Day Mark, Pan Jia Bao, Buckley Michael J, Cronin Elizabeth, Hollingsworth Peter R, Hirst Warren D, Navarra Rachel, Sullivan James P, Decker Michael W, Fox Gerard B
Discovery Translational Medicine, Wyeth Research, 500 Arcola Road, PA 19426, USA.
Biochem Pharmacol. 2007 Apr 15;73(8):1123-34. doi: 10.1016/j.bcp.2006.12.004. Epub 2006 Dec 9.
Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. While it is difficult to model such executive processes in animals, the 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. At Wyeth and Abbott, we recently investigated the utility of employing the 5-CSRTT in adult rats. This involved training and testing groups of rats over an extended period of several months and required the animals to learn to nose-poke into one of five apertures following presentation of a brief visual stimulus in that aperture in order to obtain a food reward. When the stimulus duration was short, the rat had to pay close attention to make a correct choice--a nose-poke into the aperture with the brief visual stimulus. We evaluated nicotine and the histamine H(3) receptor antagonist, ciproxifan, since compounds targeting both nicotinic and histaminergic neurotransmission are currently under investigation for treating cognitive dysfunction in ADHD, AD and schizophrenia. After approximately 12 weeks of training, rats were tested with drug when they had achieved stable performance. Nicotine (0.2, 0.4 mg/kg s.c.) significantly improved accuracy and reduced errors of omission (reflecting improved attention and vigilance) when baseline performance was <90% correct. In contrast, nicotine tended to worsen accuracy when baseline performance was >90% correct. Using the same test paradigm, ciproxifan (3mg/kg i.p.) reduced premature responding, a measure of impulsivity. Under conditions of variable stimulus duration, ciproxifan also improved accuracy and decreased impulsivity. In summary, we have replicated previous findings by others of positive effects of nicotine on attention, but also showed that this is dependent on baseline performance. We also expanded on previous positive findings by others with ciproxifan on attention and both Wyeth and Abbott demonstrate for the first time decreased impulsivity with this mechanism.
注意力和反应抑制方面的缺陷在多种神经退行性疾病和神经精神疾病中都很明显，而目前的药物治疗对此并不充分。虽然在动物中很难模拟这种执行过程，但源自人类连续性能测试（CPT）的5选择连续反应时测试（5-CSRTT），可能作为一种有用的转化试验，用于评估这些关键行为领域的疗效。在惠氏和雅培公司，我们最近研究了在成年大鼠中采用5-CSRTT的效用。这涉及在几个月的较长时间内对大鼠组进行训练和测试，要求动物在短暂视觉刺激出现在五个光圈之一后，学会用鼻子戳入该光圈以获得食物奖励。当刺激持续时间短时，大鼠必须密切注意才能做出正确选择——用鼻子戳入有短暂视觉刺激的光圈。我们评估了尼古丁和组胺H(3)受体拮抗剂西普罗沙星，因为目前正在研究针对烟碱能和组胺能神经传递的化合物用于治疗多动症、阿尔茨海默病和精神分裂症中的认知功能障碍。经过大约12周的训练后，当大鼠表现稳定时用药物进行测试。当基线表现正确率<90%时，尼古丁（0.2、0.4mg/kg皮下注射）显著提高了准确性并减少了漏报错误（反映注意力和警觉性提高）。相比之下，当基线表现正确率>90%时，尼古丁往往会降低准确性。使用相同的测试范式，西普罗沙星（3mg/kg腹腔注射）减少了过早反应，这是一种冲动性的衡量指标。在可变刺激持续时间的条件下，西普罗沙星也提高了准确性并降低了冲动性。总之，我们重复了其他人之前关于尼古丁对注意力有积极影响的发现，但也表明这取决于基线表现。我们还扩展了其他人之前关于西普罗沙星对注意力有积极影响的发现，惠氏和雅培公司首次证明了这种机制可降低冲动性。
