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.
Psychedelic drugs that activate the 5-HT2A receptor, such as psilocybin, show promise for treating alcohol-use disorders. This study tested whether psilocybin or the 5-HT2A agonist TCB-2 could reverse the sensitized locomotor activity caused by repeated ethanol exposure in male DBA/2J mice. Mice received repeated ethanol injections to induce sensitization, then five daily doses of psilocybin (0, 0.3, or 1 mg/kg) or TCB-2 (0, 1, or 3 mg/kg). A subsequent ethanol challenge showed that sensitized mice still had enhanced activity, and neither psilocybin nor TCB-2 reduced this sensitized response. The results suggest that these drugs' short-term effects on ethanol intake may not involve reversing long-term behavioral or neural adaptations from repeated ethanol exposure.