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

Ketamine and psilocybin, both fast-acting antidepressants in clinical studies, increase extracellular levels of dopamine, serotonin, glutamate, and GABA in the rat frontal cortex. Psilocybin also raises GABA in the reticular nucleus of the thalamus. However, both drugs cause oxidative DNA damage—psilocybin in the frontal cortex and both drugs in the hippocampus. Psilocybin at 10 mg/kg increases NR2A glutamate receptor subunit levels. Behavioral tests 24 hours after administration show no antidepressant or anxiolytic effects; only ketamine reduces locomotor activity. The observed neurotransmitter changes may lead to genotoxicity and altered receptor levels without markedly affecting behavior.

Study at a glance

Abstract

Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light–dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.