PSILOCYBIN INDUCES TIME-DEPENDENT CONTRASTING EFFECTS ON HIPPOCAMPAL SYNAPTIC PLASTICITY

Psilocybin shows rapid and long-lasting antidepressant effects, and enhances psychological and cognitive flexibility, potentially by induction of persistent neuroplastic effects. Nonetheless, little is known on the effects of psilocybin on hippocampal synaptic plasticity. Our aim is to evaluate the effect of psilocybin on hippocampal long-term potentiation (LTP), considered a neurophysiological correlate of learning and memory. Psilocybin (1 or 5 mg/kg, i.p., n=7-8) or saline solution (n=8-9) was administered to adult male C57BL/6J mice and head-twitch responses (HTR) were assessed. Hippocampal slice preparations were obtained at 30 min and 24 h post-administration. Field excitatory postsynaptic potentials were recorded from the CA1 region of the hippocampus following stimulation of the Schaffer collateral pathway. Baseline responses were recorded prior to high-frequency stimulation (single 5x5 θ-burst stimulation, TBS), and post-tetanic potentiation (PTP, 0-10 min post-TBS) and long-term potentiation (LTP, 50-60 min post-TBS) were calculated as percentage of the baseline slope average. Results were analysed using unpaired t-test or one-way ANOVA. Psilocybin significantly increased HTR, being 1 mg/kg the maximally active dose (F(2,34)=4.66, p<0.0001). At 30 min post-administration, psilocybin (1 mg/kg, i.p.) induced a significant reduction in PTP (t=2.46, p<0.05) and LTP (t=3.23, p<0.01) magnitude. In clear contrast, at 24 h post-administration psilocybin induced a significant increase in LTP (t=4.03, p<0.01) at 1 mg/kg, and in both PTP (t=3.31, p<0.01) and LTP (t=2.48, p<0.05) at 5 mg/kg. Results suggest that psilocybin induces time-dependent contrasting changes in hippocampal synaptic plasticity. Current experiments are focused on determining the duration of these effects and the underlying molecular mechanisms.