Translational Imaging, Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
J Pharmacol Exp Ther. 2011 Mar;336(3):709-15. doi: 10.1124/jpet.110.173880. Epub 2010 Dec 20.
Neuroimaging techniques have been exploited to characterize the effect of N-methyl-d-aspartate (NMDA) receptor antagonists on brain activation in humans and animals. However, most preclinical imaging studies were conducted in anesthetized animals and could be confounded by potential drug-anesthetic interactions as well as anesthetic agents' effect on brain activation, which may affect the translation of these basic research findings to the clinical setting. The main aim of the current study was to examine the brain activation elicited by the infusion of a subanesthetic dose of ketamine using blood oxygenation level dependence (BOLD) pharmacological magnetic resonance imaging (phMRI) in awake rats. However, a secondary aim was to determine whether a behaviorally active metabotropic glutamate 2/3 receptor agonist, (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268), could modulate the effects of ketamine-induced brain activation. Our data indicate that ketamine produces positive BOLD signals in several cortical and hippocampal regions, whereas negative BOLD signals were observed in regions, such as periaqueductal gray (PAG) (p < 0.05). Furthermore, pretreatment of LY379268 significantly attenuated ketamine-induced brain activation in a region-specific manner (posterior cingulate, entorhinal, and retrosplenial cortices, hippocampus CA1, and PAG). The [corrected] region-specific brain activations observed in this ketamine phMRI study may afford a method of confirming central activity and dose selection in early clinical trials for novel experimental therapeutics. [corrected]
神经影像学技术已被用于研究 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂对人类和动物大脑激活的影响。然而，大多数临床前成像研究是在麻醉动物中进行的，可能会受到潜在的药物-麻醉剂相互作用以及麻醉剂对大脑激活的影响的干扰，这可能会影响这些基础研究结果向临床环境的转化。本研究的主要目的是使用血氧水平依赖（BOLD）药理学磁共振成像（phMRI）在清醒大鼠中检查亚麻醉剂量氯胺酮诱导的脑激活。然而，次要目的是确定一种行为活性代谢型谷氨酸 2/3 受体激动剂，（1S,2R,5R,6R）-2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸（LY379268），是否可以调节氯胺酮诱导的脑激活的作用。我们的数据表明，氯胺酮在几个皮质和海马区域产生正 BOLD 信号，而在一些区域如导水管周围灰质（PAG）观察到负 BOLD 信号（p<0.05）。此外，LY379268 的预处理以特定于区域的方式显著减弱了氯胺酮诱导的脑激活（后扣带回、内嗅皮层和 retrosplenial 皮质、海马 CA1 和 PAG）。在这项氯胺酮 phMRI 研究中观察到的特定于区域的脑激活可能为新型实验治疗药物的早期临床试验中的中枢活性和剂量选择提供一种方法。
