Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy treatment.Nonetheless,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be identified.In this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine mescaline.We employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway elucidation.We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in Peyote.Finally,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline production.Taken together,our study opens up avenues for exploration of sustainable production approaches and responsible utiliza-tion of mescaline,safeguarding this valuable natural resource for future generations.

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.

新精神活性物质是近几年开始流行的新型滥用物质,比起传统毒品来说其种类更丰富、化学结构更复杂.新精神活性物质按照药理学作用可分为七大类,除了效果未知的类别,其余的兴奋剂类、合成大麻素受体激动剂类、经典致幻剂类、合成阿片类、身心分离剂类和镇静催眠类都可通过与特异性受体结合从而发挥作用.该文对新精神活性物质的药理作用及其机制进行综述,以期为新精神活性物质的研究提供参考.

抑郁症是一种慢性复发性精神疾病,传统抗抑郁药通常需要连续几周的治疗才能发挥显著的治疗效果.N-甲基-D-天冬氨酸受体拮抗剂氯胺酮的上市为速效抗抑郁药物的研发打开了一个全新的视角,胆碱能受体阻滞剂东莨菪碱、5-HT2A受体激动剂赛洛西宾也表现出快速抗抑郁的作用潜力.归纳了谷氨酸能速效抗抑郁药、胆碱能受体拮抗剂、5-HT2A受体激动剂(致幻剂)速效抗抑郁药的药理学靶点研究,分析了新靶点的可能策略,以期对未来抗抑郁药物研究方向有所启示.

药物辨别技术是一种研究药物主观刺激效应的行为药理学技术.目前,药物辨别技术已广泛应用于中枢神经系统药物临床前药物研发中,其中最为广泛的是用于药物的精神依赖性评价.该文简要介绍了药物辨别技术的基本原理,初步阐述了药物辨别的主观效应、时程效应、立体特异性和个体差异,以及受体机制等相关特点和应用,并对其在新型精神活性物质致幻剂和大麻类药物方面的应用进行展望.

OBJECTIVE The 5-HT2A receptor is the major target of classic hallucinogens.Both DOM(2,5-dimethoxy-4-methylamphetamine)and lisuride act at 5-HT2A receptors,and lisuride shares comparable affinity with DOM and acts as a partial agonist at 5-HT2A recep-tors.However,not like DOM,lisuride lacks hallucinogenic properties.Impulsive decision-making refers to the prefer-ence for an immediate small reinforcer(SR)over a delayed large reinforcer(LR).The current study aims to compare the effects of DOM and lisuride on impulsive decision-making and further to investigate the possible receptor mechanisms responsible for the actions of the two drugs.METHODS Impulsive decision-making was evaluated in male Sprague-Dawley rats by the percent-age of choice for the LR in delay discounting task(DDT).Delay to the LR changed in an ascending order(0,4,8,16,and 32 s)across one session.RESULTS DOM(0.3 and 0.5 mg·kg-1)increased impulsive decision-making,and the effects of DOM(0.5 mg·kg-1)was blocked by the 5-HT2A receptor antagonist ketanserin(1.0 mg·kg-1)rather than the 5-HT2C receptor antagonist SB-242084(1.0 mg·kg-1).Contrarily,lisuride(0.1,0.3 and 0.5 mg·kg-1)decreased impulsive decision-making.The effects of lisu-ride(0.3 mg·kg-1)were not antagonized by ketanserin(1.0 mg·kg-1),selective 5-HT1A antagonist WAY-100635(1.0 mg·kg-1)or selective dopamine D4 receptor antagonist L-745870(1.0 mg·kg-1),but were attenuated by the selec-tive dopamine D2/D3 receptor antagonist tiapride(40 mg·kg-1).CONCLUSION DOM and lisuride have contrasting effects on impulsive decision-making via distinct recep-tors.DOM-induced increase of impulsivity is mediated by the 5-HT2A receptor,while lisuride-induced inhibition of impulsivity is regulated by the dopamine D2/D3 receptor.

药物的起源一直是医史界长期探讨但至今仍待深入研究的问题之一.萨满教作为古老的原始宗教,较好地保存了宗教活动中使用的致幻药物,可为探究早期人类对药物的认知提供重要借鉴.不同国家与地区萨满宗教活动中使用的致幻药物可分为单一药物与混合药物2大类,主要来自于植物与真菌,且与萨满所在地具有很高的契合度.通过对萨满宗教活动中使用的具有地域特色的致幻药物进行研究,极可能会为追寻人类早期发现与使用天然药物提供重要线索,为研究药物起源另辟新蹊.

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.