Lockie Sarah H, Stefanidis Aneta, Tschöp Matthias H, Oldfield Brian J
Department of Physiology, Monash University, Wellington Rd, Clayton, Victoria, Australia.
Department of Physiology, Monash University, Wellington Rd, Clayton, Victoria, Australia.
Mol Cell Endocrinol. 2015 Dec 5;417:10-9. doi: 10.1016/j.mce.2015.09.003. Epub 2015 Sep 7.
The CB1 receptor antagonist, rimonabant, causes weight loss but also produces undesirable psychiatric side effects. We investigated using a combination of rimonabant with the opioid receptor antagonists naloxone and norBNI to treat the metabolic sequelae of long-term high fat diet feeding in mice. This combination has previously been shown to have positive effects on both weight loss and mood related behaviour. Diet-induced obese mice were treated chronically with either low dose rimonabant (1 mg/kg) or the combination of rimonabant, naloxone and norBNI (rim nal BNI). After 6 days of treatment, glucose and insulin tolerance tests were performed and body composition analysed using DEXA. Changes in BAT thermogenesis were assessed using implantable radio telemetry probes. Behavioural responses to acute rimonabant or rim nal BNI were examined in the forced swim test and elevated plus maze. Separately, we assessed shifts in Fos immunoreactivity in response to rimonabant or rim nal BNI. Rim nal BNI was significantly better than rimonabant treatment alone at reducing body weight and food intake. In addition, it improved fasting blood glucose and fat mass. Acute low dose rimonabant did not alter behaviour in either the forced swim test or elevated plus maze. Combination rim nal BNI reversed the behavioural effects of high dose (10 mg/kg) rimonabant in obese mice. Rim nal BNI altered Rimonabant-induced Fos in a number of nuclei, with particular shifts in expression in the central and basolateral amygdala, and insular cortex. This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes. These results indicate that CB1-targeted drugs for weight loss may still be feasible.
大麻素1型（CB1）受体拮抗剂利莫那班可导致体重减轻，但也会产生不良的精神副作用。我们研究了将利莫那班与阿片受体拮抗剂纳洛酮和norBNI联合使用，以治疗小鼠长期高脂饮食喂养后的代谢后遗症。此前已证明这种联合用药对体重减轻和情绪相关行为均有积极影响。给饮食诱导的肥胖小鼠长期服用低剂量利莫那班（1毫克/千克）或利莫那班、纳洛酮和norBNI的组合（利莫那班 纳洛酮 norBNI）。治疗6天后，进行葡萄糖和胰岛素耐量试验，并使用双能X线吸收法（DEXA）分析身体成分。使用植入式无线电遥测探头评估棕色脂肪组织（BAT）产热的变化。在强迫游泳试验和高架十字迷宫试验中检测对急性利莫那班或利莫那班 纳洛酮 norBNI的行为反应。另外，我们评估了对利莫那班或利莫那班 纳洛酮 norBNI反应时Fos免疫反应性的变化。在减轻体重和食物摄入量方面，利莫那班 纳洛酮 norBNI显著优于单独使用利莫那班治疗。此外，它还改善了空腹血糖和脂肪量。急性低剂量利莫那班在强迫游泳试验或高架十字迷宫试验中均未改变行为。联合用药利莫那班 纳洛酮 norBNI逆转了高剂量（10毫克/千克）利莫那班对肥胖小鼠的行为影响。利莫那班 纳洛酮 norBNI改变了利莫那班诱导的多个核团中的Fos表达，尤其是中央杏仁核、基底外侧杏仁核和岛叶皮质中的表达发生了变化。这项研究表明，利莫那班、纳洛酮和norBNI的组合在持续一段时间内有效减轻体重，同时不改变标准化小鼠行为试验中的表现。Fos表达模式为这些生理和行为变化的神经解剖学基础提供了见解。这些结果表明，以CB1为靶点的减肥药物可能仍然可行。
