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Article Abstract
Background: The psychedelic psilocybin has been posited as efficacious for the treatment of depression. However, the potential link between the intensity of acute psychedelic effects and long-term therapeutic outcomes remains undiscovered. Moreover, the impact of classical antidepressant drugs that modulate serotonergic activity on psilocybin's effects is a clinically relevant concern. The aim of the present study was to assess serotonergic mechanisms implicated in the regulation of the intensity of the psilocybin-induced acute effects.
Methods: The head-twitch response (HTR), the most translational behavioral assay to characterize the psychedelic-like effect in rodents was performed. Moreover, the role of endogenous serotonin (5-HT) on psilocybin-induced HTR was studied by in vivo brain microdialysis technique.
Results: Maximally effective psilocybin dose (1 mg/kg) induced progressively lower HTR in heterozygous and homozygous knockout mice for serotonin 2A receptor (5HT2AR), compared to wild type. Synaptic increase of 5-HT by citalopram dose-dependently attenuated psilocybin-induced HTR after both acute and chronic dosing regimens. Conversely, depletion of 5-HT by p-chlorophenylalanine potentiated psilocybin-evoked HTR. Serotonin 1A receptor (5HT1AR) agonist 8-OH-DPAT dose-dependently decreased psilocybin-induced HTR, demonstrating functional interaction between 5HT2AR and 5HT1AR for psychedelic effects.
Conclusions: The present findings reveal an inverse correlation between cortical 5-HT levels and the acute psychedelic-like effects of psilocybin. Consequently, the enhancement of serotonergic activity induced by prior antidepressant treatment may underlie interindividual variability in the acute response to psychedelics. Investigating these mechanisms in relation to the sustained therapeutic outcomes of psilocybin could contribute to optimizing the efficacy of psychedelic-based therapies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202319 | PMC |
| http://dx.doi.org/10.1093/ijnp/pyaf035 | DOI Listing |
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Article Synopsis
- There is growing interest in using psychedelics like psilocybin to treat hard-to-manage psychiatric disorders, but little is known about how the experiences they create affect mood afterward.
- In experiments with mice, it was found that psilocybin increased head-twitch responses more in females than in males, highlighting a sex difference in its effects.
- Stress exposure during or after taking psilocybin impacted anxiety-like behavior in males, blocking its calming effects, while females only experienced a partial effect, suggesting that both sex and the context of the experience are important in understanding the drug's impact.
Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications.
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