Abstract：
Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT2AR) 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-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR 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.
摘要：
作为5-羟色胺2A受体（5-HT2AR）激动剂的麻醉剂氯胺酮和经典迷幻药在难治性抑郁症患者中表现出快速和持续的抗抑郁作用。据报道，新的抗抑郁药阿氯胺酮可在脂多糖（LPS）处理的小鼠和暴露于慢性抑制应激（CRS）的小鼠中引起持久的预防作用。然而,没有研究比较DOI的预防作用（2,5-二甲氧基-4-碘苯丙胺：一种具有强效5-HT2AR激动作用的致幻迷幻药），利苏利德（具有5-HT2AR和5-HT1AR激动作用的非致幻迷幻类似物），和阿氯胺酮对小鼠抑郁样行为的影响。盐水（10ml/kg），DOI（2.0或4.0mg/kg），利苏利特（1.0或2.0mg/kg），在施用LPS(1.0mg/kg)前6天,向雄性小鼠腹膜内(i.p.)施用阿氯胺酮(10mg/kg)。用阿克他命预处理,但不是DOI和利苏利德，显著改善体重减轻，脾肿大,强迫游泳试验（FST）的不动时间增加，LPS处理的小鼠前额叶皮质（PFC）中PSD-95的表达降低。在另一个测试中，雄性小鼠在CRS前一天(7天)接受相同的治疗。用阿克他命预处理,但不是DOI和利苏利德，显着改善了FST固定时间的增加，蔗糖偏好测试中降低的蔗糖偏好，CRS暴露小鼠PFC中PSD-95的表达降低。这些发现表明,不像阿氯胺酮,在抑郁症小鼠模型中,DOI和利苏利特均未表现出长效预防作用.
