Preliminary research in healthy men suggests that the narcolepsy drug modafinil, increasingly being used to enhance cognitive abilities, affects the activity of dopamine in the brain in a way that may create the potential for abuse and dependence, according to a study in the March 18, 2009 issue of JAMA.

Modafinil, a wake-promoting drug used in the treatment of sleep disorders, may enhance cognition and is used off-label for the treatment of cognitive dysfunction in some psychiatric disorders, such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD).

The Physicians’ Desk Reference cautions modafinil can produce psycho-active and euphoric effects typical of central nervous system stimulant drugs, but there is also some debate surrounding its potential for abuse, according to background information in the article.

The mechanisms of action of modafinil are not well understood but are believed to differ from those of stimulant medications, such as methylphenidate and amphetamine, which increase dopamine — a neurotransmitter in the brain essential for the normal functioning of the central nervous system — in the brain by targeting the dopamine transporters, a mechanism that underlies the abuse potential of these drugs. There is growing evidence that dopamine may also play a role in the mode of action of modafinil.

Nora D. Volkow, M.D., of the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, and colleagues at Brookhaven National Laboratory conducted a study to test whether modafinil, at therapeutic doses, would elevate extracellular (located or occurring outside of cells) dopamine in the brain by blocking the dopamine transporter.

Volkow’s study included 10 healthy men, between the ages of 23–46 years, who received either placebo or modafinil: 200 mg, the dose recommended for narcolepsy; or 400 mg, a dose shown to be beneficial for the treatment of ADHD. The effects of modafinil on extracellular dopamine and on dopamine transporters were measured by positron emission tomography, a radiographic technique used to examine biochemical activity in tissue.

In this pilot study, the researchers found "Modafinil acutely increased dopamine levels and blocked dopamine transporters in the human brain. Because drugs that increase dopamine have the potential for abuse, and considering the increasing use of modafinil for multiple purposes, these results suggest that risk for addiction in vulnerable persons merits heightened awareness."

Modafinil also increased dopamine in the nucleus accumbens, a brain region critical for the rewarding effects of drugs of abuse.

"Modafinil was developed with an expectation that a medication could have a non-dopaminergic target for its wake-promoting effects. However, the current findings in humans, along with preclinical studies, documenting the indispensable role of dopamine in the wake-promoting effects of modafinil, support modafinil’s dopamine-enhancing effects as a mechanism for its therapeutic actions."

cforms contact form by delicious:days

In healthy people, both sleepiness and vigilance show a relationship with core body temperature and skin temperature. When core body temperature is high during the daytime, skin temperature is low, which translates into optimal vigilance.

Researchers noted during a recent study, though, that when core body temperature is low at night time, skin temperature is high, which correlates to optimal sleep. Among those suffering from narcolepsy, however, direct manipulations of their skin and core body temperatures affect their vigilance and sleepiness.

The study, authored by Rolf Fronczek, of the Netherlands Institute for Neuroscience in Amsterdam, and Leiden University Medical Center in The Netherlands, focused on eight patients who were diagnosed with narcolepsy with cataplexy and suffered from excessive daytime sleepiness. The subjects’ vigilance was measured using the Psychomotor Vigilance Task, and their sleepiness was assessed with the Maintenance of Wakefulness Test.

Meanwhile, their skin temperature was mildly manipulated using a thermosuit, while their core body temperature was manipulated using hot or cold food and drinks.

According to the results, patients were better able to maintain vigilance when core body temperature was increased than when it was lowered, indicating that vigilance in narcolepsy can be altered simply by altering the temperature of food and drinks.

The ability to maintain wakefulness was better when skin temperature was lowered than when it was increased. Therefore, the process of falling asleep in narcoleptic subjects was able to be influenced by gently cooling or warming their hands and feet.

“Patients with narcolepsy lack a specific neurotransmitter in their brains. This neurotransmitter is responsible for the regulation of the sleep/wake rhythm. That is why narcoleptic patients fall asleep during the day, but have problems sleeping during the night,” said Fronczek.

“Sleep and skin temperature are tightly related, as everybody who ever tried to go to bed with cold feet will know. Earlier researchers discovered that in healthy people, the temperature of the distal skin – hands and feet – not only increases just before falling asleep, but also influences sleep itself. Warm hands and feet thus promote sleep. Our research shows that, surprisingly, the temperature of the hands and feet of people with narcolepsy is on a high level throughout the day, a level that is normally only seen in healthy people just before falling asleep,” Fronczek added.

“We normalized this abnormal pattern of skin temperature using a specially designed thermosuit that can differentially manipulate the distal en proximal skin temperature with warm or cold water. In this way, we were able to decrease daytime sleepiness and improve vigilance. This could lead to new therapeutical applications that can help to alleviate some of the symptoms of narcolepsy,” said Fronczek.

Narcolepsy is a sleep disorder that causes people to fall asleep uncontrollably during the day. It also includes features of dreaming that occur while awake. Other common symptoms include sleep paralysis, hallucinations and cataplexy. About one out of every 2,000 people is known to have narcolepsy.

There does seem to be a genetic link to it. It is very rare for more than two people in the same family to have this sleep disorder. It affects the same number of men and women.

The majority of patients with narcolepsy/cataplexy experience a number of symptoms of eating disorders, with an irresistible craving for food and binge eating as the most prominent features, according to a study published in the March 1 issue of the journal Sleep.

Study authors Hal Droogleever Fortuyn, M.D., and Sebastiaan Overeem, M.D., of the Radboud University Nijmegen Medical Center in The Netherlands, focused on 60 patients who had been diagnosed with narcolepsy with cataplexy (N/C) who were recruited from specialized sleep centers and 120 healthy controls.

According to the results, 23.3 percent of the N/C patients fulfilled the criteria for a clinical eating disorder, as opposed to none of the control subjects. Half of the patients reported a persistent craving for food, as well as binge eating. Twenty-five percent of patients even reported binging at least twice a week.

"These data make it clear that narcolepsy is not just a sleeping disorder, but a hypothalamic disease with a much broader symptom profile," said Fortuyn.

"Hypocretin, the neurotransmitter that is lost in narcolepsy, has been implicated in the regulation of feeding through animal studies. Earlier studies in narcolepsy found a clear increase in body weight. However, we did not find a correlation between binge eating and increased weight," said Fortuyn. "Binge eating is apparently not the direct cause of the obesity in narcolepsy, and this suggests that metabolic alterations may be involved. Nevertheless, our study shows that the loss of hypocretin function makes narcolepsy patients not only struggle with staying awake, but also destabilizes their eating pattern, which makes it harder to stay away from the candy jar."

Narcolepsy is a sleep disorder that causes people to fall asleep uncontrollably during the day. It also includes features of dreaming that occur while awake. Other common symptoms include sleep paralysis, hallucinations and cataplexy. It’s estimated that about one out of every 2,000 people is known to have narcolepsy, and it affects men and women equally.

The American Academy of Sleep Medicine (AASM) offers the following tips on how to get a good night’s sleep:

• Follow a consistent bedtime routine.
• Establish a relaxing setting at bedtime.
• Get a full night’s sleep every night.
• Avoid foods or drinks that contain caffeine, as well as any medicine that has a stimulant, prior to bedtime.
• Do not bring your worries to bed with you.
• Do not go to bed hungry, but don’t eat a big meal before bedtime either.
• Avoid any rigorous exercise within six hours of your bedtime.
• Make your bedroom quiet, dark and a little bit cool.
• Get up at the same time every morning.

Researchers who had bred a group of mice in hopes of learning more about a brain hormone that stimulates appetite got a bit of a surprise when they saw that the rodents would suddenly collapse and fall fast asleep with no provocation. As a result, Howard Hughes Medical Institute investigator Masashi Yanagisawa and colleagues at the University of Texas‘ Southwestern Medical Center in Dallas have an exciting new lead into the genesis of sleep and the origins of narcolepsy, a severe sleep disorder in humans.

In 1998, Yanagisawa discovered the orexins, small brain proteins and their receptors that regulate feeding behavior in mice. To probe the role that orexins play in regulating appetite, Yanagisawa and his colleagues developed a strain of knockout mice whose orexin genes do not function properly.

After raising several generations of the mice, the investigators videotaped the animals as they went about their daily business, hoping to see how the genetic alteration changed their behavior.

Having scrutinized hundreds of videotapes of mice scampering, grooming, eating, and sleeping, Richard Chemelli, a pediatric research fellow in Yanagisawa’s laboratory, began to feel discouraged because despite months of observation, the knockout mice did not seem any different from their normal, or wild-type, counterparts.

"Then we thought, wait a minute, mice are nocturnal. So watching them during the day is the equivalent of watching human behavior in the middle of the night. They’re asleep," explained Yanagisawa. "So we started videotaping them in complete darkness using an infrared camcorder."

Chemelli studied nocturnal surveillance tapes of about 50 knockout mice and began to notice a bizarre and unexpected pattern of behavior. "The mice would be running around, burrowing, grooming themselves. Then all of a sudden, like a switch flipping, they would turn over on one side. It looked almost like they were dead. Then in a little bit, boom, they’d jump up like nothing happened. Like a switch again," Yanagisawa said.

Their observations, which are described in a research article in the August 20, 1999, issue of Cell, led to the hypothesis that the missing orexin somehow alters the mouse’s sleep/wake cycle and causes a condition similar to narcolepsy. In humans, signs of narcolepsy usually begin during a person’s teens or early 20s.

With little or no warning while driving a car, perhaps, or interviewing for a job a narcoleptic person feels irrepressibly sleepy and quickly falls into deep sleep. Some people with narcolepsy experience vivid dreams; others describe a sense of paralysis.

On occasion, narcolepsy is accompanied by catalepsy, in which a person goes limp without losing consciousness. In every case, however, the attack ends seconds to minutes after it begins. The only known triggers are sudden emotion, such as surprise, laughter, anger, or fear.

Patients can experience narcoleptic episodes several or many times a day for life, and while certain drugs can decrease the number of episodes, there is no cure. Narcolepsy affects males and females equally, and the condition tends to run in families.

Along with a paper in the August 6, 1999, issue of Cell that describes research on narcoleptic Doberman pinschers by researchers at Stanford University, Yanagisawa’s team’s discovery are the first major insights into this life-altering condition that afflicts 125,000 people in the United States. They may also shed light on the control of normal patterns of sleep and wakefulness as well.

Yanagisawa said his first thought was that the knockout mice were having seizures. To investigate this, Chemelli and UT Southwestern psychiatrist Dr. Christopher Sinton fashioned tiny electroencephalograph (EEG) electrodes, cables, and harnesses to measure the brainwaves of the mice. The investigators expected that the needles of the EEG would spike wildly during an attack, signaling that the mice were having epileptic-like seizures.

The spikes never appeared. However, the animals EEGs and electromyograms (EMGs), which measure muscle activity, were abnormal during the blackouts. "The simultaneous EEG/EMGs showed that the animals sleep patterns were grossly disturbed in a way remarkably similar to narcoleptic patients," Yanagisawa said.

Sleep normally progresses from light to deeper stages, then to the so-called dream or REM (rapid eye movement) phase. A narcoleptic person lapses directly from wakefulness to REM sleep and back to wakefulness. This is the characteristic that Yanagisawa’s team saw, sometimes a dozen or more times per mouse at night.

The finding was completely unexpected based on the HHMI team’s initial studies of the orexins, which were reported in the February 20, 1998, issue of Cell . "The orexin gene is expressed exclusively in a very deep part of the brain called the lateral hypothalamus," Yanagisawa explained. This structure has classically been implicated with the regulation of feeding behavior, so his group named the neuropeptide after the Greek word "orexis," meaning "appetite."

Yanagisawa said the biochemical link between orexin and narcolepsy is still a mystery. "But if you just think about it philosophically, it makes sense," he added. "When an animal gets hungry, it had better be alert. It would be bad from an evolutionary standpoint to be sleepy when it’s time to hunt for food."

cforms contact form by delicious:days