TEMPORAL PATTERNS OF DRUG-INDUCED BEHAVIORAL EFFECTS AND PSILOCIN LEVELS IN THE MOUSE BRAIN

Psychedelics have gained clinical interest due to their long-lasting antidepressant effects. Psilocybin, a classical psychedelic, is rapidly metabolized into its active compound psilocin, whose hallucinogenic properties are mediated by agonism at the 5-HT_2A receptor. Preclinically, the acute effects of psychedelics in mice remain insufficiently characterized despite its relevance for drug discovery research. The present study aims to elucidate the acute neurobiological and behavioral effects of psilocybin in mice. We mapped psilocybin-responsive brain regions by immunostaining for c-Fos in brain sections from mice treated with psilocybin (1 mg/kg, i.p.) or saline. To assess psilocin brain levels over time, in vivo microdialysis and fiber photometry with the 5-HT_2A receptor-based genetically-encoded sensor PsychLight2 following psilocybin administration were employed. Behavioral effects were assessed in an open-field. Psilocybin increased c-Fos expression across multiple regions, predominantly in cortical areas and the amygdala. With microdialysis, we determined peak psilocin levels 15–45 min post-injection and they were still elevated at 75 min when we stopped collecting the dialysate. This time course was also reflected with PsychLight2 in vivo fiber photometry. On the behavioral level, 1 mg/kg psilocybin elicited a strong head-twitch responses, peaking at 10 minutes post-injection, followed by rapid decrease with return to baseline by 60 min. Correlation of psilocin levels with head-twitch response revealed a temporal mismatch between pharmacokinetics and pharmacodynamics. Our findings indicate that refining behavioral experimental strategies to assess hallucination-like effects in mice could facilitate the development of novel psychedelic-like compounds.