Jones Nathan T, Zahid Zarmeen, Grady Sean M, Sultan Ziyad W, Zheng Zhen, Razidlo John, Banks Matthew I, Wenthur Cody J
Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
Neuroscience Training Program, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
ACS Pharmacol Transl Sci. 2023 Aug 2;6(8):1221-1231. doi: 10.1021/acsptsci.3c00123. eCollection 2023 Aug 11.
While correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have anxiolytic-like effects in C57BL/6 male mice at 4 h after treatment. These effects were not altered by pretreatment with a 5-HT antagonist but were blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. Anxiolytic-like effects were also observed at 4 h following treatment with the nonpsychedelic 5-HT agonist lisuride at a dose causing a similar increase in plasma glucocorticoids as that seen with psilocybin, as well as following stress-induced (via repeated injection) glucocorticoid release alone. Psilocybin's anxiolytic-like effects persisted at 7 days following administration. The long-term anxiolytic effects of psilocybin were lost when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute, resolvable psilocybin-induced glucocorticoid release drives the postacute anxiolytic-like effects of psilocybin in mice and that its long-term anxiolytic-like effects can be abolished in the presence of chronically elevated plasma glucocorticoid elevations.
虽然在裸盖菇素辅助心理治疗期间的人体研究中已报告了药物诱导的皮质醇升高、自我报告的焦虑与治疗结果之间的相关性，但血浆糖皮质激素反应中与迷幻剂相关的改变与焦虑反应的时间进程之间的机制关系仍不清楚。使用啮齿动物，可以实现糖皮质激素浓度的限时操纵和焦虑样行为的评估。在这里，发现腹腔注射3mg/kg裸盖菇素在治疗后4小时对C57BL/6雄性小鼠具有抗焦虑样作用。这些作用不受5-羟色胺拮抗剂预处理的影响，但糖皮质激素受体拮抗剂预处理或抑制裸盖菇素诱导的皮质酮升高会使其减弱。在用非迷幻性5-羟色胺激动剂利苏立得治疗后4小时也观察到抗焦虑样作用，其剂量导致血浆糖皮质激素的升高与裸盖菇素相似，以及单独应激诱导（通过重复注射）糖皮质激素释放后也观察到抗焦虑样作用。裸盖菇素的抗焦虑样作用在给药后7天持续存在。当给血浆皮质酮浓度持续慢性升高的动物施用裸盖菇素时，其长期抗焦虑作用消失。总体而言，这些实验表明，急性、可缓解的裸盖菇素诱导的糖皮质激素释放驱动了裸盖菇素在小鼠中的急性后抗焦虑样作用，并且在血浆糖皮质激素长期升高的情况下，其长期抗焦虑样作用可以被消除。
