Zhou ZhiQiang, Zhang GuangFen, Li XiaoMin, Liu XiaoYu, Wang Nan, Qiu LiLi, Liu WenXue, Zuo ZhiYi, Yang JianJun
Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Mol Neurobiol. 2015 Apr;51(2):808-19. doi: 10.1007/s12035-014-8798-2. Epub 2014 Jun 28.
Accumulating evidence has demonstrated that single subanesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant-like effects. Nevertheless, repeated subanesthetic doses of ketamine produce psychosis-like effects with dysfunction of parvalbumin (PV) interneurons. We hypothesized that PV interneurons play an important role in the antidepressant-like actions of ketamine, and different changes in PV interneurons occur with the antidepressant-like and propsychotic-like effects of ketamine. To test this hypothesis, ketamine's antidepressant-like effects were evaluated by the forced swimming test. Ketamine-induced stereotyped behaviors and hyperactivity actions and the function of PV interneurons were also assessed. We demonstrated that an acute dose of 10 mg/kg ketamine induced significant antidepressant-like effects and reduced the levels of PV and the gamma-aminobutyric acid (GABA)-producing enzyme GAD67 in the rat prefrontal cortex. Moreover, inhibition of ketamine-induced loss of PV by apocynin blocked these antidepressant-like effects. Repeated administration of 30 mg/kg ketamine elicited stereotyped behaviors and hyperactivity actions as well as a longer duration of PV and GAD67 loss, higher brain glutamate levels, and lower brain GABA levels than acute single dose of ketamine. Our results reveal that the loss of phenotype of PV interneurons in the prefrontal cortex contributes to the antidepressant-like actions and is also involved in the propsychotic-like behaviors following acute and repeated ketamine administration, which may be partially mediated by the disinhibition of glutamate signaling. The different degrees and durations of the actions on PV interneurons produced by the two regimens of ketamine may partly underline the behavioral variance between the antidepressant- and propsychotic-like effects.
越来越多的证据表明，单次亚麻醉剂量的氯胺酮能产生快速、强烈且持久的抗抑郁样效应。然而，重复给予亚麻醉剂量的氯胺酮会产生类似精神病的效应，并伴有小白蛋白（PV）中间神经元功能障碍。我们推测PV中间神经元在氯胺酮的抗抑郁样作用中起重要作用，并且氯胺酮的抗抑郁样和类精神病样效应会导致PV中间神经元发生不同变化。为了验证这一假设，通过强迫游泳试验评估氯胺酮的抗抑郁样效应。还评估了氯胺酮诱导的刻板行为和多动行为以及PV中间神经元的功能。我们发现，急性给予10mg/kg氯胺酮可诱导显著的抗抑郁样效应，并降低大鼠前额叶皮质中PV和γ-氨基丁酸（GABA）生成酶GAD67的水平。此外，阿朴吗啡抑制氯胺酮诱导的PV丢失可阻断这些抗抑郁样效应。与急性单次给予氯胺酮相比，重复给予30mg/kg氯胺酮会引发刻板行为和多动行为，以及PV和GAD67丢失的持续时间更长、脑谷氨酸水平更高和脑GABA水平更低。我们的结果表明，前额叶皮质中PV中间神经元表型的丢失有助于抗抑郁样作用，并且也参与急性和重复给予氯胺酮后的类精神病样行为，这可能部分由谷氨酸信号的去抑制介导。氯胺酮两种给药方案对PV中间神经元产生的不同程度和持续时间的作用可能部分解释了抗抑郁样和类精神病样效应之间的行为差异。
