Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
1] Translational Medicine, Eli Lilly, Indianapolis, IN, USA [2] Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
Neuropsychopharmacology. 2014 Mar;39(4):895-906. doi: 10.1038/npp.2013.290. Epub 2013 Oct 18.
Dysfunctional connectivity within the hippocampal-prefrontal circuit (HC-PFC) is associated with schizophrenia, major depression, and neurodegenerative disorders, and both the hippocampus and prefrontal cortex have dense populations of N-methyl-D-aspartate (NMDA) receptors. Ketamine, a potent NMDA receptor antagonist, is of substantial current interest as a mechanistic model of glutamatergic dysfunction in animal and human studies, a psychotomimetic agent and a rapidly acting antidepressant. In this study, we sought to understand the modulatory effect of acute ketamine administration on functional connectivity in the HC-PFC system of the rat brain using resting-state fMRI. Sprague-Dawley rats in four parallel groups (N=9 per group) received either saline or one of three behaviorally relevant, sub-anesthetic doses of S-ketamine (5, 10, and 25 mg/kg, s.c.), and connectivity changes 15- and 30-min post-injection were studied. The strongest effects were dose- and exposure-dependent increases in functional connectivity within the prefrontal cortex and in anterior-posterior connections between the posterior hippocampus and retrosplenial cortex, and prefrontal regions. The increased prefrontal connectivity is consistent with ketamine-induced increases in HC-PFC electroencephalographic gamma band power, possibly reflecting a psychotomimetic aspect of ketamine's effect, and is contrary to the data from chronic schizophrenic patients suggesting that ketamine effect does not necessarily parallel the disease pattern but might rather reflect a hyperglutamatergic state. These findings may help to clarify the brain systems underlying different dose-dependent behavioral profiles of ketamine in the rat.
海马-前额叶回路（HC-PFC）内的功能连接障碍与精神分裂症、重度抑郁症和神经退行性疾病有关，海马和前额叶皮质都有密集的 N-甲基-D-天冬氨酸（NMDA）受体。氯胺酮是一种有效的 NMDA 受体拮抗剂，作为动物和人类研究中谷氨酸能功能障碍的机制模型、致幻剂和快速作用的抗抑郁药，目前受到极大关注。在这项研究中，我们使用静息态 fMRI 来研究急性氯胺酮给药对大鼠大脑 HC-PFC 系统功能连接的调节作用。四个平行组（每组 9 只）的 Sprague-Dawley 大鼠分别接受生理盐水或三种行为相关的、亚麻醉剂量的 S-氯胺酮（5、10 和 25 mg/kg，sc），并研究注射后 15 和 30 分钟的连接变化。最强的作用是剂量和暴露依赖性的前额叶皮层内功能连接增加，以及后海马和后扣带回皮质与前额叶区域之间的前后连接增加。这种增加的前额叶连接与氯胺酮诱导的 HC-PFC 脑电图 γ 波段功率增加一致，可能反映了氯胺酮作用的致幻方面，与慢性精神分裂症患者的数据相反，表明氯胺酮的作用不一定与疾病模式平行，而可能反映了一种过度谷氨酸能状态。这些发现可能有助于阐明大鼠中氯胺酮不同剂量依赖性行为特征的大脑系统基础。
