Additive feeding inhibitory and aversive effects of naltrexone and exendin-4 combinations.
Additive feeding inhibitory and aversive effects of naltrexone and exendin-4 combinations.
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DOI：
10.1038/ijo.2012.16
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发表时间：
2013-02
影响因子：
4.9
通讯作者：
Moran, T. H.
中科院分区：
文献类型：
--
作者：
Liang, N-C;Bello, N. T.;Moran, T. H.
一种正在发展的肥胖治疗策略是使用不同作用的药物疗法的组合来改善体重减轻，同时减少副作用。本研究的目的是确定纳洛酮（一种作用于奖赏系统的阿片类拮抗剂）和exendin-4（一种作用于饱腹感信号的胰高血糖素样肽1（GLP-1）激动剂）的组合是否会比单独使用大鼠产生更大的摄食量减少。由于这两种化合物的厌食效力与恶心和不适有关，因此还确定了这些药物组合对条件性味觉厌恶（CTA）获得的影响。在实验1中，单独或联合评估了纳洛酮（0.32-3.2 mg/kg; IP）和毒蜥外泌肽-4（1-10 µg/kg; IP）的急性厌食作用。通过每日重复给予1 mg/kg纳洛酮+ 3.2 µg/kg毒蜥外泌肽-4，持续4天，进一步研究了联合给药。在实验2中，两种化合物单独或组合用作一系列CTA测试中的无条件刺激。纳洛酮和毒蜥外泌肽-4，单独或组合，抑制食物摄入量的剂量依赖性的方式，和纳洛酮和毒蜥外泌肽-4之间的相互作用的食物摄入量是相加的。在CTA范例中，单独的纳洛酮（1 mg/Kg）不支持采集，而在Ex-4（1或3.2 µg/Kg）剂量下CTA明显。纳洛酮和毒蜥外泌肽-4的组合也导致CTA的更快速和更稳健的获取。鉴于Nal和Ex-4组合不仅对食物摄入减少而且对食物厌恶学习产生累加效应，这种特定药物组合不具有使与每种单独药物相关的不良反应最小化的益处。这些数据表明，有必要在联合药物开发的早期阶段评估积极和不良反应。
One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone, an opioid antagonist acting on the reward system, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist, acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined. In Experiment 1, the acute anorectic effects of naltrexone (0.32–3.2 mg/kg; IP) and exendin-4 (1–10 µg/kg; IP) were assessed alone or in combination. Combinational doses were further investigated by the repeated daily administration of 1 mg/kg naltrexone + 3.2 µg/kg exendin-4 for 4 days. In Experiment 2, both compounds alone or in combination were used as unconditioned stimuli in a series of CTA tests. Naltrexone and exendin-4, alone or in combination, suppressed food intake in a dose dependent fashion, and the interaction on food intake between naltrexone and exendin-4 was additive. In the CTA paradigm, naltrexone (1 mg/Kg) alone did not support acquisition, whereas a CTA was evident with doses of Ex-4 (1 or 3.2 µg/Kg). Combinations of naltrexone and exendin-4 also resulted in a more rapid and robust acquisition of a CTA. Given that the Nal and Ex-4 combination produces additive effects on not only food intake reduction but also food aversion learning, this specific drug combination does not have the benefit of minimizing the adverse effects associated with each individual drug. These data suggest that it is necessary to evaluate both the positive and adverse effects at early stages of combinational drug development.
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DOI：
10.1523/jneurosci.3262-11.2011
发表时间：
2011-10-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dossat AM;Lilly N;Kay K;Williams DL
通讯作者：
Williams DL
影响因子：
5.8
作者：
Blonde, L.;Klein, E. J.;Kendall, D. M.
通讯作者：
Kendall, D. M.
DOI：
10.1152/ajpregu.00424.2010
发表时间：
2011-10-01
影响因子：
2.8
作者：
Baraboi, Elena-Dana;St-Pierre, David H.;Richard, Denis
通讯作者：
Richard, Denis
影响因子：
2.9
作者：
de Jonghe, Bart C.;Lawler, Maureen P.;Horn, Charles C.;Tordoff, Michael G.
通讯作者：
Tordoff, Michael G.
影响因子：
4.8
作者：
Kanoski, Scott E.;Fortin, Samantha M.;Hayes, Matthew R.
通讯作者：
Hayes, Matthew R.