Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT_2A receptor (5-HT_2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT_2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT_2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT_2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT_2A^−/− mice, whereas psilocybin was still effective. Moreover, neither 5-HT_1AR blockade nor dopamine D₁ or D₂ receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT_2A^−/− mice. Collectively, these findings indicate that 5-HT_2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

重度抑郁症（MDD）是世界上最严重的精神疾病之一。选择性血清素再摄取抑制剂 (SSRI) 等一线治疗仍然存在许多局限性，包括 30% 的患者对治疗产生耐药性，并且临床获益延迟，仅在治疗几周后才能观察到。越来越多的临床证据表明，对重度抑郁症患者急性服用血清素 5-HT _2A受体 (5-HT _2A R) 致幻剂（例如裸盖菇素）可产生快速抗抑郁作用，这种作用在治疗后可持续长达五周。然而，5-HT _2A R 是否参与这些抗抑郁作用仍存在争议。_{此外，5-HT 2A} R 激动剂的致幻特性是否对其抗抑郁活性是必需的仍然是一个悬而未决的问题。在这里，我们通过研究不同化学家族的两种致幻剂 DOI 和裸盖菇素以及非致幻性 5-HT _2A R 激动剂麦角乙脲在表现出强烈抑郁样表型的慢性绝望小鼠模型中的作用来解决这些问题。我们发现，对野生型小鼠单次注射每种药物，在新奇抑制喂养、蔗糖偏好和强迫游泳测试中会产生抗焦虑和抗抑郁样作用，这种作用可持续长达 15 天。DOI 和麦角乙脲给药并未在 5-HT _2A ^−/−小鼠中产生抗抑郁样作用，而裸盖菇素仍然有效。此外，5-HT _1A R 阻断和多巴胺 D ₁或 D _{2受体阻断均不影响裸盖菇素在 5-HT 2A} ^-/−小鼠中的抗抑郁样作用。总的来说，这些发现表明 5-HT _2A R 激动剂可以通过涉及或不涉及受体的机制产生独立于致幻特性的抗抑郁样作用。