Johns Hopkins researchers have developed a new method for studying an important group of brain cells that they say should help define the cells' functions and help resolve the controversy over the safety of two popular diet drugs.
Using an imaging method called positron emission tomography (PET) and a new tagging compound, the researchers have found a way to visualize brain cells that release serotonin in animals.
Hopkins scientists and others showed in previous experiments that two popular diet drugs, fenfluramine and dexfenfluramine, can damage serotonin-releasing nerve cells in animals including non-human primates. Critics insist the damage does not occur in human brains.
Hopkins researchers plan to use the new PET technique to study humans who have used fenfluramine, widely prescribed for weight loss alone or in combination with another drug, phentermine, for several years. Studies of dexfenfluramine, approved earlier this year by the FDA as a prescription diet drug, are likely to follow. Studies of Ecstasy, a chemically related recreational drug, are already in progress.
"Using this technique to study humans exposed to fenfluramine will allow us to give doctors and patients a much better idea of exactly what risks these drugs may pose," says George Ricaurte, Ph.D., M.D., a Hopkins neurologist.
Because serotonin probably helps regulate mood, sleep, appetite, impulsive behavior, aggression and sexual behavior, the new imaging technique also could be useful in studies of a wide range of disorders.
One key to the Hopkins PET method is a compound, called a ligand, that Hopkins scientists developed in the laboratory. Researchers inject the ligand, equipped with a radioactive tag, into a subject's blood stream. The ligand seeks out and temporarily attaches to a protein on serotonin neurons called the serotonin transporter protein. PET scans then reveal how much of the protein is in the brain and where it is.
Ricaurte and others used the new scan on a baboon brain before and after injections of fenfluramine, and found decreased transporter protein. Autopsy confirmed damage to serotonin neurons.
"Because the effects of serotonin are so subtle, it's hard to say what side effects one might suffer as a result of serotonin neuron damage, and it's possible that these side effects might be confused with other disorders," Ricaurte notes. These potentially could include depression, anxiety, or problems with memory, sleep or sex, he notes.
"We already have evidence that this new technique may help move the debate over fenfluramine forward," says Ursula Scheffel, Sc.D., associate professor of radiology and lead author of the study. "Some researchers have argued that fenfluramine's effects on serotonin neurons are only short-term, but the baboon in our study still had serotonin deficits 81 days after exposure to fenfluramine."
This research was supported by grants from the National Institute on Drug Abuse, a branch of the National Institutes of Health. Other authors of the study, published in the December issue of Synapse, included Zsolt Szabo and Robert Dannals, also of Hopkins.
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