Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence.
Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence.
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DOI：
10.1016/j.neuropharm.2015.05.026
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发表时间：
2015-10
影响因子：
4.7
通讯作者：
Ryabinin AE
中科院分区：
文献类型：
--
作者：
Gomez JL;Cunningham CL;Finn DA;Young EA;Helpenstell LK;Schuette LM;Fidler TL;Kosten TA;Ryabinin AE
人们正在努力了解酒精依赖的机制，以一种可能使治疗更有效的方式。长期以来，人们一直认为滥用药物会抓住基本的奖励途径，破坏体内平衡，从而产生强迫性的药物寻求行为。胃饥饿素（Ghrelin）是一种影响饥饿状态和生长激素释放的内源性激素，已被证明在服用后会增加酒精摄入量，而拮抗剂会减少摄入量。利用啮齿动物依赖模型，本研究检测了两种胃饥饿素受体拮抗剂[DLys3]-GHRP-6 （dlyys）和JMV2959对依赖诱导的酒精自我给药的影响。在两个实验中，成年雄性C57BL/6J小鼠和Wistar大鼠通过间歇性乙醇蒸汽暴露产生依赖。在另一项实验中，采用灌胃酒精消耗（IGAC）方法使成年雄性C57BL/6J小鼠产生依赖。在自愿饮酒前给予胃饥饿素受体拮抗剂。在这些模型中，胃饥饿素拮抗剂减少了乙醇的摄入、偏好和乙醇和蔗糖的操作性自我给药，但没有减少小鼠的食物消耗。在实验1和2中，胃饥饿素受体拮抗剂减少了自愿饮酒，但这种减少并没有持续数天。尽管对胃促生长素拮抗剂有短暂的影响，但如实验1所示，药物在中断给药后又恢复了效力。研究结果表明，胃饥饿素系统是研究酒精滥用的一个潜在目标。需要进一步的研究来确定这些药物的主要机制及其对成瘾的影响，以便设计有效的药物治疗。
An effort has been mounted to understand the mechanisms of alcohol dependence in a way that may allow for greater efficacy in treatment. It has long been suggested that drugs of abuse seize fundamental reward pathways and disrupt homeostasis to produce compulsive drug seeking behaviors. Ghrelin, an endogenous hormone that affects hunger state and release of growth hormone, has been shown to increased alcohol intake following administration, while antagonists decrease intake. Using rodent models of dependence, the current study examined the effects of two ghrelin receptor antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, on dependence-induced alcohol self-administration. In two experiments adult male C57BL/6J mice and Wistar rats were made dependent via intermittent ethanol vapor exposure. In another experiment, adult male C57BL/6J mice were made dependent using the intragastric alcohol consumption (IGAC) procedure. Ghrelin receptor antagonists were given prior to voluntary ethanol drinking. Ghrelin antagonists reduced ethanol intake, preference, and operant self-administration of ethanol and sucrose across these models, but did not decrease food consumption in mice. In experiments 1 and 2, voluntary drinking was reduced by ghrelin receptor antagonists, however this reduction did not persist across days. Despite the transient effects to ghrelin antagonists, the drugs had renewed effectiveness following a break in administration as seen in experiment 1. The results show the ghrelin system as a potential target for studies of alcohol abuse. Further research is needed to determine the central mechanisms of these drugs and their influence on addiction in order to design effective pharmacotherapies.