Activating the 5-HT2A serotonin receptor with drugs such as psilocybin reduces conditioned fear in male rats, an effect blocked by a 5-HT2A inverse agonist. Inverse agonists alone did not change fear behavior, but they unmasked a fear-reducing effect of the SSRI escitalopram, which by itself had no effect. These results suggest that 5-HT2A receptor activation is not required for normal conditioned freezing but can dampen fear when over-activated. In the presence of an SSRI, the 5-HT2A receptor appears to oppose the anti-freezing effect of increased serotonin levels.
Psilocybin, a psychedelic known for hallucinogenic and potential therapeutic effects, alters gene expression in rat brains in a region-specific manner. Ninety minutes after injection, several genes were upregulated across multiple brain regions, including Nfkbia and Sgk1 in all studied areas and Ddit4 in four regions. Other genes like Gpd1, Apold1, Sox9, Tsc22d3, and Slc2a1 changed in two regions. Psilocybin did not affect genes related to serotonin signaling or other neurotransmitter systems. Many affected genes are known to be activated by glucocorticoids, suggesting a link to stress hormone pathways.