine at some point in their lives.

Brookhaven scientists have done extensive research on addiction. Studies by Dr. Volkow and colleagues have shown that dopamine plays an important role in addiction to cocaine, nicotine, alcohol, heroin, and other drugs. Previous research at Brookhaven has shown that addictive drugs increase the level of dopamine in the brain while the subject is intoxicated, and that addicts have fewer dopamine receptors than non-addicts.

This study was funded by the U.S. Department of Energy; the National Institute on Drug Abuse, part of the National Institutes of Health; the Office of National Drug Control Policy; and the General Clinical Research Center at University Hospital Stony Brook. It was done in collaboration with researchers from the State University of New York at Stony Brook and the University of California, Los Angeles.

The full text of these studies will appear on the American Journal of Psychiatry web site at: http://www.ajp.psychiatryonline.org.

The U.S. Department of Energy¹s Brookhaven National Laboratory creates and operates major facilities available to university, industrial and governmental personnel for basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. The Laboratory is operated by Brookhaven Science Associates, a not-for-profit research management company, under contract with the U.S. Department of Energy.

Brain Contains Cocaine-Like Chemical

 ATLANTA ­ July 19, 2000 ­ — Dr. Michael Kuhar and a team of neuroscientists at the Yerkes Regional Primate Research Center of Emory University have found that a naturally occurring neurotransmitter produces behaviors associated with cocaine and methamphetamine. The finding suggests a role for the brain chemical, called CART (Cocaine- and Amphetamine-Regulated Transcript) peptide, in modulating or mediating the actions of drugs and a perhaps potential new avenue for treating addiction. Funded by a multi-year grant from the National Institute on Drug Abuse, the study will be reported in the August issue (vol. 294, no. 2) of The Journal of Pharmacology and Experimental Therapeutics.

Using rat models, Kuhar and his team injected CART peptide directly into the ventral tegamental area (VTA), a region of the brain stem involved in addiction and feelings of euphoria. The VTA is also one of several areas where the neurotransmitter occurs naturally. In their experiments, the researchers observed increased locomotor activity, comparable to that seen with cocaine administration.

In a separate experiment, Kuhar's team found that the administration of CART peptide caused the rats to return repeatedly to the place where they received the initial injection. The behavior, known as conditioned place preference, has been observed during animal studies on the effects of cocaine on the brain. "CART peptide seems to act as an endogenous cocaine," said Kuhar. "The rats perceived the neurotransmitter as a good feeling and wanted to reinforce that 'euphoria' by returning to the place where they received it."

Given the observed behavioral changes, Kuhar believes CART peptide could somehow influence the psychostimulant effects of cocaine and methamphetamine. Its ability to spur conditioned place preference further suggests a role for the neurotransmitter in the drug addiction process.

Previous studies have identified CART peptide in areas of the brain directly affected by cocaine and methamphetamine. Scientists have also measured increased levels of CART when cocaine was administered.

"This latest discovery about CART's cocaine-like properties gives us a potential therapeutic target for medications designed to treat addiction," said Kuhar. "Theoretically, it might be possible to modulate the neurotransmitter in such a way that craving for cocaine or methamphetamine might be altered."

The next steps will be to ascertain the role of CART peptide in other areas of the brain and possibly extend the studies to primates. As a consequence of animal studies on the effects of cocaine on the brain, scientists have determined that CART peptide also influences hunger, stress, endocrine control, and sensory processing.

In addition to Kuhar, the study's authors include Drs. Heather Kimmel and Wenhe Gong, Stephanie Dall Vechia, and Richard G. Hunter.

A nationally-known expert on the biological underpinnings of drug addiction, Kuhar has also been instrumental in the development of a new class of cocaine analogues called phenyltropanes. Kuhar's colleague at Yerkes, Dr. Leonard Howell, is currently testing the compounds as part of a five-year effort by NIDA and the Office of National Drug Control Policy to develop a medication for treating cocaine addiction.

Cocaine and methamphetamine are the only illicit drugs for which there exists no therapeutic substitute to control craving. An estimated two million Americans use cocaine and methamphetamine.

The Yerkes Regional Primate Research Center is part of the Woodruff Health Sciences Center of Emory University. It is the oldest scientific institution dedicated to primate research. Yerkes' programs cover a wide range of biomedical and behavioral sciences.

Methamphetamine Abuse Linked To Long-Term Damage To Brain Cells

New research shows that those who use methamphetamine, often called "meth" or "speed," risk long-term damage to their brain cells similar to that caused by strokes or Alzheimer's disease. In an article published in the March 28 issue of Neurology, scientists at the Harbor-UCLA Medical Center in Torrance, California, used magnetic resonance spectroscopy to take measurements of three parts of the brains of 26 participants who had used methamphetamine and then compared them with measurements of the same regions in the brains of 24 people who had no history of drug abuse.

"While the meth users in this study hadn't used the drug for some time–anywhere from two weeks to 21 months, this research strongly suggests that methamphetamine abuse causes harmful physical changes in the brain that can last for many months and perhaps longer after drug use has stopped," said Dr. Alan I. Leshner, Director, National Institute on Drug Abuse (NIDA).

In their study, Dr. Linda Chang and Dr. Thomas Ernst measured levels of brain chemicals that indicate whether brain cells are healthy or are diseased or damaged.

"We found abnormal brain chemistry in the methamphetamine users in all three brain regions we studied. In one of the regions, the amount of damage is also related to the history of drug use–those who had used the most methamphetamine had the strongest indications of cell damage," Dr. Chang said.

The researchers found that levels of one chemical marker, N-acetyl-aspartate, were reduced by at least five percent in the methamphetamine abusers. "Many diseases associated with brain cell loss or damage, such as Alzheimer's disease, stroke, and epilepsy, are also associated with reduced N-acetyl-aspartate," said Dr. Ernst. "Reduced concentrations of N-acetyl-aspartate in the drug users' brains suggest that long-term methamphetamine abuse results in loss or damage to neurons, the cells we use in thinking." Two other chemical markers, myo-inositol and choline-containing compounds, are associated with glial cells, which act to support neurons. "Methamphetamine abusers showed increases of 11 percent and 13 percent in levels of these markers compared with normal individuals," Dr. Ernst said. "This suggests an increased number or size of glial cells as a reaction to the injurious effects of methamphetamine."

The researchers, who received funding from NIDA, plan to conduct more extensive studies to determine if these brain changes caused by methamphetamine abuse might be reversed or corrected by treatment.

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The National Institute on Drug Abuse is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports more than 85 percent of the world's research on the health aspects of drug abuse and addiction. The Institute carries out a large variety of programs to ensure the rapid dissemination of research information and its implementation in policy and practice. Fact sheets on the health effects of drugs of abuse and other topics can be ordered free of charge in English and Spanish by calling NIDA Infofax at 1-888-NIH-NIDA (644-6432) or 1-888-TTY-NIDA (889-6432) for the deaf. These fact sheets and further information on NIDA research and other activities can be found on the NIDA home page at http://www.drugabuse.gov.

Scientists Identify New Pathway Of Antidepressant Action

Scientists at UC San Francisco have discovered a new chemical pathway in the brain by which the most common antidepressants may alter mood. The research demonstrates that many popular mood modulators trigger chemical activity along more than one track at a time. It shows too how a brain chemical, known as a neurosteroid, might make a prime target for drugs to improve severe mood swings.

The researchers are publishing their study in the November 9 issue of the Proceedings of the National Academy of Sciences (PNAS).

Antidepressants such as Prozac, Paxil and Zoloft are thought to relieve depression by increasing the availability of one of the body's natural mood-enhancing chemicals, the neurotransmitter serotonin. But the UCSF experimenters examined the effect of these same antidepressants on an entirely different chemical pathway — one increasingly thought to play a role in mood regulation as well. It involves a natural brain compound called a neurosteroid, only recognized in the last 10 or 15 years.

The scientists discovered that all three of these antidepressants, known as SSRI's, not only affect serotonin availability, but also greatly increase the synthesis of a key neurosteroid — 10 to 30-fold. The profound effect, they found, comes from the SSRI's ability to greatly boost the action of the final enzyme involved in the synthesis of the neurosteroid in the brain.

"Each of these three serotonin reuptake inhibitors, or SSRI's, shows a dramatic positive effect on the levels of allopregnanolone, a steroid made in the brain, which most likely modulates mood and plays a role in heightened anxiety and depression found in severe premenstrual disorders and other conditions," said Synthia Mellon, PhD, senior author on the PNAS study and a professor of reproductive endocrinology at UCSF.

"The study points to the likelihood that SSRI's control mood by more than the one pathway that has received most of our attention, and it suggests that the steroids synthesized in the human brain may play a strong physiological role in regulating anxiety and depression."

Lead author on the PNAS paper is Lisa D. Griffin, MD, PhD, assistant professor of neurology at UCSF.

Studies by other researchers have shown below-normal brain neurosteroid levels among people with some depressive disorders, and SSRI's such as Prozac have been shown to elevate these brain steroid levels and alleviate symptoms of anxiety and depression among women suffering from a severe premenstrual disorder, Mellon and Griffin said.

Since the disorder occurs during a specific phase of the menstrual cycle, researchers have deduced that it is affected by levels of ovarian hormones such as progesterone. Subsequent studies, in rats, showed that Prozac does increase levels of the neurosteroid allopregnanolone, a derivative of progesterone, they said.

As a result of these and related studies, the brain's allopregnanolone has become a focus of interest in the continuing search for the body's natural mood modulators and what regulates them. The study reported by Mellon and Griffin clarifies the specific way SSRI's lead to increased neurosteroid levels.

Interest in allopregnanolone has also been spurred by the fact that it is synthesized in the brain, unlike most of the body's potent steroids which are made in the sex glands. The term "neurosteroids" was coined to reflect the rather unexpected fact that the brain is the site of the steroid's synthesis.

While it is widely assumed that SSRI's relieve depression through their effect on the neurotransmitter serotonin, their effect on the neurosteroid allopregnanolone follows a different route: the so-called GABA pathway. In this pathway, the steroid boosts mood-enhancing neurotransmitter receptors by increasing how many and how long certain openings in the neuron's membranes –called GABA ion channels — remain open. (The anti-anxiety medication valium works by stimulating this GABA pathway.)

To study the effects of the antidepressants on allopregnanolone, Griffin, Mellon and their laboratory colleagues cloned from both rat and human tissues the DNA (cDNA) of the intermediate enzymes known to be the key players in synthesizing the neurosteroid. They subjected both the rat and human enzymes to the antidepressants in solution. They tested the three SSRI's and a tricyclic antidepressant known as imipramine.

The scientists found that each of the three SSRI's greatly increased the affinity of both the rat and human enzyme 3-alpha HSD for the steroid precursor, resulting in surges of allopregnanolone synthesis. The tricyclic antidepressant showed no such effect.

Mellon says the research strengthens the likelihood that the enzymes that synthesize neurosteroids can make prime targets for mood-regulating drugs.

"We're interested in finding compounds that may directly affect these enzymes in the brain, and thus regulate mood disorders with minimal side effects," she said.

The research was supported by the National Institutes of Health and the National Alliance for Research on Schizophrenia and Depression.

Steroids May Reverse Loss Of Substance Tied To Nervous-System Diseases

 CHAMPAIGN, Ill. — Steroids help to reduce inflammation, but University of Illinois scientists suggest they also could be used to reverse a loss of myelin — a major problem in multiple sclerosis and other demyelinating diseases and injuries associated with the central and peripheral nervous systems.

Treatment of MS already includes the use of steroids, because they relieve inflammation and speed remission. The new findings — published in September's biochemistry section of the Proceedings of the National Academy of Sciences — indicate that the steroids dexamethasone and progesterone actually signal the initiation and dramatically increase the rate of myelin synthesis.

"I think this work is very important in that it helps clarify the signals that are responsible for the synthesis of myelin," said Jonah R. Chan, a doctoral student in the department of biochemistry and neuroscience program at the U. of I.

Myelin is a white substance made of fat and proteins that forms in a protective spiral sheath around the axon of nerve fibers. The sheath is a vital component of the body's efficient and rapid

nerve-communication system. When myelin fails to form, nerve signaling breaks down, jeopardizing nerve communications and leading to altered sensations and a multitude of other problems.

What causes a loss of myelin — demyelination — in MS cases is not known, but is believed to be the result of an abnormal immune response to bacteria and viruses. While MS affects everyone differently, demyelination is a focal point of research around the world.

"Steroids seem to be very important in regulating the initiation and synthesis," said Michael Glaser, professor of biochemistry and lead investigator of the project. "They had been implicated as having a role in the overall process, but not for enhancing the actual synthesis. It is our hope that this line of work will lead to a line of treatment for nerve injuries and demyelinating diseases."

Last year in the Journal of Neuroscience Research, Glaser's team reported the first technique for observing the continual synthesis of myelin by Schwann cells around axons of neurons. In their new work, researchers added various forms of steroids and antagonists, observing their effects on the cells under a fluorescence digital-imaging microscope. When dexamethasone and progesterone were added, individually, to the tissue culture cells, the initiation of myelin production began 24 hours earlier than it did under control conditions, and the peak rate of myelin formation increased by more than 2-fold.

Their findings provided the first live look at the signals initiating myelin formation in live cells, Glaser said. Before his new assay was developed, researchers were restricted to simply observing myelin at a single stage of production.

The PNAS paper was written by Chan, Glaser and Lornie J. Phillips II, a Howard Hughes Medical Institute predoctoral fellow. The research is supported by the Multiple Sclerosis Society.

Allergy-Linked Fatigue May Stem From Nasal Congestion, Interrupted Sleep

HERSHEY, Penn. — New research from Penn State's College of Medicine finds that people with perennial allergies may attribute their daytime fatigue to causes such as the side effects of medications, when, in fact, the fatigue may be a result of nasal congestion and associated sleep fragmentation.

"We treated the subjects with topical nasal corticosteriod. A few sprays on each side improved night time sleep and reduced daytime fatigue," explains the study's lead author, Timothy Craig, D.O., associate professor of medicine at Penn State's College of Medicine.

"Unlike steroids you get by injection or orally, this has very few adverse side effects," adds Craig, also an allergist/immunologist with the Penn State Geisinger Health System.

Approximately 15 to 20 percent of the population in the United States suffer from allergic rhinitis (AR), more commonly known as hay fever. The two-month study involved 20 patients. All the patients were perennial allergy suffers. Subjects with only seasonal allergies, known sleep apnea or other respiratory diseases were not involved in the study. Over the study period, patients completed a daily diary with questions pertaining to the severity of the nasal symptoms, sleep and their response to medication. There were nine questions about the severity of symptoms.

"We found a significant reduction in nasal stuffiness and sleep problems. Simply, if these people can breath easier at night, they have a less interrupted sleep pattern," states Craig. "The subjects' sleep is often interrupted with what we call microarousals. They don't wake up during the night, however, they may complain of being tired as soon as they wake up."

In at least 75 percent of patients, nasal steroids are an effective method of reducing symptoms and are recommended as the first line of medical therapy in adults having AR with nasal congestion, says the Penn State medical researcher.

Craig's research also suggests that the use of nasal steroids during the pollen season for seasonal allergy suffers is an effective treatment.

"We believe that the seasonal allergy patient will get the same benefits as the perennial suffer including improved sleep, nasal symptoms and overall improvement to their quality of life," he says.

Craig and his colleagues' paper titled, "Nasal Congestion Secondary to Allergic Rhinitis as a Cause of Sleep Disturbance and Daytime Fatigue and the Response to Topical Nasal Corticosteroids," was published in the May issue of the Journal Allergy and Clinical Immunology.

OHSU Scientists Discover Mice Lacking Dopamine Receptor Are Supersensitive To Alcohol, Cocaine And Methamphetamine

 Scientists at Oregon Health Sciences University have discovered that mice lacking a certain brain cell receptor for the chemical messenger dopamine are supersensitive to alcohol, cocaine and methamphetamine. Their findings appear in the September 19, 1997, issue of the journal Cell and detail the increased locomotor activity of mice who lack the D4 receptor.

"Branching nerve cells communicate with each other by secreting chemical messengers like dopamine that bind to receptors on neighboring nerve cells in a lock-and-key fashion," explains, David Grandy, Ph.D., OHSU scientist and senior author of the article. "Dopamine is one of the primary chemical messengers, or neurotransmitters, and plays numerous complex roles in both movement and emotional states. Disturbances in the dopamine system are known to be associated with human disorders such as Parkinson's disease, schizophrenia and addiction. Dopamine producing neurons continue to be the focus of research because of their widespread importance in regulating complex locomotor, emotional and motivational states."

Grandy further explains that dopamine producing neurons are involved in mediating some of the positive reinforcing properties shared by drugs of abuse such as alcohol, cocaine, methamphetamine and opiates.

"We examined mice that were genetically engineered to lack the D4 dopamine receptor to investigate the role of this receptor in mediating the effects of various drugs," says Grandy. "We discovered that mice given either alcohol, cocaine or methamphetamine displayed a dramatic increase in locomotor activity compared to normal mice. Prior to their treatment with these drugs, the mutant mice tended to be less active than normal mice. Following treatment their activity level increased greatly compared to normal mice.

"Based on the observation that mice lacking the D4 receptor show a supersensitivity to certain drugs of abuse, we speculate that the D4 receptor is implicated in modulating the effects of such drugs," says Grandy. "Consequently, the D4 receptor may be a new target for the treatment of drug abuse."

Grandy explains that humans show a wide variability in the gene that encodes the D4 receptor, and there are reports that some forms of the D4 gene may predispose an individual to drug taking and novelty seeking behaviors. The D4 receptor has been the focus of intense interest since its discovery in 1990 because of its high affinity for the antipsychotic drug clozapine, which is used to treat schizophrenia. Recently, several new D4-selective drugs that are similar to clozapine have been developed and are currently undergoing clinical trials for the treatment of schizophrenia. In addition to shedding light on the role that the D4 receptor plays in an organism*s response to drugs like alcohol, cocaine and methamphetamine, the new research reported by Grandy and his colleagues underscores the relevance of this receptor to antipsychotic drug development.