小柯机器人

氯胺酮的双重作用限制了成瘾
2022-07-30 23:55
来源：小柯机器人

瑞士日内瓦大学Christian Lüscher团队发现，氯胺酮的双重作用限制了成瘾。相关论文于2022年7月27日在线发表于国际学术期刊《自然》。

据研究人员介绍，氯胺酮在临床上被用作麻醉剂和快速起效的抗抑郁剂，而在娱乐方面则因其分离的特性而被使用，这引起了人们对成瘾可能带来的副作用的关注。可卡因等成瘾药物增加了伏隔核中的多巴胺水平。这促进了间脑系统的突触可塑性，从而导致行为适应，并最终推动向强迫性过渡。氯胺酮的成瘾性是一个备受争议的问题，部分原因是其复杂的药理学，在几个靶标中包括N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）的拮抗作用。
 
研究人员表明氯胺酮不会诱发小鼠突触的可塑性，而这种可塑性通常是在小鼠身上观察到的，尽管它在伏隔核中引起了强大的多巴胺瞬时效应。然而，氯胺酮通过抑制腹侧被盖区（VTA）的多巴胺神经元来支持强化作用。这种作用是由VTA的GABA（γ-氨基丁酸）神经元的NMDAR拮抗作用介导的，但很快被多巴胺神经元上的2型多巴胺受体所终止。多巴胺瞬态的快速关闭动力学与NMDAR拮抗作用一起排除了VTA和伏隔核中突触可塑性的诱导，并且没有引起运动敏感化或失控的自我给药。总之，氯胺酮的双重作用导致了一种独特的多巴胺驱动的积极强化，但成瘾性低。
 
附：英文原文
 
Title: Dual action of ketamine confines addiction liability

Author: Simmler, Linda D., Li, Yue, Hadjas, Lotfi C., Hiver, Agns, van Zessen, Ruud, Lscher, Christian

Issue&Volume: 2022-07-27

Abstract: Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion1,2,3,4. The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N-methyl-D-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability.

DOI: 10.1038/s41586-022-04993-7

Source: https://www.nature.com/articles/s41586-022-04993-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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