难治性抑郁症是一种具有药物抵抗性的重度抑郁症亚型,目前尚缺乏有效且持久的治疗方法.赛洛西宾是裸盖菇的活性物质,是一种天然的5-羟色胺能致幻剂,能够激活5-羟色胺2A受体介导抗抑郁作用的多个方面.近年来赛洛西宾因在治疗难治性抑郁症或是其他精神类疾病方面发挥出突出显著的治疗作用而重新受到关注.本文通过总结国内外文献中赛洛西宾在神经可塑性、大脑神经连接网络、神经递质、免疫因子、微生物群-肠-脑轴和临床疗效等方面的研究,探索赛洛西宾对抗难治性抑郁症作用的可能机制,以期为临床应用该药物提供理论依据.

抗抑郁药治疗抑郁症存在起效慢、缓解率低、不良反应多等不足之处。致幻剂是一种可以改变感知觉和情绪并影响认知的强效精神活性物质。越来越多的证据显示部分致幻剂类药物能够正向促进个体社会功能，对中重度抑郁症具有快速、持续的改善作用。因此，近年来致幻剂类药物的抗抑郁作用逐渐受到关注。本文对致幻剂中代表性药物的抗抑郁效果及其潜在作用机制的研究进展进行总结，并对致幻剂类药物的使用风险进行讨论。

目的 探究经典致幻剂2,5-二甲氧基-4-甲基苯丙胺(DOM)致精神障碍的潜在电生理机制.方法 对成年雄性SD大鼠进行眶额叶皮质(OFC)微丝电极阵列植入手术,术后恢复1周,采用自身对照按以下给药顺序依次ip给药:DOM(0.5,1.5和3.0 mg·kg-1),DOM 3.0 mg·kg-1+5-羟色胺2A(5-HT2A)受体拮抗剂凯坦色林1.0 mg·kg-1,DOM 3.0 mg·kg-1+5-HT2C受体拮抗剂SB242084 3.0 mg·kg-1,凯坦色林 1.0 mg·kg-1,SB242084 3.0 mg·kg-1.每次药物处理前ip给予生理盐水作为对照组.每次药物处理间隔洗脱期1周.用Plexon在体多通道记录系统记录大鼠OFC脑区场电位,分析给药前后大鼠场电位变化.结果 与对照组相比,DOM(0.5,1.5和3.0 mg·kg-1)能够增加OFC脑区高频振荡(HFO)功率(P<0.05),降低低γ振荡功率(P<0.05,P<0.01);凯坦色林1.0 mg·kg-1能够拮抗DOM引起的低γ(P<0.01)和HFO(P<0.05)功率的变化,SB242084 3.0 mg·kg-1无拮抗作用.结论 DOM引起的幻觉等精神神经系统障碍可能与5-HT2A受体介导的OFC脑区低γ振荡功率降低和HFO功率增加有关.

Serotonin (5-HT) receptors are proteins involved in various neurological and biological processes,such as aggression,anxiety,appetite,cognition,learning,memory,mood,sleep,and thermoregulation.They are commonly associated with drug abuse and addiction due to their importance as targets for various pharmaceutical and recreational drugs.However,due to a high sequence similarity/identity among 5-HT receptors and the unavailability of the 3D structure of the different 5-HT receptor,no report was available so far regarding the systematical comparison of the key and selective residues involved in the binding pocket,making it difficult to design subtype-selective serotonergic drugs.In this work,we first built and validated three-dimensional models for all 5-HT receptors based on the existing crystal structures of 5-HT1B,5-HT2B,and 5-HT2C.Then,we performed molecular docking studies between 5-HT receptors agonists/inhibitors and our 3D models.The results from docking were consistent with the known binding affinities of each model.Sequentially,we compared the binding pose and selective residues among 5-HT receptors.Our results showed that the affinity variation could be potentially attributed to the selective residues located in the binding pockets.Moreover,we performed MD simulations for 12 5-HT receptors complexed with ligands;the results were consistent with our docking results and the reported data.Finally,we carried out off-target prediction and blood-brain barrier (BBB) prediction for Captagon using our established hallucinogen-related chemogenomics knowledgebase and in-house computational tools,with the hope to provide more information regarding the use of Captagon.We showed that 5-HT2C,5-HT5A,and 5-HT7 were the most promising targets for Captagon before metabolism.Overall,our findings can provide insights into future drug discovery and design of medications with high specificity to the individual 5-HT receptor to decrease the risk of addiction and prevent drug abuse.

Preclinical and clinical studies indicate that synthetic psychoactive substances,in addition to having abuse potential,may elicit toxic effects of varying severity at the peripheral and central levels.Nowadays,toxicity induced by synthetic psychoactive substances poses a serious harm for health,since recreational use of these substances is on the rise among young and adult people.The present review summarizes recent findings on the peripheral and central toxicity elicited by "old" and "new" synthetic psychoactive substances in humans and experimental animals,focusing on amphetamine derivatives,hallucinogen and dissociative drugs and synthetic cannabinoids.