Psilocybin increased head-twitch responses in both male and female mice, with a greater effect in females. Stress during the drug's acute effects blocked psilocybin's anxiety-reducing actions in males but only partially in females; no antidepressant-like effects were observed. Both stress and psilocybin independently raised corticosterone levels without additive or interactive effects. The findings highlight how sex and negative experiences during the drug's action influence its acute and post-acute mood effects, underscoring the importance of non-pharmacological factors for therapeutic and recreational use.
Serotonin 5-HT2A receptors (5-HT2ARs) in the thalamus increase in expression during development, shifting from interneurons to thalamocortical neurons in the ventrobasal region. Activating these receptors with the agonist TCB-2 reduces GABA uptake and enhances tonic GABAA currents in ventrobasal thalamocortical neurons, an effect absent in δ-subunit GABAA receptor knockout mice and independent of postsynaptic signaling. Bilateral injection of TCB-2 into the ventrobasal thalamus of freely moving rats induces spike-and-wave discharges and behavioral arrest, which are blocked by ethosuximide, indicating absence seizures. The findings suggest that 5-HT2AR signaling can shape thalamocortical dynamics and increase susceptibility to aberrant rhythmic activity.