Psilocybin increased Fos protein expression dose-dependently in the frontal cortex, nucleus accumbens, central and basolateral amygdala, and locus coeruleus of male rats, with the strongest effect in the central amygdala. Fos was expressed in both neurons and oligodendrocytes. The central amygdala, a region critical for emotional processing and learning, may be a key site where psilocybin initiates brain activation leading to neuroplastic changes underlying its therapeutic effects.
Drug discrimination procedures in rats confirm that hallucinogenic effects of psychedelics like psilocybin, LSD, DMT, and 5-MeO-DMT are mediated primarily by 5-HT2A and 5-HT1A receptors. Plasma levels of psilocin required for generalization in rats (5–52 ng/mL) overlapped with human perceptual effects, while DMT and LSD needed higher exposures in rats than in humans. The duration of drug-lever generalization followed LSD > psilocybin > 5-MeO-DMT ≥ DMT, matching clinical experience. LSD showed a disconnect between plasma exposure and generalization, similar to clinical findings. These results support the translational value of drug discrimination assays for studying psychedelics.