Effects of psilocybin microdoses on serotonergic pathways and lipid signaling

裸盖菇素是致幻蘑菇的主要迷幻成分。然而，关于作用机制的细节，特别是裸盖菇素的给药途径尚不清楚。虽然口服给药是裸盖菇素的常见做法，但裸盖菇素在临床前研究中的作用通常取决于给药途径，这导致作用开始、最大作用和作用持续时间的差异。其次，裸盖菇素的研究集中在致幻剂量，其作用主要是通过激活5-羟色胺5-HT 2A受体（5-HT 2AR）和炎性细胞因子介导的。因此，目前还不清楚微剂量的裸盖菇素是否会引起神经元、小胶质细胞和星形胶质细胞中5-羟色胺受体的差异，并改变大脑信号传导。这项建议有三个主要目标：1）通过四种给药途径，全面检测裸盖菇素注射后5-羟色胺受体家族和5-羟色胺-5-羟色胺通路中代谢产物的表达（口、静脉、腹腔、脑），2）比较和对比受微量致幻裸盖菇素和非致幻5-HT 2A受体激动剂麦角乙脲影响的神经网络，3）研究微量裸盖菇素对脑炎症的小胶质细胞和星形胶质细胞标志物的影响。这些研究将建立在目前对5-HT 2AR介导的裸盖菇素作用的理解基础上，并提供微剂量裸盖菇素治疗后由其他5-羟色胺受体介导的新的额外机制的关键发现。

Psilocybin is the primary psychedelic component of hallucinogenic mushrooms. However, details on the mechanism of action specifically, the route of administration of psilocybin are not clear. While oral dosing is common practice with psilocybin, the effects of psilocybin in preclinical studies often varies depending on route of administration which leads to differences in onset of effects, the maximal effects, and the duration of the effect. Secondly, psilocybin research has focused on hallucinogenic doses with which effects are predominantly mediated by activation of serotonin 5-HT2A receptors (5-HT2AR) and inflammatory cytokines. Therefore, it is unknown whether microdoses of psilocybin may elicit differential sets of serotonin receptors in neurons, microglia, and astrocytes and alter brain signaling. This proposal has three major objectives: 1) to comprehensively examine expressions of serotonin receptor families and metabolites in the tryptophan-serotonin pathway after psilocybin injection through four routes of administrations (mouth, vein, abdominal cavity, brain), 2) to compare and contrast the neural networks affected by microdoses of hallucinogenic psilocybin and non-hallucinogenic 5-HT2A receptor agonist, lisuride, and 3) to investigate the effects of microdosing psilocybin on microglial and astrocytic markers of brain inflammation. These studies will build on current understanding of 5-HT2AR-mediated actions of psilocybin and provide critical discovery of novel additional mechanisms mediated by other serotonin receptors after microdosing psilocybin treatments.