Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus—a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. We conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR–independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.

抑郁症是一种广泛且具有破坏性的精神疾病，寻找速效抗抑郁药仍然至关重要。现在有令人兴奋的证据表明，迷幻化合物裸盖菇素不仅能产生强大的意识改变，还能产生快速而持久的抗抑郁作用。裸盖菇素如何发挥其治疗作用尚不清楚，但人们普遍认为这些作用需要改变意识，已知这依赖于血清素 2A 受体 (5-HT2AR) 激活。然而，这一假设从未得到检验。因此，我们询问裸盖菇素是否会在小鼠体内产生抗抑郁样反应，如果会，这些反应是否需要 5-HT2AR 激活。使用长期承受压力的雄性小鼠，我们观察到单次注射裸盖菇素可逆转通过蔗糖偏好和雌性尿液偏好测试评估的快感缺乏反应。对裸盖菇素的反享乐反应伴随着海马体兴奋性突触的增强——这是传统和速效抗抑郁药的特征。尽管有积极的证据表明酮色林的功效，但用 5-HT2A/2C 拮抗剂酮色林预处理并不能阻止对裸盖菇素的行为和电生理反应。我们得出的结论是，裸盖菇素的抗抑郁作用机制可以在动物模型中进行研究，并表明其抗抑郁作用可能不需要改变感知。我们进一步表明，皮质-中脑边缘奖励回路中不依赖于 5-HT2AR 的突触强度恢复可能有助于其抗抑郁作用。 迷幻化合物与 5-HT2AR 拮抗剂结合的可能性提供了一种潜在的方法来提高其接受度和临床实用性，应该在人类抑郁症中进行研究。