Chemical pathways of serotonin in the nervous system pave way for future pharmaceutical treatments for depression

From mollusks to mammals, newly discovered chemical pathways of serotonin in the nervous system are paving a path toward future pharmaceutical treatments for depression and other disorders.

"Understanding novel serotonin pathways in a tissue-dependent manner is useful for the development of pharmaceuticals intended to preserve serotonergic signaling," said Jeffrey N. Stuart, a doctoral student in the department of chemistry at the University of Illinois at Urbana-Champaign.

Recent findings by Stuart and his Illinois colleagues were the topic of a talk, "Characterization of Novel Serotonin Biochemical Pathways for Potential Therapeutic Applications," last month at the American Chemical Society's 228th National Meeting in Philadelphia and of a paper in the August issue of the Journal of Neurochemistry.

Serotonin (5-hydroxytryptamine, or 5-HT) is a neurotransmitter present throughout the body. When nerve cells containing it are activated, serotonin is released. It travels and stimulates other nerve cells, enabling their message to spread through the nervous system.

"When serotonin is released, you do not want its signal to last forever," said Jonathan Sweedler, professor of chemistry and Stuart's academic adviser. The signal caused by serotonin is turned off by enzymes that inactivate it by converting it into various metabolites, such as the ones discovered by Stuart.

Disruptions of serotonin signaling pathways are thought to occur in disorders such as depression, anxiety, sudden infant death syndrome, attention deficit hyperactivity disorder and irritable bowel syndrome. Many pharmaceutical treatments restore the pathways by preventing the cellular uptake of serotonin, where it is converted to other metabolites, or by directly inhibiting the enzymes responsible for the molecular conversion.

Because serotonin is distributed throughout the body, pharmaceuticals intended to correct serotonin imbalances in a specific tissue, such as in the brain, ultimately take effect in other tissues as well. That potentially leads to unwanted side effects.

Stuart, using a detection system built to measure serotonin and related compounds, found two new serotonin metabolites in the nervous system of marine mollusks. The metabolites were in separate yet adjacent body tissues, suggesting, he said, that different chemical pathways exist to convert serotonin.

"Characterization of site-specific serotonin pathways could provide novel means by which to more precisely target tissue-specific diseases related to 5-HT, such as in the brain or enteric nervous system," he said. "Because enzymes exist in mammals that can convert serotonin into metabolites, future treatments of nervous system disorders could exploit these pathways so that only a specific pathway in a specific tissue is affected."

Marine mollusks, such as the species Aplysia californica and Pleurobranchaea californica that were used in these experiments, are considered to be ideal model systems to study serotonin processing because they have simpler nervous systems than mammals. "They have larger, more easily identified neurons," Stuart said.

Mollusks are also good model systems because they show some mammal-like qualities that influence behavior, such as learning and memory, a discovery for which the Nobel Prize in Physiology or Medicine was awarded in 2000 to Eric Kandel of Columbia University in New York. Kandel studied how learning behavior was related to serotonergic and other signaling pathways in Aplysia californica, which are sea slugs the color of a purple plum that range up to a melon in size.

Aplysia californica live in warm, shallow water off the California coast in areas rich in vegetation where they feed on algae. Pleurobranchaea californica live in the cold, dark depths of the ocean floor, "and each one resembles a wet brown paper bag with the appetite and table manners of a hyena," said Rhanor Gillette, a professor in the department of molecular and integrative physiology at Illinois. He collaborated with Stuart and Sweedler to study how serotonin metabolites relate to behavior.

As predators, Pleurobranchaea feed voraciously on marine animals, including other Pleurobranchaea, ocean-bottom dwelling invertebrates and some fish. The Pleurobranchaea used in the Illinois research are captured in trawl nets off the southern California coast.

Like Aplysia, Pleurobranchaea also display learning and memory behaviors influenced by serotonin. "Serotonin is a major factor in organizing the behavior of Pleurobranchaea, particularly for feeding," Gillette said. "Some potential prey have dangerous, stinging defenses. In a single encounter, Pleurobranchaea learn to avoid their odor, Pleurobranchaea learn to avoid it by doing a characteristic avoidance turn during subsequent encounters. We are working with the serotonin pathways that underlie the odor learning."

Stuart reported at the ACS meeting that hungry Pleurobranchaea had more serotonin sulfate, one of the newly discovered serotonin metabolites, which could indicate that serotonin sulfate is a signal for hunger.

Stuart and Jason Ebaugh, a doctoral student in the neuroscience program, measured the blood levels of serotonin sulfate as a time-of-day function. It may be important for growth, most of which occurs during sleep, Gillette said. It's possible that the role of serotonin sulfate in marine mollusks is similar to melatonin, which resests the circadian clock in humans, Stuart and colleagues suggested in the Journal of Neurochemistry.

"This is the first quantitative measure of how serotonin metabolites are related to a behavioral state in marine mollusks," Sweedler said. "What we do not know is whether serotonin sulfate causes the behavior or whether the behavior causes the elevation of serotonin sulfate."

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