Activating the 5-HT1B receptor with the drug CP-94253 produces rapid and sustained antidepressant-like effects in rodents, similar to ketamine. In mice, CP-94253 reduced immobility in the forced swim test and showed a strong antidepressant signature in a behavioral screening platform. Effects lasted at least 24 hours after a single dose in both naive rats and those receiving chronic interferon alpha treatment. The drug also enhanced hippocampal long-term potentiation measured 24 hours later. In mice subjected to chronic social defeat stress, antidepressant-like effects appeared within 1 hour in the tail suspension test and within 24 hours in the sucrose preference test.
Psilocybin produces rapid and sustained antidepressant effects in major depressive disorder, but the underlying neurobiological mechanisms are unclear. In mice, psilocybin caused dose-dependent occupancy of the 5-HT₂A receptor in the prefrontal cortex, with an inverted-U dose-response for head twitch behavior peaking between 44% and 62% receptor occupancy. A 1.5 mg/kg dose increased time spent in open areas of the elevated zero maze, indicating reduced anxiety, while 3 mg/kg reduced immobility in the forced swim test, suggesting antidepressant-like effects. Both doses shifted α-tubulin post-translational modifications toward more dynamic microtubules and selectively increased synaptic protein expression in the prefrontal cortex, but not the amygdala. These findings indicate that psilocybin's therapeutic effects may involve dose- and region-specific enhancement of neuronal plasticity, with distinct signatures for anxiolytic-like and antidepressant-like properties.