Li-Huei Tsai believes their findings may lead to anti-depressant drugs with improved efficacy.

Although less than 1 percent of the brain's neurons produce dopamine, the neurochemical exerts powerful effects on motivation, reward, learning, memory, sexual desire, and pleasure. "To a large degree, dopamine is what makes us human," says HHMI investigator Li-Huei Tsai. Yet, scientists know relatively little about how this neurotransmitter is so vital for many different behaviors.

Neurotransmitters such as dopamine and serotonin are molecular messengers released by neurons to communicate information to neighboring neurons. Studies by two independent HHMI research teams are helping to clarify the molecular events that occur after dopamine binds to its receptors. Their findings may lead to new treatment strategies for depression, Parkinson's disease, and addiction.

In studies published in the July 27, 2005, issue of Cell, a research group led by Tsai at Harvard Medical School discovered a molecule that links faulty dopamine signaling in the brain to the neural machinery that breaks down in people with depression. The findings may explain why commonly prescribed antidepressants are ineffective for some people and why, for others, they can take weeks to work.

That long lag time has been one of the enduring puzzles in the treatment of depression, says Tsai. Antidepressants work by increasing levels of the neurotransmitters serotonin and/or noradrenaline in the brain. The efficacy of antidepressants, however, may depend more on changes to much later events that occur in the dopamine-signaling pathway.

Tsai and lead author Sang Ki Park wanted to know more about those downstream events—which may involve little-known signaling pathways that are triggered when one type of dopamine receptor, D2, is activated. Park launched the studies with a broad screen that turned up surprising information: A cell suicide molecule, prostate apoptosis response 4 (Par-4), interacted with a central regulatory segment of the D2 receptor.

Photo: Sean Kernan

	PAGE 1 OF 2	Continue