Effects of histamine H3 receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup
Effects of histamine H3 receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup
复制标题
DOI：
10.1016/s0166-4328(01)00379-5
复制
发表时间：
2002-04-01
影响因子：
2.7
通讯作者：
Decker, MW
中科院分区：
文献类型：
--
作者：
Fox, GB;Pan, JB;Decker, MW
已经提出组胺H-3受体拮抗剂作为潜在有用的治疗剂用于治疗几种疾病，包括注意力缺陷、精神分裂症、抑郁症和阿尔茨海默病。我们已经开发了一个重复的收购版本的抑制性回避任务，使用自发性高血压大鼠（SHR）的幼崽，我们认为提供了一个可重复的措施，这些疾病状态的特点，认知和注意力缺陷，并评估两个H-3受体拮抗剂。训练雄性SHR、Wistar（WI）和Wistar京都（WKY）大鼠幼仔（20-24日龄）以避免轻度足电击（0.1 mA，持续时间1秒），当幼仔从明亮的隔间转移到黑暗的隔间时进行。在第一次试验后，将幼犬取出并放回其饲养笼。一分钟后，同一只小狗被换到明亮的隔间里，重复训练过程。共记录了5次试验。使用该训练计划，SHR幼鼠的表现明显比WI或WKY幼鼠差，并且SHR幼鼠用于所有后续研究。哌醋甲酯和ABT-418，临床上活跃的注意缺陷多动障碍（ADHD），进行了测试，以验证模型。哌醋甲酯（1和3 mg/kg s.c.）和ABT-418（0.03mg/kg s.c.）显着提高SHR幼鼠的性能。H-3受体拮抗剂GT-2331（lmg/kg s.c.）和ciproxifan（3mg/kg s.c.），还显著地并且以剂量相关的方式增强了SHR幼仔的表现。（R）-α-甲基组胺（3 mg/kg s.c.）阻断了环丙沙星的促认知作用表明该化合物的H-3受体作用位点。该模型可用于评估H-3受体拮抗剂的认知/注意力增强潜力。(C)2002 Elsevier Science B. V.保留所有权利。
Histamine H-3 receptor antagonists have been proposed as potentially useful therapeutic agents for the treatment of several disorders including attention deficit, schizophrenia, depression, and Alzheimer's disease. We have developed a repeated acquisition version of an inhibitory avoidance task using spontaneously hypertensive rat (SHR) pups that we believe provides a reproducible measure of the cognitive and attention deficits often characteristic of these disease states, and evaluated two H-3 receptor antagonists. Male SHR, Wistar (WI) and Wistar Kyoto (WKY) rat pups (20-24 days old) were trained to avoid a mild footshock (0.1 mA, I s duration), delivered when the pup had transferred from a brightly lit to a darkened compartment. After the first trial, the pup was removed and returned to its home cage. One minute later, the same pup was replaced in the brightly-lit compartment and the training process repeated. A total of five trials were recorded. SHR pups performed significantly more poorly than WI or WKY pups using this training schedule, and SHR pups were used for all subsequent studies. Methylphenidate and ABT-418, both clinically active in attention deficit hyperactivity disorder (ADHD), were tested to validate the model. Methylphenidate (I and 3 mg/kg s.c.) and ABT-418 (0.03 mg/kg s.c.) significantly improved SHR pup performance. The H-3 receptor antagonists GT-2331 (I mg/kg s.c.) and ciproxifan (3 mg/kg s.c.), also significantly, and in a dose-related manner, enhanced performance of the SHR pups. (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the pro-cognitive effects of ciproxifan. suggesting an H-3 receptor site of action for this compound. This model is useful for evaluating the cognition/attention-enhancing potential of H-3 receptor antagonists. (C) 2002 Elsevier Science B.V. All rights reserved.