Key Laboratory of Animal Models and Human Disease Mechanisms, and Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
Psychopharmacology (Berl). 2013 Aug;228(3):451-61. doi: 10.1007/s00213-013-3048-2. Epub 2013 Mar 14.
Subanesthetic doses of ketamine have been reported to induce psychotic states that may mimic positive and negative symptoms as well as cognitive and memory deficits similar to those observed in schizophrenia. The cognitive and memory deficits are persistent, and their underlying cellular mechanisms remain unclear.
We sought to investigate the roles of dopamine D1/D5 receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hippocampal synaptic transmission and spatial memory impairment induced by ketamine.
We examined the effects of subanesthetic ketamine on hippocampal synaptic transmission in freely moving rats. Spatial memory was tested with the Morris water maze. Pretreatment with the D1/D5 receptors antagonist SCH23390 or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y was conducted to examine their capacities to reverse ketamine-induced electrophysiological and behavioral alterations. A series of behavioral observations, including locomotion, prepulse inhibition, and social interaction, were also conducted after ketamine treatment.
Ketamine induced synaptic depression lasting at least 4 h at hippocampal Schaffer collateral-CA1 synapses in freely moving rats and long-term spatial memory impairment. Both the effects were blocked by either SCH23390 or Tat-GluR23Y. Ketamine also elicited transient behavioral changes lasting less than 90 min, such as hyperlocomotion and prepulse inhibition deficits. These changes were ameliorated by SCH23390 but not by Tat-GluR23Y. Rats treated with ketamine showed social withdrawal that was also attenuated by either SCH23390 or Tat-GluR23Y.
Our results indicate that hippocampal synaptic depression is involved in ketamine-induced memory impairment, and this is modulated by D1/D5 receptors activation and AMPA receptors endocytosis.
有报道称，亚麻醉剂量的氯胺酮可诱发精神病状态，其可能类似于精神分裂症患者所观察到的阳性和阴性症状以及认知和记忆缺陷。认知和记忆缺陷是持续存在的，其潜在的细胞机制尚不清楚。
我们旨在研究多巴胺 D1/D5 受体和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体在氯胺酮诱导的海马突触传递和空间记忆损伤中的作用。
我们检测了亚麻醉剂量氯胺酮对自由活动大鼠海马突触传递的影响。使用 Morris 水迷宫测试空间记忆。使用多巴胺 D1/D5 受体拮抗剂 SCH23390 或 AMPA 受体内吞干扰肽 Tat-GluR23Y 进行预处理，以观察它们逆转氯胺酮诱导的电生理和行为改变的能力。在氯胺酮处理后还进行了一系列行为观察，包括运动、前脉冲抑制和社会互动。
氯胺酮诱导了自由活动大鼠海马 Schaffer 侧枝-CA1 突触至少持续 4 小时的突触抑制和长期空间记忆损伤。SCH23390 或 Tat-GluR23Y 均可阻断这两种作用。氯胺酮还引起持续时间不到 90 分钟的短暂行为变化，如过度运动和前脉冲抑制缺陷。这些变化可被 SCH23390 改善，但不能被 Tat-GluR23Y 改善。接受氯胺酮治疗的大鼠表现出社交回避，这也可被 SCH23390 或 Tat-GluR23Y 减轻。
我们的结果表明，海马突触抑制参与了氯胺酮诱导的记忆损伤，而这是由 D1/D5 受体激活和 AMPA 受体内吞调节的。
