van Berckel B N, Oranje B, van Ree J M, Verbaten M N, Kahn R S
University Hospital Utrecht, Department of Psychiatry, The Netherlands.
Psychopharmacology (Berl). 1998 Jun;137(3):271-81. doi: 10.1007/s002130050620.
Recently, much interest has been given to the role of glutamatergic N-methyl-D-aspartate receptors (NMDA) in sensory gating, such as prepulse inhibition (PPI) and reduction of the P50 evoked response potential (ERP). Currently, mainly animal data are available describing the role of NMDA receptors in these stimulus evaluation processes. Human data are virtually lacking and are potentially important, for instance for the understanding of sensory gating deficits observed in schizophrenia. Therefore, the effects of the NMDA antagonist ketamine, in a dose of 0.3 mg/kg i.v., on concurrent assessment of PPI and P50 reduction was studied in 18 healthy male volunteers. Ketamine was administered in a pseudo-steady state model with a subacute loading dose. In addition, the effects of ketamine on behavior, vital signs, homovanillic acid (HVA) plasma levels and secretion of cortisol and luteinizing hormone (LH) were also determined. Ketamine did not significantly alter PPI or the reduction of the P50 ERP. A small but significant increase in Brief Psychiatric Rating Scale (BPRS) total scores and BPRS composite scores "thinking disorder" and "withdrawal/retardation" was observed. Several subjects experienced visual perceptional alterations, but complex hallucinations did not occur. Ketamine induced mild analgesia and coordination problems. In addition, ketamine induced a marked rise in cortisol secretion, while LH secretion was not affected. Finally, systolic and diastolic, blood pressure and heart rate increased during ketamine infusion. Although in humans NMDA receptors may not be involved in the regulation of PPI and P50 reduction, the most likely explanation for the lack of effect of ketamine on these sensory gating paradigms is the dose used in this experiment. However, using a higher dose is hampered by the aspecificity of racemic ketamine. Future studies should use the enantiomer S-ketamine, which is more specific to NMDA receptors, to evaluate the involvement of NMDA receptors in these neurophysiological processes further.
最近，谷氨酸能N-甲基-D-天冬氨酸受体（NMDA）在感觉门控中的作用备受关注，比如在预脉冲抑制（PPI）和P50诱发反应电位（ERP）降低方面。目前，主要是动物数据描述了NMDA受体在这些刺激评估过程中的作用。实际上缺乏人类数据，而这些数据可能很重要，例如对于理解精神分裂症中观察到的感觉门控缺陷。因此，在18名健康男性志愿者中研究了静脉注射剂量为0.3mg/kg的NMDA拮抗剂氯胺酮对同时评估PPI和P50降低的影响。氯胺酮以亚急性负荷剂量的伪稳态模型给药。此外，还测定了氯胺酮对行为、生命体征、血浆高香草酸（HVA）水平以及皮质醇和促黄体生成素（LH）分泌的影响。氯胺酮并未显著改变PPI或P50 ERP的降低。观察到简明精神病评定量表（BPRS）总分以及BPRS综合评分“思维障碍”和“退缩/迟缓”有小幅但显著的增加。几名受试者经历了视觉感知改变，但未出现复杂幻觉。氯胺酮引起轻度镇痛和协调问题。此外，氯胺酮导致皮质醇分泌显著增加，而LH分泌未受影响。最后，在输注氯胺酮期间收缩压和舒张压、血压和心率升高。尽管在人类中NMDA受体可能不参与PPI和P50降低的调节，但氯胺酮对这些感觉门控范式缺乏作用的最可能解释是本实验中使用的剂量。然而，使用更高剂量受到外消旋氯胺酮非特异性的阻碍。未来的研究应使用对NMDA受体更具特异性的对映体S-氯胺酮，以进一步评估NMDA受体在这些神经生理过程中的参与情况。
