Mu opioid receptor (MOR) activation is required for the antidepressant-like effects of both (R,S)-ketamine and the selective NMDAR antagonist fluoroethylnormemantine (FENM) against stress-induced maladaptive behaviors. (R,S)-ketamine and its enantiomers showed weak partial agonism of MOR, while FENM had negligible direct MOR activity. Despite these differences, the long-acting MOR antagonist methocinnamox (MCAM) blocked the behavioral effects of both compounds when given before or after stress. The antinociceptive effect of (R,S)-ketamine was more potent and more sensitive to MCAM blockade than that of FENM. These findings suggest that NMDAR antagonists function indirectly through endogenous opioid signaling to produce their effects.
Psilocybin activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). This activation is more pronounced in female mice and depends on serotonergic 5-HT2A and 5-HT2C receptors. The 5-HT2A receptor effects involve direct post-synaptic depolarization of CRHPVN neurons and increased presynaptic glutamate release. Psilocybin also alters how CRHPVN neurons respond to environmental changes, leading to a surprising decrease in activity that contrasts with typical stress responses. This context-specific modulation may be a key mechanism for recalibrating maladaptive stress reactivity, supporting the influence of setting on the psychedelic experience.