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.
Depression involves reduced volume of the hippocampus and amygdala and enlargement of the nucleus accumbens. Ketamine, a fast-acting antidepressant, reverses these volume reductions. This study tested whether the psychedelic psilocybin similarly affects limbic system neurotransmission in rats. Using microdialysis, both psilocybin and ketamine increased dopamine and serotonin release in the nucleus accumbens, influenced glutamate and GABA release in the nucleus accumbens, hippocampus, and amygdala, and raised acetylcholine levels in the hippocampus. Long-lasting changes in D2, 5-HT1A, and 5-HT2A receptor density occurred in the nucleus accumbens and hippocampus. Psilocybin showed a marked anxiolytic effect acutely and 24 hours later in the open field test, providing a neurobiological basis for its antidepressant and anti-stress effects.