Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior
International Journal of Molecular Sciences – June 16, 2022
Source: OpenAlex
Summary
While promising for major depression treatment, a single dose of psychedelics like psilocybin and ketamine profoundly impacts brain chemistry. Pharmacology studies show 10 mg/kg ketamine or 2-10 mg/kg psilocybin increased key neurotransmitters like dopamine and glutamate in rat frontal cortex. Psilocybin also boosted NR2A, a type of NMDA glutamate receptor. Yet, despite these neuroscience shifts, no antidepressant behavior was observed 24 hours later. Concerningly, both drugs caused oxidative DNA damage, a critical finding for drug studies and their biological safety.
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.