New target receptors: Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

A recent paper found the psychedelics promote neuropasticity through intracellular 5-HT2A receptors. This series of experiments in mice (in vivo) and human cells (in vitro) found that a specific type of receptor called intracellular serotonin 2A receptor is partially responsible for neuroplasticity (growth-promoting effect). This suggests that intracellular, versus that on the surface of a neuron, serotonin 2A receptors could be a target for developing new therapies and that there is still much to be learned about how psychedelics (and other drugs) work in the brain.

Psychedelics are 5-hydroxytryptamine (2A) receptor (5-HT2AR) agonists that can lead to profound changes in perception, cognition, and mood. Recent evidence suggests that 5-MeO-DMT increases spine density in both male and female animals and that 5-HT2AR activation is necessary for sustained increases in both frequency and amplitude of spontaneous excitatory postsynaptic currents.

Abstract

“Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. 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.“

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