Section for Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
Addict Biol. 2012 Jan;17(1):86-94. doi: 10.1111/j.1369-1600.2010.00280.x. Epub 2011 Feb 11.
The mechanisms involved in alcohol use disorders are complex. It has been shown that ghrelin is an important signal for the control of body weight homeostasis, preferably by interacting with hypothalamic circuits, as well as for drug reward by activating the mesolimbic dopamine system. The ghrelin receptor (GHS-R1A) has been shown to be required for alcohol-induced reward. Additionally, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. However, the role of central ghrelin signaling in high alcohol consumption is not known. Therefore, the role of GHS-R1A in operant self-administration of alcohol in rats as well as for high alcohol consumption in Long-Evans rats and in alcohol preferring [Alko alcohol (AA)] rats was studied here. In the present study, the GHS-R1A antagonist, JMV2959, was found to reduce the operant self-administration of alcohol in rats and to decrease high alcohol intake in Long-Evans rats as well as in AA rats. These results suggest that the ghrelin receptor signaling system, specifically GHS-R1A, is required for operant self-administration of alcohol and for high alcohol intake in rats. Therefore, the GHS-R1A may be a therapeutic target for treatment of addictive behaviors, such as alcohol dependence.
涉及酒精使用障碍的机制很复杂。已经表明，ghrelin 是控制体重稳态的重要信号，最好通过与下丘脑回路相互作用，以及通过激活中脑边缘多巴胺系统来发挥药物奖励作用。已经表明，ghrelin 受体（GHS-R1A）是酒精诱导奖励所必需的。此外，ghrelin 增加，而 GHR-R1A 拮抗剂减少小鼠中适度的酒精消耗，并且 GHS-R1A 基因中的单核苷酸多态性与人类的高酒精消耗有关。然而，中枢 ghrelin 信号在高酒精消耗中的作用尚不清楚。因此，本研究旨在研究 GHS-R1A 在大鼠操作性自我给药酒精中的作用，以及在长耳大鼠和酒精偏爱[Alko 酒精（AA）]大鼠中高酒精消耗的作用。在本研究中，发现 GHS-R1A 拮抗剂 JMV2959 可减少大鼠的操作性自我给药酒精，并减少长耳大鼠和 AA 大鼠的高酒精摄入量。这些结果表明，ghrelin 受体信号系统，特别是 GHS-R1A，是大鼠操作性自我给药酒精和高酒精摄入所必需的。因此，GHS-R1A 可能是治疗成瘾行为（如酒精依赖）的治疗靶点。
