Department of Medical Psychology, Shandong University School of Medicine, Jinan, Shandong 250012, PR China.
Neurotoxicology. 2012 Jan;33(1):70-7. doi: 10.1016/j.neuro.2011.11.001. Epub 2011 Dec 2.
Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is capable of triggering excessive glutamate release and subsequent cortical excitation which may induce psychosis-like behavior and cognitive anomalies. Growing evidence suggests that acute ketamine administration can provoke dose-dependent positive and negative schizophrenia-like symptoms. While the acute effects of ketamine are primarily linked to aberrant activation of the prefrontal cortex and limbic structures with elevated glutamate and dopamine levels, the long-term effects of ketamine on brain functions and neurochemical homeostasis remain incompletely understood. In recent years, reports of ketamine abuse, especially among young individuals, have surged rapidly, with profound socioeconomic and health impacts. We herein investigated the chronic effects of ketamine on brain function integrity in an animal model of adolescent cynomolgus monkeys (Macaca fascicularis) by functional magnetic resonance imaging (fMRI). Immunohistochemical study was also conducted to examine neurochemical changes in the dopaminergic and cholinergic systems in the prefrontal cortex following chronic ketamine administration. Our results suggest that repeated exposure to ketamine markedly reduced neural activities in the ventral tegmental area, substantia nigra in midbrain, posterior cingulate cortex, and visual cortex in ketamine-challenged monkeys. In contrast, hyperfunction was observed in the striatum and entorhinal cortex. In terms of neurochemical and locomotive changes, chronically ketamine-challenged animals were found to have reduced tyrosine hydroxylase (TH) but not choline acetyltransferase (ChAT) levels in the prefrontal cortex, which was accompanied by diminished total movement compared with the controls. Importantly, the mesolimbic, mesocortical and entorhinal-striatal systems were found to be functionally vulnerable to ketamine's chronic effects. Dysfunctions of these neural circuits have been implicated in several neuropsychiatric disorders including depression, schizophrenia and attention deficit disorder (ADD). Collectively, our results support the proposition that repeated ketamine exposure can be exploited as a pharmacological paradigm for studying the central effects of ketamine relevant to neuropsychiatric disorders.
氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，能够引发谷氨酸的过度释放和随后的皮质兴奋，从而可能诱导精神病样行为和认知异常。越来越多的证据表明，急性氯胺酮给药会引起剂量依赖性的阳性和阴性精神分裂样症状。虽然氯胺酮的急性作用主要与前额叶皮层和边缘结构的异常激活有关，这些结构中谷氨酸和多巴胺水平升高，但氯胺酮对大脑功能和神经化学平衡的长期影响仍不完全清楚。近年来，氯胺酮滥用的报告，尤其是在年轻人中，迅速增加，对社会经济和健康造成了深远影响。我们在此通过功能磁共振成像（fMRI）研究了氯胺酮在青少年食蟹猴（Macaca fascicularis）动物模型中的慢性脑功能完整性的影响。我们还进行了免疫组织化学研究，以检查慢性氯胺酮给药后前额叶皮层多巴胺能和胆碱能系统的神经化学变化。我们的结果表明，反复暴露于氯胺酮会显著降低氯胺酮挑战猴的腹侧被盖区、中脑黑质、后扣带皮层和视觉皮层的神经活动。相比之下，纹状体和内嗅皮层则表现出过度兴奋。在神经化学和运动变化方面，慢性氯胺酮挑战的动物在前额叶皮层中发现酪氨酸羟化酶（TH）水平降低，但胆碱乙酰转移酶（ChAT）水平没有降低，与对照组相比，总运动减少。重要的是，中边缘系统、中皮质系统和内嗅纹状体系统被发现对氯胺酮的慢性作用具有功能脆弱性。这些神经回路的功能障碍与包括抑郁症、精神分裂症和注意力缺陷障碍（ADD）在内的几种神经精神疾病有关。总的来说，我们的研究结果支持了这样一种观点，即反复暴露于氯胺酮可以被用作研究与神经精神疾病相关的氯胺酮中枢作用的药理学范例。
