Summary: Researchers have uncovered two key brain mechanisms—specific neurons and a serotonin receptor—that help explain how psilocybin produces long-lasting antidepressant effects. Their study identified pyramidal tract neurons in the medial frontal cortex and the serotonin 5-HT2A receptor as essential to the therapeutic action of psilocybin.
Interestingly, while the mood-boosting effects depend on the frontal cortex, the hallucinatory “trip” may arise from different brain areas like the visual system. These insights could inform new ways to deliver psychedelics more selectively, maximizing benefits while minimizing perceptual side effects.
Key Facts:
- Cell Target Identified: Pyramidal tract neurons in the medial frontal cortex mediate psilocybin’s antidepressant effects.
- Receptor Involved: The serotonin 5-HT2A receptor is essential for both therapeutic and hallucinatory responses.
- Implication for Drug Design: Region-specific drug delivery may separate therapeutic benefits from hallucinations.
Source: Cornell University
Psilocybin is the active ingredient that gives so-called “magic mushrooms” their hallucinogenic kick. It also has a therapeutic potential for treating depression.
Now, Cornell University researchers have identified a pair of key neurological mechanisms in the brain – a cell type and receptor – that enable the psychedelic compound’s long-lasting effects.
Targeting the pyramidal tract neurons and their specific serotonin 5-HT2A receptor in the medial frontal cortex could enable pharmaceuticals to deliver psilocybin’s mood-altering benefits while suppressing the perceptual hallucinatory trip.
The findings were published in Nature.
The lab of senior author Alex Kwan, associate professor of biomedical engineering, led the project.
“Building off a previous study, we wanted to see where the neuronal connections are grown in the different cell types in the brain,” said Kwan.
“We started playing around with these cell types, and we asked: Which are important for psilocybin’s behavioral effects? If we silence some of these neurons, will psilocybin still be able to do its thing and be therapeutic?”
Essentially, the frontal cortex is important for therapeutic effects, whereas the subjective perceptual effects – i.e., “the trip” – likely rely on another region of the brain, such as visual pathways. This could have important implications for pharmaceutical treatment.
“Right now, a huge focus from the pharmaceutical companies is on developing drugs that may be able to take out the trip but still give you the benefit for treating mental illnesses,” Kwan said.
“But what this work shows is that that could be difficult, because in the end, they target the same receptor. So one might think about just delivering the drug to some specific brain areas, which can be a better way to do it.”
Funding: The research was supported by the National Institutes of Health; a One Mind–COMPASS Rising Star Award; Source Research Foundation; and the Connecticut Department of Mental Health and Addiction Services.
About this neuropharmacology and psychedelics research news
Author: Becka Bowyer
Source: Cornell University
Contact: Becka Bowyer – Cornell University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors” by Alex Kwan et al. Nature
Abstract
Psilocybin’s lasting action requires pyramidal cell types and 5-HT2A receptors
Psilocybin is a serotonergic psychedelic with therapeutic potential for treating mental illnesses.
At the cellular level, psychedelics induce structural neural plasticity, exemplified by the drug-evoked growth and remodelling of dendritic spines in cortical pyramidal cells.
A key question is how these cellular modifications map onto cell-type-specific circuits to produce the psychedelics’ behavioural actions.
Here we use in vivo optical imaging, chemogenetic perturbation and cell-type-specific electrophysiology to investigate the impact of psilocybin on the two main types of pyramidal cells in the mouse medial frontal cortex.
We find that a single dose of psilocybin increases the density of dendritic spines in both the subcortical-projecting, pyramidal tract (PT) and intratelencephalic (IT) cell types.
Behaviourally, silencing the PT neurons eliminates psilocybin’s ability to ameliorate stress-related phenotypes, whereas silencing IT neurons has no detectable effect. In PT neurons only, psilocybin boosts synaptic calcium transients and elevates firing rates acutely after administration.
Targeted knockout of 5-HT2A receptors abolishes psilocybin’s effects on stress-related behaviour and structural plasticity.
Collectively, these results identify that a pyramidal cell type and the 5-HT2A receptor in the medial frontal cortex have essential roles in psilocybin’s long-term drug action.
