UT scientist conducts studies into effects of party drugs; may aid in new drug discoveries for Parkinson’s, Huntington disease

March 18, 2009 | Research
By Jim Winkler

Disco biscuits. Love doves. Shamrocks.

Colorful street nicknames, to be sure, but don’t be fooled by the recreational drug ecstasy and its close cousin, methamphetamine, said Dr. Bryan Yamamoto. They hold the potential of causing long-term damage to brain cells controlling mood, feelings of pleasure and emotions.

Dr. Bryan Yamamoto posed for a photo in his lab.

The laboratory research of Dr. Bryan Yamamoto is aimed at helping uncover the long-term health dangers of the party drugs ecstasy and methamphetamine.

Yamamoto, professor and chairman of the College of Medicine’s Department of Neurosciences, applies a wide-ranging research program to the dangers the two party drugs pose to the brain. He joined the UT faculty last year from the Boston University School of Medicine and has enjoyed continuous funding from the National Institutes of Health since 1986.

His studies, funded with grants totaling $1 million a year, could be used to develop better ways to prevent and treat drug abuse and to help develop therapies to fend off Parkinson’s and Huntington’s disease and other neurological disorders.

In low doses, methamphetamine and ecstasy generate feelings of euphoria and alertness — part of the brain’s so-called reward center — through the release of brain chemical messengers dopamine and serotonin. The drugs can increase blood pressure and heart rate and dangerously constrict blood vessels.

A growing concern, according to Yamamoto, is that the drugs may harm the brain over the long run. Methamphetamine causes the brain to produce free radicals — highly reactive molecules that kill brain cells, including those that produce dopamine and serotonin. Both drugs exhaust the brain’s supply of serotonin or dopamine, possibly by causing serotonin and dopamine transporters to reverse direction, pumping serotonin and dopamine out of neurons instead of sucking them back in. Some studies suggest that ecstasy — classified by the federal government as a drug with no known medical use and high potential for abuse — actually kills cells that produce serotonin.

The damage ecstasy causes to serotonin-producing cells, in fact, is oddly familiar, noted Yamamoto: “We are discovering that all these players involved in mediating the toxicity of amphetamines and ecstasy appear to be the same types of mechanisms that have been linked to the damage produced by Parkinson’s and Huntington’s disease. There are very close parallels to both of those drugs.”

“Free radicals have been implicated in mediating the damage in these diseases,” he continued. “By understanding how those free radicals are being produced, maybe we can understand the underlying causes of these diseases. These drugs are providing a valuable tool to produce and then better understand the damage.”

A major focus of his rat studies is the relationship between chronic stress and brain mechanisms affecting drug-use behaviors. In 2003, he was the first to demonstrate that if the animals are exposed to chronic stress prior to being given amphetamines, the drugs’ neurotoxicity dramatically increases. The findings appeared in the journal Psychopharmacology.

In vivo microdialysis studies allow him to peer inside the rats’ brains with probes that simultaneously monitor and record the release of dopamine at timed intervals and record the neural activity. “Most drug abusers are under a lot of stress — psychological stress, environmental stress,” he explained. “Many sufferers of post-traumatic stress syndrome have substance-abuse disorders. We are interested in examining how stress impacts the neurotoxicity of these drugs.”

An FDA-approved clinical trial is under way in South Carolina to determine whether ecstasy will benefit people, such as returning U.S combat troops, suffering from post-traumatic stress disorder. “Our animal studies would suggest that this is a very bad combination because chronically stressed individuals are more vulnerable to the toxic effects of these drugs,” Yamamoto said.

He also is studying how ecstasy can compromise neurons in the brain by damaging their mitochondria — the structures responsible for cellular energy production — causing the cells to essentially lose power.

Yamamoto’s research teams have made several significant findings. In 1992, he was the first researcher to demonstrate that at excessive levels, the brain amino acid glutamate is toxic, causing nerve cell stress that ends in cell death. The finding appeared in the journal Brain Research.

In 2005, he discovered in animal studies that by damaging the blood-brain barrier, a physical and chemical entity that provides a protective, stable environment for the brain, ecstasy leaves the brain vulnerable to invasion by viruses and other pathogens. His rat studies showed this vulnerability even 10 weeks after the initial exposure to the drug.

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