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 compulsion^1,2,3,4. 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) antagonism^5,6. 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.

氯胺酮在临床上被用作麻醉剂和速效抗抑郁药，并因其解离特性而被娱乐性使用，引起人们对成瘾可能的副作用的担忧。可卡因等成瘾药物会增加伏隔核中的多巴胺水平。这有助于中脑边缘系统的突触可塑性，从而导致行为适应并最终推动向强迫^1,2,3,4的过渡。氯胺酮的成瘾倾向是一个备受争议的问题，部分原因是其复杂的药理学，在几个目标中包括N-甲基-d-天冬氨酸 (NMDA) 受体 (NMDAR) 拮抗作用^5,6. 在这里，我们表明氯胺酮不会诱导通常在小鼠中用成瘾药物观察到的突触可塑性，尽管会在伏隔核中引发强烈的多巴胺瞬变。然而，氯胺酮通过去抑制腹侧被盖区 (VTA) 中的多巴胺神经元来支持强化。这种作用是由 VTA 的 GABA（γ-氨基丁酸）神经元中的 NMDAR 拮抗作用介导的，但很快被多巴胺神经元上的 2 型多巴胺受体终止。多巴胺瞬变的快速非动力学以及 NMDAR 拮抗作用排除了 VTA 和伏隔核中突触可塑性的诱导，并且不会引起运动致敏或不受控制的自我管理。总之，氯胺酮的双重作用导致了多巴胺驱动的正强化的独特星座，