Neuroscience Institute, New York University Medical Center, New York, NY, 10016, USA.
Department of Neuroscience and Physiology, New York University Medical Center, New York, NY, USA.
Psychopharmacology (Berl). 2017 Oct;234(19):2837-2857. doi: 10.1007/s00213-017-4679-5. Epub 2017 Jul 26.
Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies.
We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs.
MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated.
Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm.
The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.
注意力和抑制控制损伤是精神神经障碍（如精神分裂症）的内表型标志物，代表治疗管理的关键靶点。稳健的临床前模型和对临床相关治疗敏感的检测方法对于改善认知增强策略至关重要。
我们评估了一种具有与精神分裂症相关的神经和行为特征的啮齿动物模型（妊娠第 17 天甲基澳甲氧基乙醇乙酸酯处理（MAM-E17）），该模型在一种新的注意力和执行功能测试中进行了评估，并检查了潜在的益智药的影响。
MAM-E17 和假对照大鼠在一种新的基于触摸屏的啮齿动物连续绩效测试（rCPT）上进行训练，该测试旨在紧密模拟人类 CPT 范式。研究了一系列药物化合物的急性、系统治疗后对性能的影响。
两个 MAM-E17 大鼠队列在 rCPT 表现上受损，包括敏感性（d'）降低和假警报率（FAR）升高。舒必利（0-30mg/kg）剂量依赖性地降低了 MAM-E17 大鼠的 FAR 升高，而低剂量莫达非尼（8mg/kg）仅改善了假对照大鼠的 d'。ABT-594（5.9-19.4μg/kg）和莫达非尼（64mg/kg）显示出预期的兴奋剂样作用，而 LSN2463359（5mg/kg）、RO493858（10mg/kg）、阿托西汀（0.3-1mg/kg）和舒必利（30mg/kg）在所有动物中均表现出预期的抑制作用。多奈哌齐（0.1-1mg/kg）显示 d'有近显著增强，而 EVP-6124（0.3-3mg/kg）在 rCPT 范式中没有作用。
MAM-E17 模型在 rCPT 表现中表现出稳健且可重复的损伤，类似于精神分裂症中观察到的注意力和抑制控制缺陷。药理学特征与临床前和临床研究中已知的药物对认知的影响高度一致。rCPT 是一种敏感且可靠的工具，具有高度的转化潜力，可用于了解影响注意力和执行功能障碍的疾病的病因和治疗。
