Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters
Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters
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DOI：
10.1124/jpet.116.235838
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发表时间：
2016-10-01
影响因子：
3.5
通讯作者：
Gould, Todd D.
中科院分区：
文献类型：
--
作者：
Can, Adem;Zanos, Panos;Gould, Todd D.
在亚麻醉剂量下给药后，（R，S）-氯胺酮（氯胺酮）在难治性抑郁症患者中诱导抑郁症状的快速和稳健缓解。先前的研究表明，氯胺酮的抗抑郁特性涉及多巴胺（DA）神经传递的增强。氯胺酮迅速代谢为（2S，6S）-和（2 R，6 R）-羟基去甲氯胺酮（HNK），其具有不依赖于N-甲基-D-天冬氨酸谷氨酸受体抑制的抗抑郁作用。（2S，6S; 2 R，6 R）- HNK或其他代谢物的这些抗抑郁作用以及氯胺酮的副作用（包括滥用潜力）可能与对多巴胺能（DA能）系统组分的直接作用有关。在此，评估了氯胺酮及其主要代谢产物（去甲氯胺酮、去氢去甲氯胺酮和HNK）在DA受体（D1-D5）和DA、去甲肾上腺素和5-羟色胺转运蛋白的脑和血液分布/清除率和药效学分析。此外，我们测量了电诱发的中脑边缘DA释放和衰减，使用快速扫描循环伏安法急性给药后的亚麻醉剂量的氯胺酮（2，10，和50毫克/公斤，腹腔注射）。氯胺酮注射后，在小鼠血浆和脑中检测到氯胺酮、去甲氯胺酮和多种羟基去甲氯胺酮。在血浆中可检测到脱氢去甲氯胺酮，但脑中的浓度低于检测限。氯胺酮并没有改变麻醉小鼠的延髓核中诱发DA释放的幅度或动力学。氯胺酮的对映异构体和代谢产物对DA受体或DA、去甲肾上腺素和5-羟色胺转运蛋白（高达10 μ M）均无亲和力。这些结果表明，氯胺酮或氯胺酮代谢物的副作用或抗抑郁作用均与对中脑边缘DA能神经传递的直接影响无关。氯胺酮给药后先前观察到的DA能神经传递的体内变化可能是间接的。
Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine's antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-D-aspartate glutamate receptor inhibition. These antidepressant actions of (2S, 6S; 2R, 6R)- HNK, or other metabolites, as well as ketamine's side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1-D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine's enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters ( up to 10 mu M). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect.