Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, Il 60611, USA.
Int J Neuropsychopharmacol. 2013 Nov;16(10):2181-94. doi: 10.1017/S1461145713000928.
The N-methyl-D-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT(1A), and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT(1A) partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5-10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.
N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，如苯环利定（PCP）、地卓西平（MK-801）或氯胺酮，给予啮齿类动物和灵长类动物亚慢性（sc）给药，会导致认知功能长期受损，包括新物体识别（NOR），这是人类陈述性记忆的模拟，是精神分裂症受损的认知领域之一。非典型抗精神病药物（AAPD）已被报道可改善一些精神分裂症患者的陈述性记忆，并可改善和预防 scNMDAR 拮抗剂治疗后啮齿动物的 NOR 缺陷。虽然 AAPD 改善精神分裂症认知障碍（CIS）的疗效是有限的，甚至存在争议，但迄今为止测试的所有现有 AAPD 的单次剂量在 scNMDAR 拮抗剂治疗后可短暂恢复 NOR。典型抗精神病药物（APD），如氟哌啶醇和奋乃静，在这种啮齿动物模型中无效，并且可能对某些 CIS 领域的治疗效果较差。血清素能机制，包括但不限于血清素（5-HT）2A 和 5-HT7 拮抗作用、5-HT（1A）和 GABA（A）激动作用，有助于 AAPD 在 scNMDAR 拮抗剂啮齿动物模型中的疗效，这与 GABA 中间神经元/谷氨酸过度假说有关 CIS 的病因。亚有效剂量的非典型 APD 改善 scNMDAR 治疗的啮齿动物 NOR 的能力可以通过添加亚有效剂量的 5-HT（1A）部分激动剂坦度螺酮或 5-HT7 拮抗剂 SB269970 来恢复。mGluR2/3 激动剂 LY379268 本身不能恢复 scNMDAR 治疗的啮齿动物的 NOR，当与 AAPD 鲁拉西酮一起给予时，也可以恢复 NOR。增强皮质和海马多巴胺和乙酰胆碱的外排，或两者兼而有之，可能有助于非典型 APD 恢复 NOR。重要的是，将鲁拉西酮、坦度螺酮或 SB269970 与 PCP 一起给予啮齿动物，剂量为 scPCP 产生持久 NOR 缺陷的 5-10 倍，可预防 scPCP 的作用。这种剂量差异可能与利用 AAPD 预防有发展为精神分裂症风险的个体的 CIS 发作有关。scNMDAR 范式可用于确定可能的治疗和预防 CIS 的方法。
