For psychedelic medications to effectively cure mental disease by swiftly re-establishing connections between nerve cells, the location happens to be crucial. In a study published on February 17 in Science, scientists from the University of California, Davis, demonstrate that while activating serotonin 2A receptors inside neurons encourages the formation of new connections, doing so on the surface of nerve cells does not.
According to senior author David E. Olson, biochemistry and molecular medicine director of the Center for Psychedelics and Neurotherapeutics at UC Davis, the findings will help drive attempts to identify novel medications for depression, PTSD, and other diseases.
LSD, MDMA, and psilocybin show significant potential for treating a variety of mental diseases defined by a loss of neural connections. A single dose of these medications has been shown in laboratory trials to stimulate the rapid growth of new dendrites, or branches, from the nerve cells, as well as the production of new spines on those dendrites.
Olson refers to this class of medications as psychoplastogens due to their potential to repair and remodel brain connections.
Previous research from Olson’s and other labs demonstrated that psychedelic drugs function by activating the serotonin 2A receptor (5-HT2AR). That said, other medicines that act on the same receptor, such as serotonin, do not have the same growth effects.
Graduate student Maxemiliano Vargas worked in Olson’s lab as he and his colleagues experimented with modifying medications chemically and employing transporters to alter how easily or difficult substances crossed cell membranes. The polar nature of serotonin makes it highly soluble in water but difficult to pass through lipid membranes that enclose cells. Yet, psychedelics are far less polar and can easily enter the inside of a cell.
They discovered that the ability of compounds to cross cell membranes was connected to their ability to promote growth.
Drug receptors are frequently depicted as being on the cell membrane and pointing outward. Serotonin 2A receptors, however, were discovered by the researchers to be concentrated inside nerve cells, primarily surrounding a structure known as the Golgi body, with some receptors being present on the cell surface. On the surface, there were additional types of signalling receptors in the same class.
The outcomes demonstrate a bias in these medications’ actions based on geography, according to Olson. A distinct result is obtained when the serotonin 2A receptor is activated inside a cell as opposed to when it is activated externally.
Olson added that it allows them to create better medications because it offers them a deeper mechanistic understanding of how the receptor promotes plasticity.