RECEPTORS THAT ACT AS A SWITCH IN BRAIN WIDEN DRUG RESEARCH

Portland scientists are researching a brain switch that has turned on
everyone from tribal shamans to tripping hippies to today's raving club-goers.

The "switch" is a recently discovered, specialized brain protein that
interacts with a group of chemicals present in small amounts in the body.
The chemicals, called trace amines, connect with the specialized protein
receptors to send signals to the brain.

A host of drugs -- including many illegal recreational drugs such as
Ecstasy, amphetamines and LSD -- also turn on the receptors, said David
Grandy, an Oregon Health & Science University associate professor who
helped discover the trace amine receptors.

The brain signaling system may provide clues to how those drugs work, from
their perception-altering effects to dangerous side effects such as high
body temperatures, Grandy said.

OHSU researchers, seeking to better understand how drugs affect behavior on
the level of chemical molecules, started on their discovery trip about
eight years ago. They were studying receptors for dopamine, another
chemical messenger in the brain, and looking for similar receptors.

The scientists found one they couldn't turn on with several drugs they
tried. After more study, they realized that trace amines meshed with the
receptors, as did amphetamine and other drugs.

It was "sort of like you have a bunch of keys and one lock," Grandy said.
"And once we found the key that fit, it opened up a whole new world, I
think, of information."

The finding was surprising, because some scientists thought humans did not
have specialized trace amine receptors, Grandy said, but that trace amines
interacted with other systems, such as adrenaline receptors. More
surprising, Grandy said, is that the discovery indicated scientists did not
fully understand how amphetamine works, though it had been widely studied.

Grandy and others want to better understand the significance of the newly
discovered receptor. They know that such systems help people sense changes
in their environment and respond to them, he said.

For trace amines, "we're trying to understand what part of the experience
they control." To do that, OHSU researchers are mapping which genes in the
body make the receptors and where those receptors are in the brain.
Already, the scientists know that several genes code for the receptors,
providing "backup" copies. That indicates the system plays an important
biological role.

Grandy suspects the trace amine system "has something to do with how the
body regulates its energy metabolism." That could help explain some drug
effects, including why users of Ecstasy, a drug popular at rave parties,
have increases in their body temperature that can be fatal.

Trace amine receptors also may be linked to perception-altering
experiences, including hallucinations. Research has shown that the
receptors interact with LSD and mescaline, the drug that is found in cactus
and which is used by some tribal shamans, Grandy said.

Discovering more about trace amine receptors could help in the search for
new treatments for people who overdose on Ecstasy or amphetamine, Grandy
said, and perhaps help identify people prone to suffer ill effects from
those drugs.

Amphetamines and related drugs are prescribed fairly often, including for
attention deficit disorder. Better knowledge of how the drugs affect the
brain could help researchers design safer drugs and increase understanding
of attention deficit disorder, Grandy said.

The research also could shine light on schizophrenia, which is accompanied
by higher blood levels of trace amines. And it could improve the design of
ergotamines, a family of drugs that includes LSD and legal drugs used to
treat migraines and bleeding during childbirth.