The effect of low-dose psilocybin on brain neurotransmission and rat behavior

Psilocybin has various therapeutic effects in mental and psychological disorders, including depression and mood disorders, obsessive-compulsive disorders, substance addiction and anxiety. Pharmacodynamic properties of psilocybin depend on doses used and time after administration. The psilocybin dose range varies depending on whether it is used therapeutically or for recreational purposes in humans, but most animal studies require larger doses to induce an effect on brain neurotransmission and animal behavior. The aim of this study was to investigate the effect of psilocybin on the release of cortical neurotransmitters and rat behavior when it was administered subcutaneously at doses of 0.1, 0.3 and 0.6 mg/kg. Psilocybin affected the release of dopamine, noradrenaline, serotonin and acetylcholine in the frontal cortex as measured by microdialysis in freely moving rats. Psilocybin increased the release of aminergic transmitters in a non-linear manner with the dose of 0.3 mg/kg being the weakest. Psilocybin also increased the release of γ-aminobutyric acid, but glutamate release was enhanced only for the first 2 h after drug injection and was followed by a decrease for the rest of the experimental period. In contrast to 25I-NBOMe, an agonist of 5-HT2A receptors, psilocybin did not produce hallucinogenic activity expressed as wet dog shakes and did not disrupt sensorimotor gating in the acoustic startle response test. Furthermore, psilocybin showed anxiolytic effect in the light dark box test 1 h after administration. It also modulated the hypothalamic-pituitary-adrenal axis activity as it transiently increased serum corticosterone level, decreased serotonin, but increased dopamine turnover rates in the hypothalamus and inhibited the content of noradrenaline and adrenaline in the adrenal glands. The changes in the neurotransmitter release seem to play a role in psilocybin behavioral effects. The lack of hallucinogenic activity and disruptive effect on sensorimotor gating by psilocybin lower doses indicates that psychotomimetic effects did not occur. Psilocybin in contrast to 25I-NBOMe, ketamine and MDMA did not produce oxidative damage of DNA in the frontal cortex and hippocampus. Thus, the single low doses of psilocybin may have some beneficial properties and fewer harmful effects.