PSILOCYBIN INDUCES LONG-LASTING EXCITATORY SYNAPTIC PLASTICITY AND EFFECTS IN THE LIGHT/DARK TEST IN MICE

Psilocybin, a classic psychedelic acting via the 5-HT_2A receptor activation, has demonstrated rapid and long-lasting antidepressant effects following a single administration. Recent evidence established a mechanistic link between psilocybin-induced neuronal changes and antidepressant-like effects in mice. Given the profound effects psychedelic drugs induce, the neurobiological mechanisms underlying potential therapeutic effects still remain insufficiently investigated. Here we studied long-lasting behavioral and neuronal effects of psilocybin in mice. The plasticity marker EGR1 was quantified in brain slices obtained 90 minutes after a single injection of psilocybin (1 mg/kg) or saline, using immunohistochemistry. Using whole-cell patch-clamp electrophysiology, miniature excitatory postsynaptic currents (mEPSCs) were recorded from cortical areas and the amygdala 24 h after injecting mice once with psilocybin or saline. Anxiety-like behavior was assessed using the light/dark test 24 h or one week after a single dose. Psilocybin increased EGR1 expression in cortical regions and the amygdala. Psilocybin increased mEPSC frequency in the prelimbic, ventrolateral orbitofrontal and insular cortices and the amygdala. Increased mEPSC amplitudes were evident in the infralimbic cortex and decay time was decreased in the prelimbic cortex. In the light/dark test, mice assessed 24 h after psilocybin displayed anxiogenic-like behavior, whereas mice assessed one week after treatment displayed an anxiolytic-like effect. Our data revealed brain areas where psilocybin-induced neuronal activation and synaptic potentiation may potentially lead to long-lasting circuit remodeling. Furthermore, behavioral changes outlasting the acute drug effects indicate that psilocybin administration has long-lasting behavioral consequences, which may be linked to synaptic changes in future experiments.