Abstract：
Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro-immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown.
Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Neurotransmitter levels were assessed via HPLC-UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing.
LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2-docosahexaenoylglycerol (1/2-DHG); the prostaglandins D2 (PGD2 ) and F2α (PGF2α ); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline-treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9.
The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome.
Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid-like mediators and metabolites were quantified via high-pressure liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Neurotransmitter levels were assessed via HPLC-UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing.
LSD increased social preference and novelty and decreased hippocampal levels of the N-acylethanolamines N-linoleoylethanolamine (LEA), anandamide (N-arachidonoylethanolamine) and N-docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2-docosahexaenoylglycerol (1/2-DHG); the prostaglandins D2 (PGD2 ) and F2α (PGF2α ); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline-treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9.
The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome.
摘要：
目标：迷幻药引发亲社会，通过神经可塑性的抗抑郁和抗焦虑作用，神经传递和神经免疫调节机制。迷幻药是否会影响大脑内源性大麻素系统及其扩展版本，内源性大麻素（eCBome）或肠道微生物组，仍然未知。
方法:向成年C57BL/6N雄性小鼠施用麦角酰二乙胺(LSD)或盐水7天。在直接的社交互动和三室测试中评估了社交能力。前额叶皮质和海马内源性大麻素，内源性大麻素样介质和代谢物通过高压液相色谱-串联质谱（HPLC-MS/MS）进行定量。通过HPLC-UV/荧光评估神经递质水平。通过16S核糖体DNA测序研究了肠道微生物组的变化。
结果：LSD增加了社会偏好和新颖性，并降低了N-酰基乙醇胺N-亚油酰基乙醇胺（LEA）的海马水平，anandamide（N-花生四酰基乙醇胺）和N-二十二碳六酰基乙醇胺（DHEA）；单酰基甘油1/2-二十二碳六酰基甘油（1/2-DHG）；前列腺素D2（PGD2）和F2α（PGF2α）；血栓素2和犬尿氨酸。前额叶eCBome介质和代谢物水平受治疗影响较小。LSD降低了肠道微生物群的Shannonα多样性，防止了在盐水处理的小鼠中观察到的Firmicutes：拟杆菌比率的降低，并改变了细菌类群双歧杆菌的相对丰度，肠杆菌,Dubosiella和RikenellaceaeRC9。
结论：反复施用LSD引起的亲社会效应伴随着海马eCBome和犬尿氨酸水平的改变，和肠道微生物群的组成。海马eCBome和犬尿氨酸途径的调节可能代表迷幻药化合物引起亲社会效应并影响肠道微生物组的机制。
方法:向成年C57BL/6N雄性小鼠施用麦角酰二乙胺(LSD)或盐水7天。在直接的社交互动和三室测试中评估了社交能力。前额叶皮质和海马内源性大麻素，内源性大麻素样介质和代谢物通过高压液相色谱-串联质谱（HPLC-MS/MS）进行定量。通过HPLC-UV/荧光评估神经递质水平。通过16S核糖体DNA测序研究了肠道微生物组的变化。
结果：LSD增加了社会偏好和新颖性，并降低了N-酰基乙醇胺N-亚油酰基乙醇胺（LEA）的海马水平，anandamide（N-花生四酰基乙醇胺）和N-二十二碳六酰基乙醇胺（DHEA）；单酰基甘油1/2-二十二碳六酰基甘油（1/2-DHG）；前列腺素D2（PGD2）和F2α（PGF2α）；血栓素2和犬尿氨酸。前额叶eCBome介质和代谢物水平受治疗影响较小。LSD降低了肠道微生物群的Shannonα多样性，防止了在盐水处理的小鼠中观察到的Firmicutes：拟杆菌比率的降低，并改变了细菌类群双歧杆菌的相对丰度，肠杆菌,Dubosiella和RikenellaceaeRC9。
结论：反复施用LSD引起的亲社会效应伴随着海马eCBome和犬尿氨酸水平的改变，和肠道微生物群的组成。海马eCBome和犬尿氨酸途径的调节可能代表迷幻药化合物引起亲社会效应并影响肠道微生物组的机制。
