Duncan G E, Moy S S, Knapp D J, Mueller R A, Breese G R
UNC Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Brain Res. 1998 Mar 23;787(2):181-90. doi: 10.1016/s0006-8993(97)01390-5.
Subanesthetic doses of ketamine have been shown to exacerbate symptoms in schizophrenia and to induce positive, negative, and cognitive schizophrenic-like symptoms in normal subjects. The present investigation sought to define brain regions affected by subanesthetic doses of ketamine, using high resolution autoradiographic analysis of 14C-2-deoxyglucose (2-DG) uptake and immunocytochemical staining for Fos-like immunoreactivity (Fos-LI). Both functional mapping approaches were used because distinct and complementary information is often obtained with these two mapping methods. Ketamine, at a subanesthetic dose of 35 mg/kg, substantially increased 2-DG uptake in certain limbic cortical regions, including medial prefrontal, ventrolateral orbital, cingulate, and retrosplenial cortices. In the hippocampal formation, the subanesthetic dose of ketamine induced prominent increases in 2-DG uptake in the dentate gyrus, CA-3 stratum radiatum, stratum lacunosum moleculare, and presubiculum. Increased 2-DG uptake in response to 35 mg/kg ketamine was also observed in select thalamic nuclei and basolateral amygdala. Ketamine induced Fos-LI in the same limbic cortical regions that exhibited increased 2-DG uptake in response to the subanesthetic dose of the drug. However, no Fos was induced in some brain regions that showed increased 2-DG uptake, such as the hippocampal formation, anterioventral thalamic nucleus, and basolateral amygdala. Conversely, ketamine induced Fos in the paraventricular nucleus of the hypothalamus and central amygdala, although no effect of the drug on 2-DG uptake was apparent in these regions. In contrast to the increase in 2-DG uptake observed in select brain regions after the subanesthetic dose, an anesthetic dose of ketamine (100 mg/kg) produced a global suppression of 2-DG uptake. By contrast, a robust induction of Fos-LI was observed after the anesthetic dose of ketamine that was neuroanatomically identical to that produced by the subanesthetic dose. Results of the present investigation show that anesthetic and subanesthetic doses of ketamine have pronounced effects on regional brain 2-DG uptake and induction of Fos-LI. The alterations in regional brain metabolism induced by the subanesthetic dose may be relevant to effects of ketamine to induce schizophrenic-like symptoms.
已表明，亚麻醉剂量的氯胺酮会加重精神分裂症患者的症状，并在正常受试者中诱发阳性、阴性及认知性精神分裂症样症状。本研究旨在通过对14C-2-脱氧葡萄糖（2-DG）摄取进行高分辨率放射自显影分析以及对Fos样免疫反应性（Fos-LI）进行免疫细胞化学染色，来确定受亚麻醉剂量氯胺酮影响的脑区。之所以使用这两种功能图谱绘制方法，是因为通过这两种图谱绘制方法常常能获得不同但互补的信息。氯胺酮以35毫克/千克的亚麻醉剂量给药时，会显著增加某些边缘皮质区域的2-DG摄取，这些区域包括内侧前额叶、腹外侧眶额、扣带回及压后皮质。在海马结构中，氯胺酮的亚麻醉剂量会使齿状回、CA-3放射层、分子层及前下托的2-DG摄取显著增加。在某些丘脑核团及基底外侧杏仁核中也观察到，对35毫克/千克氯胺酮有反应的2-DG摄取增加。氯胺酮在与亚麻醉剂量药物反应时表现出2-DG摄取增加的相同边缘皮质区域诱导Fos-LI。然而，在一些显示2-DG摄取增加的脑区，如海马结构、丘脑前腹核及基底外侧杏仁核中，并未诱导出Fos。相反，氯胺酮在下丘脑室旁核及中央杏仁核中诱导出Fos，尽管在这些区域未观察到该药物对2-DG摄取有明显影响。与亚麻醉剂量后在某些脑区观察到的2-DG摄取增加相反，并麻醉剂量的氯胺酮（100毫克/千克）会使2-DG摄取全面受到抑制。相比之下，在氯胺酮麻醉剂量后观察到Fos-LI的强烈诱导，其神经解剖学特征与亚麻醉剂量所产生的相同。本研究结果表明，麻醉剂量和亚麻醉剂量的氯胺酮对脑区局部2-DG摄取及Fos-LI的诱导有显著影响。亚麻醉剂量诱导的脑区局部代谢改变可能与氯胺酮诱导精神分裂症样症状的作用相关。
