Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior

Introduction

Mood and anxiety disorders remain leading causes of global disability, and current antidepressants often require weeks to take effect and fail in treatment-resistant cases. Recent clinical work has reported rapid antidepressant effects of ketamine and serotonergic psychedelics such as psilocybin, but the precise mechanisms that underlie these benefits and possible toxicities are incompletely understood. Earlier research implicates glutamate-mediated synaptic plasticity—via NMDA receptor modulation for ketamine and 5-HT2A receptor activation for classical psychedelics—as a shared pathway, yet direct comparative data on neurotransmitter dynamics, receptor adaptations and potential genotoxic effects are limited. Wojtas and colleagues set out to address these gaps by directly comparing a single administration of ketamine and two doses of psilocybin in rats. They measured extracellular dopamine (DA), serotonin (5-HT), glutamate and GABA in the frontal cortex and the reticular nucleus of the thalamus using in vivo microdialysis, assessed DNA damage in frontal cortex and hippocampus with the alkaline comet assay, quantified selected NMDA and AMPA receptor subunit proteins by Western blot, and evaluated behaviour in the open field, light–dark box and forced swim tests. Behavioural and molecular end points (except microdialysis) were assessed at least 24 h after dosing to distinguish persistent from acute effects, and MDMA was included as a comparator in the genotoxicity assays.