Efficacy evaluation and neurobiological mechanism of psychedelics based on looming model / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To investigate the effect of psychedelics on innate fear behavior of mice in Looming model(LM)and its neurobiological mechanism.METH-ODS ① Adult male C57BL/6J mice were randomly divid-ed into saline group,DOM group,psilocybin group and mescaline group.The drugs of the corresponding groups were given ip injecction 5 min in advance and LM were used to test the effect of them on freezing time in shelter of mice.② The mice were performing ip given DOM or psilocybin following 5-HT2A receptor antagonist M100907 ip 30 min later involved looming experiments.③Quan-tified the expression of EGR1 protein in mouse brains by immunofluorescence staining,then use ibotenic acid(IBO)damaged the mouse brain regions based on the result above and performed looming experiments.④ Specifically activate or inhibit CaMK Ⅱ,PV,VIP and SOM neurons of mice in saline or psilocybin groups respec-tively by chemical genetic methods and followed looming experiments.RESULTS ① In LM,the freezing time in shelter of mice in DOM,psilocybin and mescaline groups was significantly shorter compared to the saline group(P<0.05),and the dose-effect curves of above psyche-delics were U-shaped.② Compared with the vehicle + psilocybin/DOM groups,the freezing time in shelter of mice in M100907 + psilocybin/DOM groups was signifi-cantly prolonged(P<0.05),and there was no significant difference between the vehicle + saline group and the M100907 + psilocybin/DOM groups.③ Psilocybin signifi-cantly increased the expression of EGR1 protein in prelim-bic cortex(PrL)compared with saline,and the damage of PrL could effectively antagonized the effect of psilocybin shortening the freezing time in LM.④ Chemicalgenetic specific inhibition of CaMK Ⅱ,PV or VIP neurons in PrL could effectively antagonize the effect of psilocybin in LM,while chemicalgenetic specific activation of CaMK Ⅱneurons could significantly shorten the freezing time of saline-treated mice.CONCLUSION Psychedelics have capability to waken the innate fear behavior like freez-ing of mice in LM,and this effect is mediated by 5-HT2A receptor and CaMK Ⅱneuron in PrL.