Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Behav Brain Res. 2011 Jan 20;216(2):561-8. doi: 10.1016/j.bbr.2010.08.046. Epub 2010 Sep 15.
Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4h/day). With acute olanzapine (0.5, 1, and 2mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.
体重增加是抗精神病药物临床应用中最严重的副作用之一。然而，抗精神病药引起体重增加的机制尚不清楚，也没有建立可靠的抗精神病药引起体重增加的动物模型。本研究旨在建立慢性和急性抗精神病药治疗诱导雄性大鼠体重增加的模型。6 周慢性给予奥氮平（5、7.5 和 10mg/kg/天）治疗，雄性 Sprague-Dawley 大鼠给予类似于人类宏量营养素饮食的每日饮食，显著增加体重增加和脂肪组织重量。相比之下，齐拉西酮（1.25、2.5 和 5mg/kg/天）给药没有观察到不良反应。然后，我们使用自动食物测量仪器在雄性大鼠中进行了急性抗精神病治疗的摄食行为研究。大鼠被允许限制摄入正常实验室饲料（4 小时/天）。在光照期给予急性奥氮平（0.5、1 和 2mg/kg，ip）治疗时，食物摄入量和持续时间显著增加，而齐拉西酮（0.3、1 和 3mg/kg，ip）治疗时食物摄入量或进餐时间持续时间没有增加。本研究的结果表明，雄性大鼠慢性给予奥氮平可诱导体重增加，急性注射可引起暴食，提示暴食可能与慢性给予奥氮平引起的体重增加和肥胖有关。这些动物模型可能为分析暴食的机制和评估新型抗精神病药在人类中引起体重增加的潜在风险提供有用的实验平台。
