Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive. We found that one day after the injection of a low dose of ketamine, long-term potentiation (LTP) in the nucleus accumbens (NAc) was impaired. Loss of LTP was maintained for 7 days and was not associated with an altered basal synaptic transmission mediated by AMPARs and N-methyl-D-aspartate receptors (NMDARs). Inhibition of mammalian target of rapamycin signaling with rapamycin did not prevent the ketamine-induced loss of LTP but inhibited LTP in saline-treated mice. However, ketamine blunted the increase in the phosphorylation of the GluA1 subunit of AMPARs at a calcium/calmodulin-dependent protein kinase II/protein kinase C site induced by an LTP induction protocol. Moreover, ketamine caused a persistent increased phosphorylation of GluA1 at a protein kinase A site. (2R,6R)-HNK also impaired LTP in the NAc. In dopaminergic neurons of the ventral tegmental area from ketamine- or (2R,6R)-HNK-treated mice, AMPAR-mediated responses were depressed, while those mediated by NMDARs were unaltered, which resulted in a reduced AMPA/NMDA ratio, a measure of long-term synaptic depression. These results demonstrate that a single injection of ketamine or (2R,6R)-HNK induces enduring alterations in the function of AMPARs and synaptic plasticity in brain regions involved in reward-related behaviors.

中文翻译：

---

氯胺酮及其代谢物（2R，6R）-羟基降氯胺酮引起中脑边缘回路中谷氨酸能突触可塑性的持久变化。

低剂量的氯胺酮注射一次后，对具有治疗作用的重度抑郁症患者具有抗抑郁作用。建议调节海马和前额叶皮层中的AMPA受体（AMPAR），以介导氯胺酮及其代谢物之一（2R，6R）-羟基降甲胺（（2R，6R）-HNK）的抗抑郁作用。我们已经研究了氯胺酮和（2R，6R）-HNK是否会影响中脑边缘系统中的谷氨酸能传递和可塑性，这是已知的大脑区域在奖励动机，情绪和享乐驱动中具有关键作用。我们发现，注射低剂量的氯胺酮后一天，伏隔核（NAc）的长期增强（LTP）受到损害。LTP的损失维持了7天，并且与AMPAR和N-甲基-D-天冬氨酸受体（NMDARs）介导的基础突触传递的改变无关。雷帕霉素抑制哺乳动物雷帕霉素信号转导靶标不能阻止氯胺酮诱导的LTP损失，但可以抑制盐水处理小鼠的LTP。然而，氯胺酮抑制了LTP诱导方案诱导的钙/钙调蛋白依赖性蛋白激酶II /蛋白激酶C位点处AMPARs GluA1亚基磷酸化的增加。此外，氯胺酮导致蛋白激酶A位点的GluA1持续磷酸化。（2R，6R）-HNK也损害了NAc中的LTP。在氯胺酮或（2R，6R）-HNK处理的小鼠腹侧被盖区的多巴胺能神经元中，AMPAR介导的反应受到抑制，而由NMDAR介导的那些未改变，导致AMPA / NMDA比率降低，这是长期突触抑制的一种度量。这些结果表明，单次注射氯胺酮或（2R，6R）-HNK可以诱导参与奖励相关行为的大脑区域中AMPAR功能的持久性改变和突触可塑性。