A parametric analysis of olanzapine-induced weight gain in female rats
A parametric analysis of olanzapine-induced weight gain in female rats
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DOI：
10.1007/s00213-005-2224-4
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发表时间：
2005-08-01
影响因子：
3.4
通讯作者：
Goudie, AJ
中科院分区：
文献类型：
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作者：
Cooper, GD;Pickavance, LC;Goudie, AJ
基本原理：包括奥氮平在内的一些新型抗精神病药物可引起体重增加和代谢异常，这是这些药物的主要不良反应。然而，这种影响所涉及的机制尚不清楚。目的：本研究的目的是在雌性大鼠中开发奥氮平诱导的体重增加和代谢异常的参数模型，并根据临床结果对其进行评价。方法：雌性大鼠每日2次给予奥氮平。以0、1、2和4 mg/kg的剂量给药20天，在给药期间和给药后记录了广泛的变量。结果：奥氮平增加24 h和总摄食量。这与体重快速增加和肥胖增加有关（通过内脏脂肪垫质量评估）。胰岛素（而非葡萄糖）浓度升高，HOMA-IR指数显著增加，表明胰岛素抵抗。观察到瘦素水平升高的非显著趋势。特别是，脂联素显著增加。所有这些变量在1或2 mg/kg时均显示最大增加，在4 mg/kg时效应减弱。奥氮平也增加了催乳素水平。然而，对于该变量，存在明确的剂量-反应曲线，在最高剂量（4 mg/kg）下具有最大效应。结论：这些数据表明，奥氮平诱导的体重增加和代谢异常方面可能是在雌性大鼠中建模。这表明，奥氮平诱导的摄食过多作为一个初始刺激，导致体重增加，内脏肥胖和随后的胰岛素抵抗，虽然后者可以改善脂联素水平的代偿反应。催乳素升高似乎不太可能参与该模型中观察到的体重增加、肥胖和代谢变化。
Rationale: Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear. Objective: The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings. Methods: Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration. Results: Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg). Conclusions: These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.