205. SYNERGISTIC BEHAVIORAL AND NEUROPLASTIC EFFECTS OF PSILOCYBIN-NMDAR MODULATOR ADMINISTRATION

Abstract Background The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the potential synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. We have hypothesized (Heresco-Levy and Lerer, 2024) that concurrent administration of SPs and NMDAR modulators may synergistically upgrade SP efficacy and attenuate SP-induced subjective reactions and side effects. This study seeks preclinical proof of concept for this hypothesis. Aims & Objectives To determine the potential efficacy of PSIL-DSER and PSIL-DCS treatment combinations by establishing their hallucinogenic potential, their possible antipsychotic effects, and their effects on neuroplasticity. Method Using male ICR mice, we examined the effect of PSIL-DSER and PSIL-DCS combination treatment on head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity-related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. HTR is closely correlated with hallucinogenic (psychedelic) effects in humans and was measured using a magnetometer. MK-801-induced hyperlocomotion is a well-established preclinical predictor of antipsychotic effects and was assayed in an open field using the Ethovision system. Synaptic proteins (GAP43, PSD95, synaptophysin, and SV2A) were assayed in the frontal cortex, hippocampus, amygdala, and striatum by Western blots. Results Our results indicate that PSIL significantly increased HTR—a surrogate measure for hallucinogenic effects—which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. PSIL alone did not affect MK-801-induced hyperactivity. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain areas examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions. Discussion & Conclusions These findings support the hypothesis that combinations of SPs with NMDAR modulators could optimize the therapeutic potential of SPs by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.