Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York 14853, United States.
Department of Psychiatry, Weill Cornell Medicine, New York, New York 10065, United States.
ACS Chem Neurosci. 2024 Aug 21;15(16):3034-3043. doi: 10.1021/acschemneuro.4c00279. Epub 2024 Aug 1.
A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.
各种经典迷幻剂和 MDMA 已被证明可增强啮齿动物模型中的恐惧消退。这具有转化意义，因为创伤后应激障碍 (PTSD) 的标准治疗方法是延长暴露疗法。然而，很少有研究调查裸盖菇素对恐惧学习范式的潜在影响。更具体地说，剂量、给药时间和血清素受体的影响可能会影响裸盖菇素对恐惧消退的影响程度尚不清楚。在这项研究中，我们使用延迟恐惧条件反射范式来确定裸盖菇素对雄性和雌性小鼠恐惧消退、消退保持和恐惧再现的影响。在测试前急性给予裸盖菇素时，所有测试剂量均可强烈增强恐惧消退。裸盖菇素还具有长期作用，可提高在新环境中的消退保持和抑制恐惧再现，尽管这些变化对剂量敏感。对性别差异的分析表明，女性可能对比男性更窄的剂量范围有反应。在恐惧学习之前或在消退后立即给予裸盖菇素不会导致行为发生变化，这表明同时进行的消退体验对于药物的作用是必要的。5-HT 受体拮抗剂的共同治疗阻断了裸盖菇素对消退、消退保持和恐惧再现的作用，而 5-HT 受体拮抗作用仅减弱了对恐惧再现的作用。总的来说，这些结果强调了剂量、情境和血清素受体是裸盖菇素促进恐惧消退能力的关键因素。该研究为将裸盖菇素作为 PTSD 基于消退的治疗的药理学辅助手段提供了临床前证据。
