Location, location, location is the key to psychedelic drugs that might treat mental illness by rapidly rebuilding the connections between nerve cells. In an article published on February 17 in Scienceresearchers from the University of California, Davis show that the engagement of serotonin 2A receptors inside neurons promotes the growth of new connections, but not the engagement of the same receptor on the surface of nerve cells.
The findings will help guide efforts to discover new drugs for depression, PTSD and other disorders, said lead author David E. Olson, associate professor of chemistry, biochemistry and molecular medicine and director of the Institute of Psychedelics and Neurotherapy at UC Davis.
Drugs such as LSD, MDMA and psilocybin show great promise for treating a wide range of mental disorders characterized by a loss of neural connections. In laboratory studies, a single dose of these drugs can cause new dendrites — branches — to grow rapidly from nerve cells and new spines to form on those dendrites.
Olson calls this group of drugs “psychoplastogens” because of their ability to regrow and reshape connections in the brain.
Previous work by Olson and other labs has shown that psychedelic drugs work by engaging the serotonin 2A (5-HT2AR) receptor. But other drugs that engage the same receptor, including serotonin, don’t have the same effects on growth.
Maxemiliano Vargas, a graduate student in Olson’s lab, Olson and his colleagues experimented with drugs that chemically modify and use transporters to make it easier or harder for compounds to glide across cell membranes. Serotonin itself is polar, which means it dissolves well in water but does not easily cross the lipid membranes that surround cells. Psychedelics, on the other hand, are much less polar and can easily penetrate inside a cell.
They found that the growth-promoting ability of the compounds correlated with the ability to cross cell membranes.
Drug receptors are generally considered to be on the cell membrane, facing outward. But the researchers found that in nerve cells, serotonin 2A receptors were concentrated inside the cells, mostly around a structure called the Golgi body, with some receptors on the cell surface. Other types of signaling receptors of the same class were on the surface.
The results show that there is a locational bias in how these drugs work, Olson said. Engaging the serotonin 2A receptor when it is inside a cell produces a different effect than firing it when it is outside.
“This gives us deeper mechanistic insight into how the receptor promotes plasticity and allows us to design better drugs,” Olson said.
Other authors of the article include: from UC Davis, Lee Dunlap, Chunyang Dong, Samuel Carter, Robert Tombari, Lin Tian, John Gray, Shekib Jami, Seona Patel, Lindsay Cameron and Hannah Saeger; Joseph Hennessey and John McCorvy of the Medical College of Wisconsin, Milwaukee. The work was supported by grants from the National Institutes of Health and the Camille and Henry Dreyfus Foundation, and by a sponsored research agreement with Delix Therapeutics.
