Psilocybin induces stereotyped movements and reduces defensive responding in planarians through 5-hydroxytryptamine mechanisms

Psilocybin is a serotonergic 5-HT2AR agonist that causes psychedelic and anxiolytic effects in human users. To delineate conservation of psilocybin pharmacology, we investigated behavioral effects of psilocybin in planarians (Dugesia dorotocephala), the simplest living animal with cephalization that also has a well defined serotonin (5-hydroxytryptamine [5-HT]) system. We quantified stereotyped movements (e.g. head bops, twists, scrunches, and C-shapes) and defensive responding (negative phototaxis) and probed a 5-HT2AR mechanism for psilocybin using a selective 5-HT2AR antagonist (volinanserin). Psilocybin (0.01, 0.1, 1, and 10 nM) increased all stereotyped movements and, at higher concentrations, reduced motility. Volinanserin (1, 10, and 100 nM) did not induce any stereotyped movements or reduce motility. For combination experiments, volinanserin reduced cumulative stereotyped movements produced by psilocybin (0.01 nM) and specifically reduced psilocybin-evoked twists and head bops. Concentrations (<0.01 nM) of psilocybin that did not significantly reduce motility decreased defensive responding (i.e. increased time spent in light side of Petri dish). The reduction in defensive responding by psilocybin (0.01 nM) was prevented by volinanserin (100 nM). Our results show that psilocybin induces stereotypies and anxiolytic-like effects in planarians, likely through mechanisms involving 5-HT2AR, and suggest conservation of certain aspects of psilocybin pharmacology.