Therapeutic Effects of Psychedelic Drugs May Depend on Receptor Location, Study Suggests

The results of research by scientists at the University of California, Davis, suggest that receptor location may be key to the function of psychedelic drugs that could potentially treat mental illness by rapidly rebuilding connections between nerve cells. The team’s work, using molecular and genetic techniques, showed that engaging the 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) inside neurons promotes growth of new connections, but engaging the same receptor on the surface of nerve cells does not.

The findings could help guide efforts to discover new drugs for depression, post-traumatic stress disorder (PTSD) and other disorders, suggested senior author David E. Olson, PhD, associate professor of chemistry, biochemistry and molecular medicine and director of the Institute for Psychedelics and Neurotherapeutics at UC Davis. Reporting on their work in SciencePsychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptor,” Olsen and colleagues stated, “This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.”

Drugs such as LSD (lysergic acid diethylamide), MDMA (3,4-methylenedioxy-N-methamphetamine) and psilocybin show potential promise for treating a wide range of mental disorders that are characterized by a loss of neural connections. “Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases,” the authors explained, “and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics.”

In laboratory studies, just a single dose of these drugs can cause rapid growth of new dendrites—branches—from nerve cells, and formation of new spines on those dendrites. Olson calls this group of compounds psychoplastogens because of their ability to regrow and remodel connections in the brain. This rapid activity appears distinct from that of drugs such as selective serotonin reuptake inhibitors (SSRI), which require longer-term administration, the authors pointed out. “A class of therapeutic compounds known as psychoplastogens are differentiated from SSRIs by their ability to produce both rapid and sustained effects on structural plasticity and behavior after a single administration,” the authors stated.

Earlier work from Olson’s and other labs had showed that psychedelic drugs work by engaging the serotonin 2A receptor. But other drugs that engage the same receptor, including serotonin, do not have the same growth effects. And interestingly the team noted, “Unlike psychedelics, the physicochemical properties of serotonin prevent it from entering cells by passively diffusing across the membrane.” Serotonin itself is polar, meaning it dissolves well in water but does not easily cross the lipid membranes that surround cells. The psychedelics, on the other hand, are much less polar and can easily enter the interior of a cell. “Thus, we reasoned that another form of functional selectivity, known as location bias, might explain the difference in cellular signaling elicited by serotonin and psychedelics.”

For the newly reported study, Olsen, together with Maxemiliano Vargas, a graduate student in Olson’s lab, and colleagues experimented with chemically manipulating drugs and using transporters to make it easier or harder for compounds to slip across cell membranes. The team’ work found that the growth-promoting ability of compounds was correlated with the ability to cross cell membranes.

Drug receptors are usually thought of as being on the cell membrane, facing out. But the researchers found that in nerve cells, serotonin 2A receptors were concentrated inside cells, mostly around the Golgi body structure, with some receptors being located on the cell surface. Other types of signaling receptors in the same class were on the surface.

The results showed that there is a location bias in how these drugs work, Olson said. Engaging the serotonin 2A receptor when it is inside a cell produces a different effect from triggering it when it is on the outside. “It gives us deeper mechanistic insight into how the receptor promotes plasticity, and allows us to design better drugs,” Olson commented. As the authors noted, “Our results demonstrate that membrane permeability is essential for a ligand to activate 5-HT2ARs in cortical neurons …”. However, they acknowledged, “… our experiments did not distinguish between intracellular signaling or the possibility of psychedelics acting as pharmacological chaperones.” And as they further pointed out, “future studies should determine whether intracellular 5-HT2AR signaling is distinct from 5-HT2AR signaling at the plasma membrane … Our results raise the intriguing possibility that serotonin may not be the endogenous ligand for the population of 5-HT2ARs expressed inside cortical neurons.”

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