A significant discovery surrounding the inner workings of serotonin in the brain could someday have far-reaching impact on the development of new therapies for a number of disorders, including schizophrenia and depression.
Conducted by scientists at Scripps Research Institute, the study’s findings reveal that the neurotransmitter serotonin uses a specialized signaling pathway to mediate biological functions that are distinct from the signaling pathways used by hallucinogenic substances.
One of the key influencers of numerous functions in the brain, serotonin affects such areas as perception, cognition, sleep, appetite, pain, and mood by interacting with receptors located throughout the central and peripheral nervous systems.
“Our study shows that while both serotonin and hallucinogens act at the serotonin 2A receptor, serotonin utilizes a very specific pathway and its actions are independent of those produced by hallucinogens,” said Laura Bohn, an associate professor at The Scripps Research Institute.
“Future drug discovery efforts to identify lead compounds for treatment of depression may consider focusing upon those that only engage that pathway. This work may also lend insight into the mechanisms that underlie the hallucinations that occur in schizophrenia.”
This finding could impact treatment considerations for depression going forward as many drug therapies focus on elevating serotonin levels, which can lead to a serious side effect called serotonin syndrome. Often accompanied by hallucinations, this condition is especially serious when antidepressant treatments such as selective serotonin reuptake inhibitors (SSRIs) are mixed with monoamine oxidase inhibitors (MAOIs).
Supporting a long-standing belief that hallucinations may arise from the metabolites formed from elevated serotonin levels, the discovery of this specialized pathway may represent a means to preserve the effects of serotonin while preventing the adverse side effects caused by the metabolites, researchers said.
Specifically, the study revealed that serotonin signals through the serotonin 2A receptor by recruiting a regulatory protein called β-arrestin2. The actions of serotonin at the receptor were found to be far different than those produced by hallucinogenic N-methyltryptamines, a class of naturally occurring substances found in several plants and in minute amounts in the human body.
These substances are also found in the abused drug DMT.
The N-methyltryptamines activate the serotonin 2A receptor independently of β-arrestin2, researchers said.
The serotonin and the N-methyltryptamines both produce what is known as a head twitch response in animal models. Researchers determined that any interruption in the exclusive serotonin pathway prevents that response to serotonin but has no effect on N-methyltryptamine-induced head twitches.
This difference in response points to a distinct divergence in the signaling pathways utilized by these two neurotransmitters.
“Despite the fact that they activate the same receptor, serotonin leads to the assembly of a number of proteins associated with the receptor that the metabolites of serotonin do not produce,” Bohn said. “But whether the lack of this complex formation is why compounds like DMT lead to hallucinations is not clear.”
Bohn plans to continue investigating these questions.
The study was coauthored by Cullen Schmid, a graduate student in the lab and was published in the October 6, 2010 issue of the Journal of Neuroscience.
Source: Scripps Research Institute