Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Biol Psychiatry. 2012 Jun 1;71(11):969-77. doi: 10.1016/j.biopsych.2011.09.031. Epub 2011 Oct 29.
Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans.
This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day.
Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive.
NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.
听觉失匹配负波（MMN）和 P300 事件相关电位（ERP）在给予 N-甲基-D-天冬氨酸谷氨酸受体拮抗剂氯胺酮的精神分裂症患者和健康志愿者中减少。在啮齿动物中，N-乙酰半胱氨酸（NAC），胱氨酸-谷氨酸交换体的刺激物，可减轻 N-甲基-D-天冬氨酸受体拮抗剂的认知和行为作用。基于这些发现，我们测试了 NAC 是否会减少健康人对氯胺酮的行为、MMN 和 P300 的影响。
这项随机、双盲、安慰剂对照研究包括 2 个测试日，在此期间，受试者（n = 16）在口服 NAC（3000 mg 分剂量）或匹配安慰剂 165 分钟后，静脉输注生理盐水，然后静脉输注氯胺酮（以 0.23 mg/kg 的剂量推注 1 分钟，然后以 0.58 mg/kg 输注 30 分钟，然后以 0.29 mg/kg 输注 40 分钟），顺序固定。在每个测试日收集行为和 ERP 数据，包括听觉 MMN 和 P300。
氯胺酮产生类精神病阳性症状、工作记忆和持续注意力表现下降，以及频率和强度偏差 MMN 和 P300 振幅降低。NAC 预处理不能减轻氯胺酮的行为或 ERP 效应。此外，NAC 降低了频率偏差 MMN 振幅并增加了靶刺激和新奇刺激 P3 振幅。氯胺酮和 NAC 引起的频率偏差 MMN 振幅降低不具有加性。
NAC 没有减轻人类氯胺酮的作用，与以前的动物研究相反。由于其增加 P300 振幅的能力，NAC 值得进一步研究作为认知增强剂。
