How Do Psychedelics Promote Neuroplasticity?
Post by Leanna Kalinowski
The takeaway
Activating serotonin 2A receptors within the cell membrane is necessary for promoting the neuroplasticity-inducing and antidepressant-like effects of psychedelics.
What's the science?
Several neuropsychiatric diseases, including depression, are marked by a decrease in dendritic spine density in the cortex. Due to the ability of psychedelics to promote neuroplasticity (e.g., the regrowth of these dendritic spines) in the brain, psychedelics have emerged as a promising treatment for neuropsychiatric diseases. While it is known that neuroplasticity can be promoted by activating serotonin 2A receptors (5-HT2ARs) in the brain, the mechanisms by which this occurs following psychedelic administration are still poorly understood. This week in Science, Vargas and colleagues uncovered the mechanisms by which psychedelic-induced activation of 5-HT2ARs promotes neuroplasticity and antidepressive-like behaviors in mice.
How did they do it?
In the first experiment, the researchers determined the primary location of serotonin 2A receptors (5-HT2ARs) within neurons. To do this, they first tagged in vitro (i.e., in a petri dish) human embryonic kidney cells (a control) and cortical neurons with a fluorescent marker, and then tagged b2 adrenergic receptors (control receptors) and 5-HT2ARs with a different fluorescent marker. The location of each receptor type was then mapped relative to the cell membrane of each cell type.
In the second experiment, the researchers tested whether it was necessary for psychedelics to cross the cell membrane in order to promote neuroplasticity. To do this, they treated in vitro rat embryonic cortical neurons in a petri dish with either (1) psychedelics that are capable of crossing cell membranes (i.e., DMT & psilocin) or (2) versions of these psychedelics that were chemically modified into substances that are incapable of crossing cell membranes (i.e., TMT & psilocybin). Half of these substance administrations were done in the presence of electroporation, which creates temporary openings in the cell membrane so membrane-impermeable substances can cross, while the other half were not. Following substance administration, the researchers measured dendritogenesis, which is a form of neuroplasticity defined as the formation of new dendrites.
In the third experiment, the researchers tested whether importing serotonin into neurons promotes neuroplasticity in mice. To do this, they first engineered mouse neurons to express serotonin transporter (SERT), which acts as a gate to allow serotonin into the cell. Half of the mice received an intra-mPFC injection of the virus that causes its neurons to express SERT, while the other half of the mice received a control injection into the mPFC. Then, after three weeks, both groups of mice were given an intraperitoneal injection of para-chloroamphetamine (PCA), which is a drug that causes the release of serotonin. 24 hours following this injection, markers of neuroplasticity (i.e., dendritic spine density) were assessed.
The fourth and final experiment was like the third experiment, except this time, the researchers tested whether importing serotonin into neurons promotes antidepressant-like behaviors in mice. Three weeks after the procedure to create SERT-positive neurons in the mPFC, mice were placed in a container of water and given a baseline forced swim test to test depressive-like behaviors without the presence of serotonin. In this test, mice who stop trying to swim to escape the container after a shorter period of time are considered to be exhibiting more depressive-like behaviors. Two days after the baseline forced swim test, mice were injected with PCA to facilitate the release of serotonin, after which they were once again administered a forced swim test.
What did they find?
From the first experiment, the researchers found that within kidney cells (controls), both receptor types (b2 adrenergic & 5-HT2ARs) were localized along the cell membrane. However, within cortical neurons, b2 adrenergic cells (controls) were localized on the cell membrane, while 5-HT2ARs were localized within the cell membrane. This is unique from most other G-protein-coupled receptors that are generally located along the cell membrane.
From the second experiment, the researchers found that regardless of whether electroporation was applied, membrane-permeable psychedelics (i.e., DMT and psilocin) always promoted neuroplasticity within cortical neurons. On the other hand, membrane-impermeable psychedelics (i.e., TMT and psilocybin) were only able to promote neuroplasticity when temporary openings in the cell membrane were present due to electroporation. Together, these findings suggest that psychedelics can only promote neuroplasticity when they are able to cross neuronal cell membranes.
From the final two experiments, the researchers first found that SERT-expressing mice that were administered PCA displayed higher markers of neuroplasticity (i.e., dendritic spine density) compared to controls. In addition, they found that these mice also displayed a reduction of immobility in the forced swim test, which is indicative of anti-depressive-like behaviors. Together, these results suggest that importing serotonin into neurons promotes neuroplasticity and antidepressant-like effects in mice.
What's the impact?
Results from this study have the potential to transform how scientists think about psychedelics and other drugs that target the serotonin system. Now that we know that (1) 5-HT2ARs are located within the cell membrane, (2) serotonin generally cannot cross the cell membrane to bind to these 5-HT2ARs, and (3) many psychedelics can cross the cell membrane to bind to these 5-HT2ARs, scientists are equipped to develop future treatments for neuropsychiatric disorders in which 5-HT2ARs are implicated. Future studies should evaluate the potential of other drug classes to bind to intracellular targets and produce therapeutic effects.
