Effects of psilocybin microdoses on serotonergic pathways and lipid signaling

裸盖菇素是致幻蘑菇的主要致幻成分。然而，关于裸盖菇素的具体作用机制和给药途径的细节尚不清楚。虽然口服给药是裸盖菇素的常用做法，但裸盖菇素在临床前研究中的作用往往因给药途径而异，这导致了作用的开始、最大作用和持续时间的差异。其次，裸盖菇素的研究主要集中在致幻剂量上，其作用主要是通过激活5-HT2A受体（5-HT2AR）和炎症细胞因子介导的。因此，尚不清楚微剂量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不同的血清素受体，并改变脑信号。这项建议有三个主要目标：1)综合检测4种给药途径（口腔、静脉、腹腔、脑）注射裸盖菇素后色氨酸-血清素通路中5-羟色胺受体家族及代谢物的表达情况；2)比较微剂量致幻裸盖菇素与非致幻5-HT2A受体激动剂、利尿苷对神经网络的影响；3)探讨微剂量裸盖菇素对脑炎症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- ht2ar介导的裸盖菇素作用的理解基础上，并提供在微剂量裸盖菇素治疗后其他5-羟色胺受体介导的新的附加机制的重要发现。

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.