Department of Pharmacology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
PLoS One. 2011 Mar 23;6(3):e18170. doi: 10.1371/journal.pone.0018170.
The gastric-derived orexigenic peptide ghrelin affects brain circuits involved in energy balance as well as in reward. Indeed, ghrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link. It has been hypothesized that there is a common reward mechanism for alcohol and sweet substances in both animals and humans. Alcohol dependent individuals have higher craving for sweets than do healthy controls and the hedonic response to sweet taste may, at least in part, depend on genetic factors. Rat selectively bred for high sucrose intake have higher alcohol consumption than non-sucrose preferring rats and vice versa. In the present study a group of alcohol-consuming individuals selected from a population cohort was investigated for genetic variants of the ghrelin signalling system in relation to both their alcohol and sucrose consumption. Moreover, the effects of GHS-R1A antagonism on voluntary sucrose-intake and operant self-administration, as well as saccharin intake were investigated in preclinical studies using rodents. The effects of peripheral grelin administration on sucrose intake were also examined. Here we found associations with the ghrelin gene haplotypes and increased sucrose consumption, and a trend for the same association was seen in the high alcohol consumers. The preclinical data show that a GHS-R1A antagonist reduces the intake and self-administration of sucrose in rats as well as saccharin intake in mice. Further, ghrelin increases the intake of sucrose in rats. Collectively, our data provide a clear indication that the GHS-R1A antagonists reduces and ghrelin increases the intake of rewarding substances and hence, the central ghrelin signalling system provides a novel target for the development of drug strategies to treat addictive behaviours.
胃来源的食欲肽 ghrelin 影响涉及能量平衡以及奖赏的大脑回路。事实上，ghrelin 激活了一个重要的奖赏回路，涉及自然和药物诱导的奖赏，即胆碱能多巴胺奖赏联系。人们假设，在动物和人类中，酒精和甜味物质存在共同的奖赏机制。与健康对照组相比，酒精依赖个体对甜食的渴望更高，而对甜味的快感反应至少部分取决于遗传因素。选择性繁殖高蔗糖摄入量的大鼠比非蔗糖偏好大鼠消耗更多的酒精，反之亦然。在本研究中，从人群队列中选择了一组饮酒者，研究了 ghrelin 信号系统的遗传变异与他们的酒精和蔗糖消耗之间的关系。此外，使用啮齿动物在临床前研究中研究了 GHS-R1A 拮抗剂对自愿蔗糖摄入量和操作性自我给药以及蔗糖精摄入量的影响。还检查了外周 grelin 给药对蔗糖摄入量的影响。在这里，我们发现 ghrelin 基因单倍型与蔗糖消耗增加有关，并且在高酒精消费者中也观察到了相同的关联趋势。临床前数据表明，GHS-R1A 拮抗剂减少了大鼠蔗糖的摄入量和自我给药以及小鼠蔗糖精的摄入量。此外，ghrelin 增加了大鼠蔗糖的摄入量。总之，我们的数据清楚地表明，GHS-R1A 拮抗剂减少了奖赏物质的摄入量，而 ghrelin 增加了奖赏物质的摄入量，因此，中枢 ghrelin 信号系统为开发治疗成瘾行为的药物策略提供了一个新的靶点。
