Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.
Neuropharmacology. 2018 Nov;142:41-62. doi: 10.1016/j.neuropharm.2017.11.045. Epub 2017 Nov 28.
Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of cognitive dysfunction in the illness is urgently required to enhance the development of new improved therapeutic strategies. Careful validation of animal models that mimic the behaviour and pathology of complex psychiatric disorders is an essential step towards this goal. Non-competitive NMDAR (N-Methyl-d-aspartate receptor) antagonists e.g. phencyclidine (PCP), ketamine and dizocilpine (MK-801) can effectively replicate certain aspects of negative and cognitive deficits associated with schizophrenia in animals. In 2010 we reviewed the effects of NMDAR antagonism in tests for domains of cognition affected in schizophrenia, social behaviour and neuropathology, and in 2014, in tests for negative symptoms. In this update, we evaluate the most recent pharmacological strategies for restoring cognition in schizophrenia using NMDAR antagonist models, published since our original review in 2010 (cited over 225 times, excluding self-citations). Tests reviewed are, novel object recognition for visual recognition memory, attentional set shifting for executive function, and operant tests incorporating recent touchscreen technology for a range of domains including working memory, problem solving and attention, all impaired in schizophrenia. Moreover, we include an update on parvalbumin (PV)-expressing GABAergic interneurons and review, for the first time, the effects of NMDAR antagonists on gamma oscillations, circuitry integral for effective cognition. Data summarized in this review strongly confirm the reliability and usefulness of NMDAR antagonist animal models for evaluating novel therapeutic candidates, and for improving our understanding of the pathophysiology of cognitive deficits in schizophrenia. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
精神分裂症的阴性和认知缺陷症状仍然是一个未满足的临床需求。为了增强新的治疗策略的发展，迫切需要深入了解疾病中认知功能障碍的神经和精神病理学。仔细验证模仿复杂精神疾病行为和病理学的动物模型是实现这一目标的重要步骤。非竞争性 NMDA 受体（N-甲基-D-天冬氨酸受体）拮抗剂，如苯环己哌啶（PCP）、氯胺酮和地卓西平（MK-801），可有效复制动物模型中与精神分裂症相关的阴性和认知缺陷的某些方面。2010 年，我们综述了 NMDA 受体拮抗作用在检测与精神分裂症相关的认知领域、社会行为和神经病理学的影响，以及 2014 年，在检测阴性症状中的影响。在本次更新中，我们评估了自 2010 年我们的原始综述以来（不包括自引，被引超过 225 次）使用 NMDA 受体拮抗剂模型恢复精神分裂症认知的最新药理学策略。综述的测试包括，新物体识别用于视觉识别记忆，注意定势转移用于执行功能，以及操作性测试，包括最近的触摸屏技术，用于包括工作记忆、解决问题和注意力等在内的一系列领域。此外，我们还包括了对钙调蛋白结合蛋白 1（PV）表达 GABA 能中间神经元的更新，并首次综述了 NMDA 受体拮抗剂对伽马振荡的影响，这是有效认知的电路完整性的关键。本综述中总结的数据强烈证实了 NMDA 受体拮抗剂动物模型在评估新型治疗候选物以及提高我们对精神分裂症认知缺陷病理生理学的理解方面的可靠性和有用性。本文是题为“迷幻剂：新的门，改变的感知”的特刊的一部分。
