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.