Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2024
Mehdi Sekssaoui, Joël Bockaert, Philippe Marin et al.
76 citations
A single injection of psychedelic or non-hallucinogenic drugs that activate the serotonin 5-HT2A receptor can produce antidepressant- and anxiety-reducing effects in mice with a depression-like condition, lasting up to 15 days. The non-hallucinogenic drug lisuride was effective, suggesting hallucinogenic properties are not required for antidepressant action. In mice lacking the 5-HT2A receptor, the psychedelic DOI was ineffective, but psilocybin still worked, indicating psilocybin's effects can occur through other mechanisms. Blocking other serotonin or dopamine receptors did not stop psilocybin's effects in these mice. These results suggest that 5-HT2A receptor agonists can relieve depression through multiple pathways, independent of whether they cause hallucinations.
Molecular & Cellular Proteomics
March 18, 2014
Samah Karaki, Carine Bécamel, Samy Murat et al.
73 citations
The serotonin 5-HT(2A) receptor is a primary target of psychedelic hallucinogens like LSD, mescaline, and psilocybin, which mimic some schizophrenia symptoms. A paradox is that some 5-HT(2A) receptor agonists cause hallucinations while structurally similar ones do not. Comparing the phosphoproteome in HEK-293 cells expressing the 5-HT(2A) receptor, 16 phosphorylation sites differed between the hallucinogen DOI and the nonhallucinogenic agonist lisuride. One site, serine 280 in the receptor's third intracellular loop, was specifically phosphorylated by hallucinogens. In mice, DOI enhanced this phosphorylation in the prefrontal cortex, while lisuride did not. Hallucinogens caused less receptor desensitization than nonhallucinogenic agonists. Mutating serine 280 altered desensitization, revealing biased phosphorylation underlies different desensitization capacities.
Current psychiatry reports
October 1, 2022
Damien Prouzeau, Ismaël Conejero, Peter L Voyvodic et al.
32 citations
Psilocybin shows large, rapid, and persistent clinical effects in treating resistant or end-of-life depression, with good tolerance and mild side effects limited to a few hours after dosing. However, studies to date have had small sample sizes, and one clinical trial against escitalopram did not show significant superiority of psilocybin on the main outcome. The neurobiological mechanisms, which differ from those of SSRI antidepressants, remain mostly unknown. Psilocybin is a promising alternative, but further research with larger samples and comparisons to standard treatments is needed.
bioRxiv Preprint Server
July 23, 2025
Tomas Del Olmo, Mathilde Decourcelle, Martial Séveno et al.
preprint
Psychedelic drugs like DOI trigger neuroplasticity in mouse brain cells through a reciprocal interaction between the serotonin 5-HT2A receptor and the metabotropic glutamate mGlu5 receptor, linked by the scaffolding protein Shank3. Phosphoproteomics showed that DOI increases phosphorylation of synaptic proteins including mGlu5 and Shank3. Both hallucinogenic and non-hallucinogenic 5-HT2A agonists promoted mGlu5's movement to synapses and its binding to Shank3. Neuroplasticity in cortical neurons required mGlu5, protein kinase C, and Shank3; conversely, mGlu5-driven plasticity depended on the 5-HT2A receptor. These findings demonstrate that psychedelics' neuroplasticity relies on a functional interplay between these two receptors and Shank3.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2022
Błażej D Pędzich, Sarah Rubens, Mehdi Sekssaoui et al.
Activation of the serotonin 2A (5-HT2A) receptor suppresses fear expression but does not affect retention of fear extinction. Using the psychedelic DOI in mice, the authors found that 5-HT2A receptor activation reduced anxiety-like avoidance behavior and diminished fear expression in multiple tasks, including passive avoidance and auditory fear conditioning. The effect depended on 5-HT2A receptors in the amygdala: local infusion of a 5-HT2A antagonist into the amygdala reversed the effect, while local DOI infusion into the amygdala was sufficient to suppress fear expression. These findings clarify a neural mechanism by which psychedelics may reduce fear, but provide no evidence that they enhance fear extinction memory.