Obscure brain chemicals draw new attention.

When it comes to the chemistry of the human brain, dopamine and serotonin are the reigning stars. Like other neurotransmitters, they trigger and modulate the electrical signals that nerve cells use to communicate.

In comparison, the chemicals called trace amines are considered mere bit players. Now, a study reveals that people have genes that encode cell-surface proteins dedicated to responding to trace amines.

"I think this is going to reinvigorate the field [of trace amines]," says Beth Borowsky of Synaptic Pharmaceutical Corp. in Paramus, N.J. "There's a lot of evidence that they may be involved with both schizophrenia and depression." Borowsky and her colleagues at the firm describe the genes for the trace-amine receptors in an upcoming issue of the PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

Trace amines, so-named because they're present at low concentrations in the human brain, drew considerable interest in the 1960s. They turned out to be the key neurotransmitters in insect brains, but interest in the chemicals waned when scientists failed to find dedicated receptors in vertebrates. The low concentrations of trace amines and their rapid turnover in the brain also made them difficult to study. Meanwhile, scientists identified receptors for dopamine and serotonin, which led to the development of crucial drugs.

The trace amines, which include tyramine, beta-phenylethylamine (beta-PEA), tryptamine, and octopamine, continued to draw some attention. Studies showed that diets rich in these chemicals, can elevate a person's blood pressure and trigger migraines in patients taking antidepressants known as MAO inhibitors.

Borowsky and her colleagues didn't set out to find trace-amine receptors. They were instead looking for new serotonin receptors. Using DNA sequences of known serotonin receptors, they scanned the rat and human genomes for related genes. The search pulled up a new family of receptors, numbering 15 so far.

Curiously, rats have more than a dozen genes in the new family, while the human genome seems to contain just four. The researchers haven't tested all the new receptors, but they've shown that several respond to octopamine, tyramine, and beta-PEA. They've also confirmed that cells in the human brain, as well as those elsewhere in the body, make the receptors.

To tease out the function of the receptors, Synaptic Pharmaceuticals is developing compounds that block or activate the proteins. The firm has also begun testing such compounds in animals with symptoms associated with depression or schizophrenia.

"We think these [receptors] are potentially good drug targets," says Borowsky.

Although still speculative, the link between mental illness and trace amines has several lines of evidence supporting it. Depressed people often have less than normal concentrations of beta-PEA and tyramine in their urine. This finding led to a theory that a deficiency in trace amines causes depression. Moreover, MAO inhibitors and newer antidepressants such as fluoxetine hydrochloride (Prozac) alter the concentrations of trace amines in the brain.

As for schizophrenia, a surplus of trace amines may be part of the problem. Scientists have found elevated concentrations of beta-PEA in the urine of people with paranoid schizophrenia.

Marc G. Caron of Duke University Medical Center in Durham, N.C., is also curious about the role the new receptors play in the brain pathways active in drug addiction. A recent study in fruit flies implicated one of the trace amines in the insect's response to cocaine, for example.

With their receptors now center stage, trace amines will step back into the limelight, predicts Borowsky.

"It's a whole new ball game," agrees Caron.