Matrov Denis, Imbeault Sophie, Kanarik Margus, Shkolnaya Marianna, Schikorra Patricia, Miljan Ergo, Shimmo Ruth, Harro Jaanus
Department of Neuroscience, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Tartu, Estonia.
Tallinn University Centre of Excellence in Neural and Behavioural Sciences, School of Natural Sciences and Health, Tallinn University, Tallinn, Estonia.
Acta Histochem. 2020 Apr;122(3):151531. doi: 10.1016/j.acthis.2020.151531. Epub 2020 Mar 2.
Ketamine is a noncompetitive antagonist of glutamatergic N-methyl-d-aspartate receptors. Its acute effects on healthy volunteers and schizophrenia patients mimic some acute psychotic, but also cognitive and negative symptoms of schizophrenia, and subchronic treatment with ketamine has been used as an animal model of psychotic disorders. Glutamatergic neurotransmission is tightly coupled to oxidative metabolism in the brain. Quantitative histochemical mapping of cytochrome c oxidase (COX) activity, which reflect long-term energy metabolism, was carried out in rats that received a daily subanaesthetic dose (30 mg/kg) of ketamine for 10 days. In total, COX activity was measured in 190 brain regions to map out metabolic adaptations to the subchronic administration of ketamine. Ketamine treatment was associated with elevated COX activity in nine brain sub-regions in sensory thalamus, basal ganglia, cortical areas, hippocampus and superior colliculi. Changes in pairwise correlations between brain regions were studied with differential correlation analysis. Ketamine treatment was associated with the reduction of positive association between brain regions in 66 % of the significant comparisons. Different layers of the superior colliculi showed the strongest effects. Changes in other visual and auditory brain centres were also of note. The locus coeruleus showed opposite pattern of increased coupling to mainly limbic brain regions in ketamine-treated rats. Our study replicated commonly observed activating effects of ketamine in the hippocampus, cingulate cortex, and basal ganglia. The current study is the first to extensively map the oxidative metabolism in the CNS in the ketamine model of schizophrenia. It shows that ketamine treatment leads to the re-organization of activity in sensory and memory-related brain circuits.
氯胺酮是谷氨酸能N-甲基-D-天冬氨酸受体的非竞争性拮抗剂。它对健康志愿者和精神分裂症患者的急性作用模拟了精神分裂症的一些急性精神病性症状，但也包括认知和阴性症状，并且氯胺酮的亚慢性治疗已被用作精神障碍的动物模型。谷氨酸能神经传递与大脑中的氧化代谢紧密相关。在每天接受亚麻醉剂量（30mg/kg）氯胺酮治疗10天的大鼠中，进行了反映长期能量代谢的细胞色素c氧化酶（COX）活性的定量组织化学图谱分析。总共在190个脑区测量了COX活性，以描绘对氯胺酮亚慢性给药的代谢适应性。氯胺酮治疗与感觉丘脑、基底神经节、皮质区域、海马体和上丘的九个脑亚区域中COX活性升高有关。通过差异相关性分析研究了脑区之间成对相关性的变化。在66%的显著比较中，氯胺酮治疗与脑区之间正相关性的降低有关。上丘的不同层显示出最强的效应。其他视觉和听觉脑中心的变化也值得注意。在氯胺酮治疗的大鼠中，蓝斑显示出与主要边缘脑区耦合增加的相反模式。我们的研究重复了氯胺酮在海马体、扣带回皮质和基底神经节中常见的激活作用。本研究首次在精神分裂症的氯胺酮模型中广泛描绘了中枢神经系统中的氧化代谢。结果表明，氯胺酮治疗导致感觉和记忆相关脑回路活动的重新组织。
