Sahr Allison E, Sindelar Dana K, Alexander-Chacko Jesline T, Eastwood Brian J, Mitch Charles H, Statnick Michael A
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0403, USA.
Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R463-71. doi: 10.1152/ajpregu.00390.2007. Epub 2008 Jun 4.
An analog of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series (LY255582) exhibits high in vitro binding affinity and antagonist potency for the mu-, delta-, and kappa-opioid receptors. In vivo, LY255582 exhibits potent effects in reducing food intake and body weight in several rodent models of obesity. In the present study, we evaluated the effects of LY255582 to prevent the consumption of a highly palatable (HP) diet (a high-fat/high-carbohydrate diet) both when the food was novel and following daily limited access to the HP diet. Additionally, we examined the effects of consumption of the HP diet and of LY255582 treatment on mesolimbic dopamine (DA) signaling by in vivo microdialysis. Consumption of the HP diet increased extracellular DA levels within the nucleus accumbens (NAc) shell. Increased DA in the NAc shell was not related to the quantity of the HP diet consumed, and the DA response did not habituate following daily scheduled access to the HP diet. Interestingly, treatment with LY255582 inhibited consumption of the HP diet and the HP diet-associated increase in NAc shell DA levels. Moreover, the increased HP diet consumption observed following daily limited access to the HP diet was completely prevented by LY255582 treatment. LY255582 may be a useful tool in understanding the neural mechanisms involved in the reinforcement mechanisms regulating food intake.
反式-3,4-二甲基-4-(3-羟基苯基)哌啶系列的一种类似物（LY255582）对μ-、δ-和κ-阿片受体表现出高体外结合亲和力和拮抗剂效力。在体内，LY255582在几种肥胖啮齿动物模型中对减少食物摄入量和体重具有显著作用。在本研究中，我们评估了LY255582在食物新颖时以及在每日有限接触高脂高糖（HP）饮食后预防其消耗的效果。此外，我们通过体内微透析研究了HP饮食的消耗以及LY255582处理对中脑边缘多巴胺（DA）信号传导的影响。食用HP饮食会增加伏隔核（NAc）壳内的细胞外DA水平。NAc壳内DA的增加与所消耗的HP饮食量无关，并且在每日定时接触HP饮食后DA反应不会产生习惯化。有趣的是，LY255582处理可抑制HP饮食的消耗以及HP饮食相关的NAc壳DA水平升高。此外，LY255582处理完全阻止了在每日有限接触HP饮食后观察到的HP饮食消耗量增加。LY255582可能是理解调节食物摄入的强化机制中所涉及神经机制的有用工具。
