In what marks a significant finding in the advancement of psychedelic research, a new study has demonstrated that the location of serotonin 2A receptors (5-HT2A) is key to the effects of psychedelics.
Psychedelic drugs – such as LSD and psilocybin – have been showing potential as efficacious treatments for mental health conditions including depression and PTSD.
With mental health conditions often being characterized by a loss of neural connections, it is hypothosised that psychedelic substances may improve mental health by allowing the brain to enter into a state of ‘neuroplasticity’ – essentially enabling the creation of new neural pathways in the brain.
Previous studies have shown the substances cause the growth of new dendrites from nerve cells, and the formation of new spines on the dendrites. They do this by impacting the 5-HT2A receptor.
However, other drugs that also engage this receptor do not have the same growth impact on the nerve cells.
Previously, it wad unclear what caused psychedelic drugs to impact the growth of dendrites, however, now, a team of researchers at the University of California, Davis, has found that receptor location is key.
Location is key
Serotonin is able to dissolve in water, however, it is not able to easily cross the lipid membrane barriers of cells, while psychedelics can easily cross this lipid barrier and enter the interior of a cell.
For the study, senior author David E. Olson, associate professor of chemistry, biochemistry and molecular medicine and director of the Institute for Psychedelics and Neurotherapeutics at UC Davis, and his team including Maxemiliano Vargas, a graduate student in Olson’s lab, experimented with chemically tweaking drugs and using ‘transporters’ to make it easier or harder for compounds to cross cell membranes.
Vargas, Olson and the team found that the growth-promoting ability of compounds was correlated with the ability to cross cell membranes.
The researchers highlight that while drug receptors are usually thought of as being on the cell membrane, facing out, they found that in nerve cells, 5-HT2A receptors were concentrated inside cells. Mostly, they were concentrated around a structure called the Golgi body, with only some receptors on the cell surface.
Other types of signaling receptors in the same class were on the surface.
The results show there is a location bias in how these drugs work, Olson said, noting that engaging the 5-HT2A receptor when it is inside a cell produces a different effect from triggering it when it is on the outside.
Essentially, the findings show that engaging these receptors inside neurons promotes the growth of new connections – however, engaging the same receptor on the surface of nerve cells does not.
Olson said the study gives deeper insight into how the 5-HT2A receptor promotes plasticity and will enable the design of better drugs for mental health conditions.
The authors state:
The study has been published in the journal Science.
