Give me a G
by Will SansomGHB, a naturally occurring substance in our brains that people learned to make outside the body, found its way into modern culture as a recreationally abused drug and as the "date-rape drug" used by sexual predators to sedate unsuspecting young women. But GHB is much more than the date-rape drug. Indeed, this brain chemical, in the form of an oral medication, is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, a neurological disorder characterized by fragmented sleep and daytime sleepiness. The most severe symptom is cataplexy, in which the person abruptly falls asleep. GHB normalizes sleep patterns of narcoleptics and even is used in Europe to treat alcohol dependence.
But how does GHB exert its effects? Scientists concede they don’t know. Three Health Science Center researchers, their laboratory teams and a University of Maryland collaborator are hard at work sniffing out the clues. Their interdisciplinary project, which extends from test-tube studies to observation of effects of GHB in rats, mice and pigeons, is funded by a $3 million grant from the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
"Where this could lead down the road is to the development of GHB-selective antidotes to help those who show up in emergency rooms with GHB overdose, either from abuse or date-rape victimization," says Charles P. France, Ph.D., professor of pharmacology at the Health Science Center and the project co-leader with Maharaj K. Ticku, Ph.D., professor of pharmacology. Dr. France, who joined the Health Science Center in 2000 from the Louisiana State University Medical School, has studied drug abuse for 26 years and has 150 scholarly publications. He is supported by a prestigious Research Scientist Award from NIDA.
"Like most brain chemicals, GHB is very complex and difficult to understand," says Dr. Ticku, who has 180 scholarly papers. "Its known interactions with other nerve cell systems do not adequately explain the date-rape effect nor do they explain GHB’s mediation of sleep and arousal." His work on this project is supported by research grants from both NIDA and NIAAA, and he is a National Institutes of Health MERIT award recipient. MERIT awards are bestowed on only the top 1 percent of the nation’s scientists.
GHB is a "neurotransmitter" – a courier that relays information between nerve cells. Continuous, efficient transfer of countless bits of information is essential for healthy brain function. GHB in the brain is converted into another neurotransmitter, GABA, which is the main inhibitory neurotransmitter in the body. GABA decreases activity of a third neurotransmitter, glutamate, which is the main excitatory neurotransmitter in the body. "It’s a finely tuned system," comments GHB project contributor Wouter Koek, Ph.D., associate professor of psychiatry at the Health Science Center and holder of the START Center Medication Research Professorship.
The Health Science Center researchers contracted with Andrew Coop, Ph.D., of the University of Maryland, Baltimore, to make GHB look-alikes that no longer interact with GABA receptors and therefore are not converted to GABA. "These are chemical tools for teasing out the role of GHB," Dr. Koek says. Dr. Ticku says Dr. Coop’s contribution is vital because no such tools exist to study the pharmacology of GHB.
GHB can be a powder or a liquid, is odorless and dissolves easily – a prime reason that users put it into alcohol. Because of its abuse potential, GHB is a significant public health hazard. It caught the eye of the National Institutes of Health in the 1990s after GHB formulations began to be used as club drugs and as ingredients in body-building supplements. GHB overdose can generate seizures and a near-coma state. Because it rapidly clears the body, it is difficult to detect. "Six to eight hours after exposure, you can only find small traces if any," Dr. Ticku says.
Although dangerous when it is abused, GHB is the best – and currently only – FDA-approved medication to treat narcolepsy. "It normalizes sleep patterns, which is a quirky thing about GHB," Dr. France says. Whereas sedative drugs interfere with the most restful phase of sleep, called REM or rapid eye movement, GHB increases it. "It improves the quality of sleep in narcoleptics, who have fragmented sleep and daytime sleepiness," says Paul Ingmundson, Ph.D., clinical professor of psychiatry and neurology at the Health Science Center and director of the sleep clinic at the South Texas Veterans Health Care System.
Because of its history as an abused drug, GHB has an FDA approval that is unlike any other medication. "There is a central pharmacy in the Washington, D.C., area and a central registry of physicians and patients," Dr. Ingmundson said. "You don’t go to the corner drugstore and pick up your GHB. The FDA knows how many pills are out there."
Narcolepsy has a prevalence of about 6 in 10,000, similar to other neurological disorders. "Learning more about how GHB works could help us learn how to even more efficiently induce beneficial sleep," Dr. Koek says. And with the problem of GHB abuse and GHB-related crime, learning how this neurotransmitter relays information among the brain’s nerve cells could save lives in hospital emergency rooms. "There are so many mechanisms with which it interacts," Dr. Ticku says. "These are targets of future research."
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