Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT_2AR) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. The new antidepressant arketamine is reported to cause long-lasting prophylactic effects in lipopolysaccharide (LPS)-treated mice and mice exposed to chronic restrain stress (CRS). However, no study has compared the prophylactic effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT_2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT_2AR and 5-HT_1AR agonism), and arketamine on depression-like behaviors in mice. Saline (10 ml/kg), DOI (2.0 or 4.0 mg/kg), lisuride (1.0 or 2.0 mg/kg), or arketamine (10 mg/kg) was administered intraperitoneally (i.p.) to male mice 6 days before administration of LPS (1.0 mg/kg). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated body weight loss, splenomegaly, the increased immobility time of forced swimming test (FST), and the decreased expression of PSD-95 in the prefrontal cortex (PFC) of LPS-treated mice. In another test, male mice received the same treatment one day before CRS (7 days). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression.

麻醉氯胺酮和作为 5-羟色胺-2A 受体 (5-HT _2A R) 激动剂的经典致幻剂对难治性抑郁症患者具有快速且持续的抗抑郁作用。据报道，新型抗抑郁药阿氯胺酮对脂多糖（LPS）治疗的小鼠和暴露于慢性束缚应激（CRS）的小鼠具有持久的预防作用。然而，尚无研究比较 DOI（2,5-二甲氧基-4-碘苯丙胺：一种具有强效 5-HT _{2A R 激动作用的致幻性迷幻药物）、麦角乙脲（具有 5-HT 2A} R的非致幻性迷幻类似物）和5-HT _1A R 激动剂）和阿酮胺对小鼠抑郁样行为的影响。在给药前6天，将盐水（10ml/kg）、DOI（2.0或4.0mg/kg）、麦角乙脲（1.0或2.0mg/kg）或阿氯胺酮（10mg/kg）腹膜内（ip）给予雄性小鼠。 LPS（1.0 毫克/千克）。用氯胺酮预处理，但不使用 DOI 和麦角乙脲，可显着改善LPS 处理小鼠的体重减轻、脾肿大、强迫游泳试验(FST)不动时间增加以及前额皮质 (PFC) 中 PSD-95 表达降低。在另一项测试中，雄性小鼠在 CRS 前一天（7 天）接受了相同的治疗。用氯胺酮预处理，而非 DOI 和麦角乙脲，显着改善了 CRS暴露小鼠 FST 不动时间的增加、蔗糖偏好测试中蔗糖偏好的降低以及 PFC 中 PSD-95 表达的降低。这些发现表明，与阿氯胺酮不同，DOI 和麦角乙脲在小鼠抑郁模型中均未表现出持久的预防作用。