Scientists from The Scripps Research Institute have figured out the pathway serotonin uses to mediate biological functions. They discovered that it is distinct from the signaling pathways used by hallucinogenic substances.
The study is published in the October 6 issue of the Journal of Neuroscience. The paper is titled “Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor via an ßArrestin2/Src/Akt Signaling Complex in Vivo.”
“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,” explains Laura Bohn, Ph.D., an associate professor on the Florida campus. “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.”
Traditional therapies for depression focus on elevating serotonin levels, Dr. Bohn points out. This can sometimes produce serious side effects such as a serotonin syndrome, which is often accompanied by hallucinations. It is especially serious when antidepressant treatments such as selective serotonin reuptake inhibitors (SSRIs) are mixed with monoamine oxidase inhibitors (MAOIs).
The scientists' current study supports a long-standing hypothesis that hallucinations may arise from the metabolites formed from elevated serotonin levels. Since there is a difference in the way the two neurotransmitters signal, this may represent a means to preserve the effects of serotonin while preventing the adverse side effects caused by the metabolites.
Dr. Bohn and her team showed that serotonin signals through the serotonin 2A receptor by recruiting a regulatory protein called ßarrestin2. They found that the actions of serotonin at the receptor are far different from those produced by hallucinogenic N-methyltryptamines, a class of naturally occurring substances found in several plants and in minute amounts in the human body and includes the abused drug DMT. The study found that the N-methyltryptamines activate the serotonin 2A receptor independently of ßarrestin2.
Both serotonin and the N-methyltryptamines produce what is known as a head twitch response in animal models, which indicates that the serotonin 2A receptor has been activated. Any interruption in the exclusive serotonin pathway prevents that behavioral response to serotonin but has no effect on N-methyltryptamine-induced head twitches, indicating 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,” Dr. Bohn notes. “But whether the lack of this complex formation is why compounds like DMT lead to hallucinations is not clear.”