Di Lazzaro V, Oliviero A, Profice P, Pennisi M A, Pilato F, Zito G, Dileone M, Nicoletti R, Pasqualetti P, Tonali P A
Institute of Neurology, Università Cattolica, Largo A. Gemelli 8, 00168 Rome, Italy.
J Physiol. 2003 Mar 1;547(Pt 2):485-96. doi: 10.1113/jphysiol.2002.030486. Epub 2003 Jan 17.
Subanaesthetic doses of the N-methyl-D-aspartate (NMDA) antagonist ketamine have been shown to determine a dual modulating effect on glutamatergic transmission in experimental animals, blocking NMDA receptor activity and enhancing non-NMDA transmission through an increase in the release of endogenous glutamate. Little is known about the effects of ketamine on the excitability of the human central nervous system. The effects of subanaesthetic, graded incremental doses of ketamine (0.01, 0.02 and 0.04 mg kg-1 min-1, I.V.) on the excitability of cortical networks of the human motor cortex were examined with a range of transcranial magnetic and electric stimulation protocols in seven normal subjects. Administration of ketamine at increasing doses produced a progressive reduction in the mean resting motor threshold (RMT) (F(3, 18) = 22.33, P < 0.001) and active motor threshold (AMT) (F(3, 18) = 12.17, P < 0.001). Before ketamine administration, mean RMT +/- S.D. was 49 +/- 3.3 % of maximum stimulator output and at the highest infusion level it was 42.6 +/- 2.6 % (P < 0.001). Before ketamine administration, AMT +/- S.D. was 38 +/- 3.3 % of maximum stimulator output and at the highest infusion level it was 33 +/- 4.4 % (P < 0.002). Ketamine also led to an increase in the amplitude of EMG responses evoked by magnetic stimulation at rest; this increase was a function of ketamine dosage (F(3, 18) = 5.29, P = 0.009). In contrast to responses evoked by magnetic stimulation, responses evoked by electric stimulation were not modified by ketamine. The differential effect of ketamine on responses evoked by magnetic and electric stimulation demonstrates that subanaesthetic doses of ketamine enhance the recruitment of excitatory cortical networks in motor cortex. Transcranial magnetic stimulation produces a high-frequency repetitive discharge of pyramidal neurones and for this reason probably depends mostly on short-lasting AMPA transmission. An increase in this transmission might facilitate the repetitive discharge of pyramidal cells after transcranial magnetic stimulation which, in turn, results in larger motor responses and lower thresholds. We suggest that the enhancement of human motor cortex excitability to transcranial magnetic stimulation is the effect of an increase in glutamatergic transmission at non-NMDA receptors similar to that described in experimental studies.
已表明，亚麻醉剂量的N-甲基-D-天冬氨酸（NMDA）拮抗剂氯胺酮对实验动物的谷氨酸能传递具有双重调节作用，即阻断NMDA受体活性，并通过增加内源性谷氨酸的释放来增强非NMDA传递。关于氯胺酮对人中枢神经系统兴奋性的影响，人们了解甚少。在七名正常受试者中，采用一系列经颅磁刺激和电刺激方案，研究了亚麻醉剂量的递增氯胺酮（0.01、0.02和0.04 mg·kg⁻¹·min⁻¹，静脉注射）对人运动皮层皮质网络兴奋性的影响。递增剂量的氯胺酮给药导致平均静息运动阈值（RMT）逐渐降低（F(3, 18) = 22.33，P < 0.001）和主动运动阈值（AMT）逐渐降低（F(3, 18) = 12.17，P < 0.001）。在给予氯胺酮之前，平均RMT±标准差为最大刺激器输出的49±3.3%，在最高输注水平时为42.6±2.6%（P < 0.001）。在给予氯胺酮之前，AMT±标准差为最大刺激器输出的38±3.3%，在最高输注水平时为33±4.4%（P < 0.002）。氯胺酮还导致静息时磁刺激诱发的肌电图反应幅度增加；这种增加是氯胺酮剂量的函数（F(3, 18) = 5.29，P = 0.009）。与磁刺激诱发的反应不同，电刺激诱发的反应未被氯胺酮改变。氯胺酮对磁刺激和电刺激诱发反应的不同影响表明，亚麻醉剂量的氯胺酮增强了运动皮层兴奋性皮质网络的募集。经颅磁刺激会产生锥体神经元的高频重复放电，因此可能主要依赖于短暂的AMPA传递。这种传递的增加可能会促进经颅磁刺激后锥体细胞的重复放电，进而导致更大的运动反应和更低的阈值。我们认为，人运动皮层对经颅磁刺激兴奋性的增强是类似于实验研究中所描述的非NMDA受体处谷氨酸能传递增加的结果。
