Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex
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DOI：
10.1523/jneurosci.17-08-02921.1997
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发表时间：
1997-04
期刊：
影响因子：
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通讯作者：
B. Moghaddam;Barbara W. Adams;A. Verma;D. Daly
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文献类型：
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作者：
B. Moghaddam;Barbara W. Adams;A. Verma;D. Daly
亚麻醉剂量的氯胺酮是一种非竞争性NMDA受体拮抗剂，会损害大鼠的前额叶皮质(PFC)功能，并在人类身上产生类似于精神分裂症和分离性状态下观察到的症状，包括额叶敏感测试的表现受损。一些证据表明，氯胺酮可能部分通过与该区域的多巴胺神经传递相互作用而损害PFC功能。这项研究试图确定氯胺酮可能扰乱PFC中的多巴胺能神经传递及其相关认知功能的机制。对清醒大鼠进行的剂量-反应研究表明，小剂量氯胺酮(10、20和30 mg/kg)可增加前额叶细胞谷氨酸外流，提示在这些剂量下，氯胺酮可能增加前额叶细胞中非NMDA谷氨酸受体的谷氨酸能神经传递。麻醉剂量的氯胺酮(200 mg/kg)降低了谷氨酸水平，而中等剂量的氯胺酮(50 mg/kg)不影响谷氨酸水平。30 mg/kg的氯胺酮也增加了前额叶内多巴胺的释放。这种增加可被PFC内应用AMPA/海人藻酸受体拮抗剂6-氰基-7-硝基-2，3-二酮CNQX所阻断。此外，AMPA/海人藻酸受体拮抗剂LY293558可改善氯胺酮引起的多巴胺释放激活和啮齿动物空间延迟交替障碍，这是一项PFC敏感的认知任务。这些发现表明，氯胺酮可能通过增加谷氨酸的释放，从而刺激突触后非NMDA谷氨酸受体，从而扰乱PFC的多巴胺能神经传递以及与该区域相关的认知功能。
Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimulating postsynaptic non-NMDA glutamate receptors.