Rajagopal Lakshmi, Massey Bill W, Huang Mei, Oyamada Yoshihiro, Meltzer Herbert Y
Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 12-014, Chicago, IL 60611.
Curr Pharm Des. 2014;20(31):5104-14. doi: 10.2174/1381612819666131216114240.
Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic-induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside.
啮齿动物的新奇物体识别（NOR）在某些方面类似于人类的陈述性（情景性）记忆，而陈述性记忆是精神分裂症中七个异常的认知领域之一。精神分裂症的认知障碍（CIS）在这一复杂综合征的不良功能结局中占比最大，其余大部分则由精神病性症状和阴性症状导致。目前的非典型抗精神病药物（APD），如氨磺必利、阿立哌唑、氯氮平、鲁拉西酮、奥氮平和利培酮，以及典型的APD，虽能显著改善CIS的某些方面，但并非全部，包括陈述性记忆，但并非对所有患者都有效，且很少能恢复正常功能。因此，寻找预防或治疗CIS的新方法是当前精神分裂症研究的主要目标，动物模型是必不可少的工具。啮齿动物的NOR在这方面很有价值，因为它与陈述性记忆相关，对其潜在神经回路有广泛了解，且评估简便可靠。亚慢性给予N-甲基-D-天冬氨酸受体（NMDAR）非竞争性拮抗剂，如苯环己哌啶（PCP）、地佐环平（MK-801）或氯胺酮，是研究NOR作为CIS模型的常用方法，因为它会导致谷氨酸能和γ-氨基丁酸能功能缺陷，而这两种功能缺陷都与CIS的发生有关。转基因小鼠和抗胆碱能药物诱导的NOR缺陷受到的关注较少。我们在此回顾了与CIS相关的啮齿动物NOR研究，包括证据表明非典型而非典型APD以及特定配体，如5-HT₁A部分激动剂、5-HT₇拮抗剂、D₁激动剂等，可在亚慢性NMDAR拮抗剂治疗后恢复NOR，还可预防亚慢性NMDAR拮抗剂引起的NOR损伤。我们讨论了这些发现与临床应用的契合程度。
