Agnieszka Bysiek is a PhD student in Maj Institute of Pharmacology Polish Academy of Sciences in Kraków, Poland. She is currently investigating neurotoxicity, behavioral changes and neurotransmitters’ release after administration of psilocybin, 25I-NBOMe and ketamine in chronic mild stress model in rat. She is a coauthor of 9 publications in this field.

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Psilocybin effect on monoaminergic and amino acid neurotransmitter release in the chronically stressed rats

Psilocybin is proposed as a natural fast acting antidepressant drug. Clinical trials show that in contrast to typical antidepressants, psilocybin effect lasts for several months after administration  of one or two doses.  It is accepted that the therapeutic effect of typical antidepressants is closely related to an  increase in monoamine levels in the synaptic cleft. Antidepressants also influence amino acid neurotransmitter levels.

Methods. The aim of our study was to investigate whether psilocybin antidepressant effects may be related to changes in neurotransmitter release in the chronic mild stress (CMS) animal model. For this purpose, rats which showed depressive-like behavior expressed as anhedonia were treated with a 0.6 mg/kg dose of psilocybin. The extracellular levels of noradrenaline (NA), dopamine (DA), serotonin (5-HT), glutamate and γ-aminobutyric acid (GABA) were measured in the frontal cortex of rats by microdialysis and HPLC.

A significant increase in NA, DA, 5-HT and glutamate levels was observed in non-stressed animals, while no increase in NA, DA and glutamate was found in the stressed animals. The GABA extracellular level decreased in both groups but a stronger effect was seen in stressed rats. An increase in 5-HT levels constitutes a risk of oxidative stress and cellular damage. Administration of psilocybin at the dose of 0.6 mg/kg resulted in an oxidative damage of DNA in the nuclear fraction obtained from frontal cortex and hippocampus of both, non stressed and stressed animals.

It is concluded that the lack of psilocybin effect in stressed animals may result from the loss of 5-HT2A receptor functionality, as psilocybin is an agonist of this receptor.

Funding: National Science Centre grant no. 2020/37/B/NZ7/03753 (Leader Krystyna Gołembiowska)"