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OHSU Researchers Discover New Cellular Signaling System

   Portland, Ore.

Newly discovered receptor is stimulated by the rave party drug ecstasy and appears to regulate important physiological and behavioral processes in the body

Researchers at Oregon Health & Science University have discovered a new signaling system in the brain. Scientists at OHSU, joined by an international team of scientists, report the discovery of cellular structures called trace amine receptors (TARs) that respond to mood-altering drugs like amphetamine and the rave party drug ecstasy (MDMA). The finding provides scientists with a new perspective on how these widely used drugs produce their effects. David K. Grandy, Ph.D., an associate professor of physiology and pharmacology in the OHSU School of Medicine, directed the work. The results of the study were recently published in the journal Molecular Pharmacology and presented at the annual meeting of the American College of Neuropsychopharmacology.

As their name implies, the trace amines are molecules that are found in our bodies in low amounts. These compounds have been of interest to doctors and scientists for years. Structurally related to the neurotransmitters dopamine, adrenaline and serotonin, the trace amines have long been suspected of having effects on body temperature, blood pressure and mood, but their mode of action was unclear. Intriguingly, trace amines can be found in some foods and beverages, including chocolate, hard cheeses, red wine and beer, but they are usually rapidly broken down during digestion.

The OHSU effort that led to the characterization of these TARs began when James Bunzow, a research associate at OHSU, discovered a piece of what looked like a previously unknown receptor.

"Because this fragment shared many features with the G protein-coupled receptors for dopamine, serotonin and adrenaline, we suspected it was from a receptor activated by a small, biogenic amine-like molecule," said Bunzow.

Although their hypothesis turned out to be correct, it was difficult to test for years due to some unusual properties of the TARs. However, a structure-function analysis was eventually performed in collaboration with Mark Sonders, Ph.D., working in the laboratory of Susan Amara, Ph.D., at the OHSU Vollum Institute. According to Grandy, what they found was "pretty remarkable!"

"First, our results clearly demonstrate that vertebrates express a receptor for trace amines, thereby resolving a nearly century-old debate about the existence of such a signaling pathway in species other than insects. Second, these studies reveal a new target for mood-altering drugs, such as amphetamines and ecstasy, demonstrating that these widely abused drugs have at least two molecular modes of action, a finding that may help explain some of the life-threatening side effects, such as extreme hyperthermia that has been associated with ecstasy overdoses. Finally, and perhaps most intriguingly, TAR is activated by compounds that were previously thought to be inactive degradation products of the more abundant neurotransmitters dopamine and adrenaline," said Grandy.

Given the drug profile of this receptor and its location in the body, Bunzow and Grandy have speculated that the activation of human TARs may account for some of the clinical side effects produced by therapeutic medications that affect metabolism.

"It also seems noteworthy that the drugs that stimulate TAR, such as LSD, mescaline, ecstasy, methamphetamine, amphetamine and others, are also capable of profoundly altering a person's perception of reality," said Grandy. "This relationship suggests to us that trace amine signaling may be important for the brain to process and respond to external and internal sensory information. If so, a dysfunctional trace amine system might contribute to a variety of mental states, including depression, anxiety and perhaps even psychosis. Such conjecture may not be too far-fetched since the gene for a human TAR is located on chromosome 6 in a region that has been repeatedly associated with schizophrenia."

"We're hoping that this receptor might turn out to be a target site for drugs designed to combat schizoprenia and other mental disorders," added Bunzow. "Overall, this discovery is very special because it defines a novel transmitter system in the brain that may be involved in numerous brain functions and disease."

This research was supported by the National Institute on Drug Abuse, a component of the National Institutes of Health.

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