PSILOCYBIN MITIGATES BEHAVIORAL DESPAIR AND COGNITIVE RECOGNITION IMPAIRMENTS BY REGULATING THE HYPOTHALAMIC- PITUITARY-ADRENAL (HPA) AXIS VIA THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) SIGNALING PATHWAY MEDIATED BY THE ENDOCANNABINOID SYSTEM (ECS)
Authors: Wang *Zitong , Zhang Yanbo , Li Xin-Min 
Published: February 2025

Abstract

Background
Dr. George Engel introduced the biopsychosocial model into the field of psychiatry 40 years ago, highlighting the profound connection between social environment and mental health. Factors have been categorized into biological, psychological, and socio-environmental domains. Numerous animal models have been developed to investigate the pathophysiology and treatment of depression; however, none have effectively encapsulated the biopsychosocial model.Several studies have underscored the importance of the HPA axis in regulating mood and cognitive functions under stress. The Endocannabinoid System (ECS) is a well-studied neuromodulatory system that operates within the CNS, playing a central role in stress response. Hypothalamus contains cannabinoid CB1 receptors and synthesizes endocannabinoids, which facilitate rapid negative-feedback regulation of the HPA axis through retrograde release.In recent years, research efforts have focused on the therapeutic effects of psilocybin in psychiatric conditions, including depression. This has raised questions about whether psilocybin can serve as a mono therapy and what is the mechanism behinds it.

Aims & Objectives
1) Compare the behavioral outcomes of psilocybin treatment in two distinct animal models of depression;
2) Investigate the regulation of stress hormones and the underlying mechanisms influenced by psilocybin.

Methods
The study employed two animal models: 1) The biopsychosocial animal model of depression, represented by introducing chronic social instability stress (SIS) to Wistar-Kyoto (WKY) rats - the model of treatment-resistant depression; 2) The stress-induced animal model of depression, generated by subjecting Wistar (WIS) rats, a wildtype control, to chronic SIS. Series of behavioral test have been conducted followed by postmortem analysis.

Results
In the OFT, 1.0mg/kg psilocybin notably increased the distance traveled and reduced immobility in stressed WIS rats but not in stressed WKY rats. The EPM showed no significant reductions in freezing time or time spent in the arms for both strains, yet risk assessment time was significantly reduced. In the FST, psilocybin reduced immobility and increased swimming and climbing in both strains. In the SPT, psilocybin elevated sucrose preference in stressed WIS rats. Lastly, in the NOR, psilocybin significantly enhanced recognition in both rat strains. Biochemical analysis of cardiac blood revealed that 1.0mg/kg psilocybin significantly downregulated ACTH and corticosterone levels in stressed WIS rats but not in stressed WKY rats. In contrast, it upregulated TSH and melatonin levels in both rat strains. Psilocybin also increased BDNF levels in blood and specific brain regions, affecting the PFC, amygdala, hippocampus, and hypothalamus. Psilocybin was found to upregulate the levels of CB1R and TrkB and activate Akt, ERK, and mTOR pathways. Additionally, psilocybin improved the level of 2-AG in all four brain regions in both rat strains.

Discussion and Conclusion
Psilocybin appears to mitigate stress-induced dysregulation of the HPA axis by modulating the BDNF signaling pathway mediated by the ECS. This contributes to the observed positive effects on depressive- like behavior and cognitive impairment. This study enhances our understanding of how psilocybin exerts antidepressant-like effects and offers insights into the development of depression treatment strategies by providing a biopsychosocial animal model of depression.

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