Sitting at a lab desk, more like a console than a table, Jane Smith intently grasps the space-age controls. A hint of perspiration crowns her forehead as the faint whine of a drill is replaced by the sound of slick-moving mechanical parts. She focuses on the deft hand movements needed to manipulate a threadlike glass pipette. Slowly it enters the shaved skull of her "anesthetized recording preparation" (in this case, a rat). Carefully she explores its brain cavity. She's hunting for certain cells, and she can hear them coming.

Smith, a graduate student in pharmacology at Penn State's Hershey Medical Center, is immersed in a lab technique called electrophysiology -- the study of electrical conductivity in animal tissue. She is trying to find the best chemical treatment for depression in the elderly."The incident rate of depression is over 18 percent in the elderly, compared to about 8 percent in young adults," she explains, "and it is also an early sign of Alzheimer's disease."

Depression affects 18 percent of the elderly, but only 8 percent of the young. Why? Is there a medical reason -- and perhaps a cure?

The playground for depression is, of course, the brain, but more specifically, the serotonergic system. The central nervous system abounds in molecules that shuttle back and forth between brain cells, or neurons, in spaces called synapses. One of these molecules, serotonin, can be likened to a good diplomat. Serotonin's headquarters is in the raphe nuclei, located in the most primitive part of the brain, the brainstem. Serotonin molecules travel like an entourage of ambassadors, opening up channels of communication between neurons. Despite being outnumbered one million-to-one by other neurons in the brain, the few hundred thousand serotonin neurons have great connections: each one exerts an influence over as many as 500,000 target neurons, according to a 1994 study by Barry Jacobs of Princeton University. Serotonin is a major player in such involuntary actions as digestion, respiration, and sensory processing, as well as in voluntary actions like the movement of limbs and fine motor functions. Most importantly for Smith, the lack of serotonin around brain synapses has been linked to depression.

Chemical treatments for depression pivot around keeping serotonin around the synapses for a longer time. Serotonin is normally removed by proteins called serotonin transporters, which take the molecule back into the cell where it is broken down. Antidepressants bind the serotonin transporters, making serotonin uptake impossible.

How, Smith asks, do these serotonin transporters change with age? To find out, she studied the interaction of antidepressants with serotonin transporters in four groups of rats: young (3-8 months), middle aged (11-12 months), old (17-22 months), and oldest old (27 months).Her pipette -- actually a very sophisticated instrument -- contains five barrels, one in the middle that records the cells' firing across the synapse, and four others that release serotonin and several different antidepressants, including one akin to prozac, and a new drug named duloxetine. The recording is done with a tiny electrode (only 10 microns or one-ten-thousandth of a millimeter across). Smith controls a filter, or window discriminator, that refines the electrode's recording signal by blocking out background noise. She hears cells coming because the discriminator is hooked up to a speaker as well as to a visual instrument called an oscilloscope. Watching and listening, Smith picks out a promising cell from its neighbors and starts collecting clues.

Interestingly, she has found that antidepressants don't work as well in older brains, especially in the oldest old category. Since many antidepressants work selectively on the serotonin transporter, antidepressant ineffectiveness means that the transporter is not functioning the same as it does in younger subjects. "Some people have done similar tests in the young and the oldest old, or young and middle age, but no one has looked at it over all four ages and using this in vivo preparation," she notes.

Smith must now unravel these electrophysiological clues. "I've started molecular work that will look at the actual serotonin transporter protein and correlate it with the animal's age," she says. "I want to see what declines: the number of proteins? or their efficiency in binding?"

Jane E. Smith is a graduate student in the department of pharmacology in the College of Medicine. Her adviser is Joan M. Lakoski, Ph.D., associate professor of pharmacology and anesthesia in the College of Medicine, Milton S. Hershey Medical Center, 500 University Dr.,Box 850, Hershey, PA 17033; 717-531-8287. Her work is supported by the Interdisciplinary Training Program in Gerontology and the deparment of pharmacology at Penn State, and by the National Institute on Aging.