Efficacy Evaluation And Neurobiological Mechanism Of Psychedelics Based On Looming Model

Psychedelics are a class of non-addictive psychoactive substances that act on 5-HT_2Areceptor and produce hallucinogenic effects.Its representative drugs mainly include 2,5-dimethoxymethylbenzo-isopropylamine（DOM）,psilocybin and mescaline.Psychedelics can alter human cognition,emotion,perception and mood,and even cause hallucinations.However,due to complex mechanism of action and lack of animal models,the neural mechanism of psychedelics is still unclear.Present animal models have poor specificity for psychedelics and cannot reflect the psychotropic effects in animals.Therefore,finding an animal model that reflects the subjective effects is the key to carry out the mechanism research.It is known that psychedelics can effectively alleviate fear in humans,and clinical trials have shown that psychedelics are effective in treatment of post-traumatic stress disorder（PTSD）.In animal experiments,psychedelics have been shown to significantly inhibit fear behavior of mice in conditioned fear model,but whether they can affect innate fear behaviors of animals has not been reported.Therefore,we focus on innate fear,hoping to find a nice animal model to reveal the neural mechanism of psychedelics alleviating fear,and to provide some theoretical and experimental basis for the research and development of treatment programs for fear related diseases.Firstly,we investigated the effects of psychedelics on freezing time in shelter in Looming model（LM）,and explore the efficacy of LM evaluating psychedelics with the Head Twitch Response（HTR）as a control.The results showed that DOM,psilocybin and mescaline could shorten the freezing time in shelter of mice in LM,which had the same dose-effect relationship as HTR.The selective specificity of psychedelics on LM was investigated via multiple psychoactive substances（R-MDMA,S-MDMA,TBG,IHCH7086,caffeine,morphine and methamphetamine）.The results showed that none of these psychoactive substances affected the freezing time of mice in LM,which told us that the LM has better specificity for psychedelics.Then we investigated the receptors and signaling pathways of psychedelics in HTR and LM,and found that psychedelics DOM and psilocybin induced HTR and shortened the freezing time in LM by activating5-HT_2A receptor independent ofβ-arrestin2 signaling pathway.Secondly,behavioral experiments such as heart rate monitoring,pupil tracking,visual cliff test,open field test,elevated plus maze and place aversion test were performed to investigate the underlying mechanism of psilocybin altering the innate fear behavior in LM.Psilocybin was found to significantly inhibit the increase in heart rate during Looming stimulus,but did not affect the behavior of mice in other experiments.These results pointed to psilocybin changed the innate fear behavior of mice in the LM by alleviating innate fear of mice.Thirdly,we explored the neural mechanism of psychedelics changing the innate fear behavior of mice in LM.Using local brain lesion method,chemicalgenetic method and behavioral experiments of 5-HT_2AR KO mice,we revealed that psilocybin induced the shortened freezing time in LM by directly activating 5-HT_2A receptors on CaMKII neurons in prelimbic cortex（Pr L）.In conclusion,this study demonstrated that psychedelics could alleviate innate fear of mice in LM and revealed the underlying neural mechanism.At the same time,the LM may has the potential to evaluate and distinguish psychedelics.