Some antipsychotic drugs that work by stimulating serotonin receptors in the brain may be missing their mark. A new study revealed that those drugs that treat depression, schizophrenia, and other psychotic conditions and that target a particular protein on brain cells might not be triggering the most appropriate response in those cells. The Ohio State University Medical Center research examined the serotonin 2A receptor, a protein on brain cells that is sensitive to the neurotransmitter serotonin. The study examined the early chemical events that occur within neurons when the 2A receptor is stimulated by serotonin and by a synthetic hallucinogenic agent that is thought to mimic serotonin. The findings, published online in the early edition of the Proceedings of the National Academy of Sciences with an accompanying editorial, show that although both compounds combine with and activate this receptor, they trigger different chemical pathways inside the neuron. Researchers claim the work could have important implications for the development of drugs that affect the serotonin 2A receptor.
“This new insight into how serotonin and a hallucinogenic drug affect this serotonin receptor could lead to changes in how new drugs are screened and developed for depression, schizophrenia, and other neuropsychiatric disorders,” says study leader Laura M. Bohn, an associate professor of pharmacology and psychiatry. Currently, it is thought that when serotonin binds with the receptor, it sends a signal that activates molecules inside the cell called G proteins. This study shows, however, that the receptor responds to serotonin by also activating a protein called beta-arrestin inside the cell. The synthetic hallucinogen, on the other hand, causes the receptor to activate only the G proteins. The hallucinogen does not seem to use beta-arrestins to cause its effects. For this study, Bohn and her colleagues used laboratory-grown cells and a strain of mice that lacked beta-arrestin. The hallucinogen was a hallucinogenic amphetamine called DOI.
When the researchers injected normal—or control—and experimental mice with DOI, both groups showed a head-twitch behavior, a characteristic response in mice to hallucinogens. But when the mice were given high doses of serotonin, which typically also causes the head-twitch behavior, the behavior occurred in the control animals only, and not in the mice lacking beta-arrestin. “That demonstrates that the signal for serotonin requires beta-arrestin for that biological effect,” Bohn says. “The synthetic hallucinogen, on the other hand, induces the head-twitch behavior whether beta-arrestin is present or not. Overall, our findings suggest that the screening of agents intended to be serotonin mimics must also determine if the agent signals through beta-arrestin,” Bohn says. “That isn’t done now.”
In the central nervous system, serotonin is believed to play an important role as a neurotransmitter in the regulation of anger, aggression, body temperature, mood, sleep, vomiting, sexuality, and appetite. Serotonin is also a peripheral signal mediator and is found extensively (nearly 90%) in the human gastrointestinal tract; the major storage place is platelets in the blood stream. Recent research also suggests that serotonin plays an important role in liver regeneration and acts as a mitogen—induces cell division—throughout the body.
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