Effects of the hallucinogenic drugs mescaline, phencyclidine and psilocybin on zebrafish behavior and physiology

Mescaline, phencyclidine (PCP) and psilocybin are potent hallucinogenic drugs strongly affecting both human and animal behavior. However, these compounds have not been previously investigated in zebrafish (Danio rerio), rapidly gaining popularity as a model in psychopharmacology research. Here, we examine the effects of mescaline, PCP and psilocybin in multiple behavioral paradigms. Mescaline (10–20 mg/L) generally displayed an anxiolytic effect in the novel tank test, while PCP (1–3 mg/L) reduced freezing behavior and elicited a pattern of erratic swimming. Mescaline‐treated fish markedly increased shoaling behavior and altered movement patterns in the open field test. Additionally, mescaline and PCP disrupted normal zebrafish exploratory behavior, as assessed by ethograms. Psilocybin at doses tested (0.5–3 mg/L) was inactive in all of the behavioral tests. Interestingly, both psilocybin and PCP raised whole‐body cortisol levels without affecting brain c‐fos expression, and mescaline did not alter cortisol or c‐fos levels. Overall, this confirms the high sensitivity of zebrafish models to various hallucinogenic compounds with complex behavioral and physiological profiles. This study was supported by the National Institute on Drug Abuse (NIDA) R03 grant to AVK.