Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121

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• 作者：Jia Bao Pan ; Betty B. Yao ; Thomas R. Miller ; Paul E. Kroeger ; Youssef L. Bennani ; Victoria A. Komater ; Timothy A. Esbenshade ; Arthur A. Hancock ; Michael W. Decker and Gerard B. Fox
• 关键词：Histamine H₃ receptor inverse agonist ; Tolerance ; Chronic treatment ; Ciproxifan ; A-304121
• 刊名：Life Sciences
• 出版年：2006
• 出版时间：29 August 2006
• 年：2006
• 卷：79
• 期：14
• 页码：1366-1379
• 全文大小：349 K

文摘

Blockade of presynaptic histamine H₃ receptors with potent and selective ligands improves cognitive function in rodents and there is significant interest in developing such drugs for long-term symptomatic treatment of CNS disorders such as attention deficit hyperactivity disorder (ADHD). Unfortunately, little is known about the effects of repeated exposure to H₃ receptor antagonists/inverse agonists. We therefore investigated the effects of acute and repeated daily administration of two potent, brain penetrating H₃ receptor antagonists/inverse agonists, ciproxifan and A-304121, on rat body weight, food and water intake, core temperature and locomotor activity, as well as H₃ receptor density and gene expression levels. Methylphenidate, used clinically for the treatment of ADHD, was included as an additional comparator. Ciproxifan, an imidazole-based compound, decreased food intake over the first 10 days and locomotor activity acutely, but these effects were lost after further repeated administration. The ex vivo binding studies revealed increased H₃ receptor density in rats following repeated administration of ciproxifan for 10 or 15 days; however, H₃ receptor gene expression was not changed. In contrast, rats treated with the non-imidazole, A-304121, did not differ from controls on any measure during the observation period, while rats treated with methylphenidate exhibited hyperthermia and hyperactivity. The implications for potential long-term treatment with H₃ receptor antagonists in CNS disorders such as ADHD are discussed.