Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Medicinaregatan 11, PO Box 434, SE-405 30 Gothenburg, Sweden.
Neuropharmacology. 2013 Oct;73:274-83. doi: 10.1016/j.neuropharm.2013.06.004. Epub 2013 Jun 14.
Obesity has reached global epidemic proportions and creating an urgent need to understand mechanisms underlying excessive and uncontrolled food intake. Ghrelin, the only known circulating orexigenic hormone, potently increases food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic reward system and to the increased food reward behavior remains unclear. Here we examine whether VTA-NAc dopaminergic signaling is required for the effects of ghrelin on food reward and intake. In addition, we examine the possibility of endogenous ghrelin acting on the VTA-NAc dopamine neurons. A D1-like or a D2 receptor antagonist was injected into the NAc in combination with ghrelin microinjection into the VTA to investigate whether this blockade attenuates ghrelin-induced food reward behavior. VTA injections of ghrelin produced a significant increase in food motivation/reward behavior, as measured by sucrose-induced progressive ratio operant conditioning, and chow intake. Pretreatment with either a D1-like or D2 receptor antagonist into the NAc, completely blocked the reward effect of ghrelin, leaving chow intake intact. We also found that this circuit is potentially relevant for the effects of endogenously released ghrelin as both antagonists reduced fasting (a state of high circulating levels of ghrelin) elevated sucrose-motivated behavior but not chow hyperphagia. Taken together our data identify the VTA to NAc dopaminergic projections, along with D1-like and D2 receptors in the NAc, as essential elements of the ghrelin responsive circuits controlling food reward behavior. Interestingly results also suggest that food reward behavior and simple intake of chow are controlled by divergent circuitry, where NAc dopamine plays an important role in food reward but not in food intake.
肥胖已成为全球性流行病，迫切需要了解导致过度和无法控制进食的机制。胃饥饿素是唯一已知的循环食欲激素，它能强烈增加食物奖励行为。将胃饥饿素与中脑边缘奖励系统联系起来，并增加食物奖励行为的神经化学回路尚不清楚。在这里，我们研究 VTA-NAc 多巴胺能信号是否是胃饥饿素对食物奖励和摄入的影响所必需的。此外，我们还研究了内源性胃饥饿素作用于 VTA-NAc 多巴胺神经元的可能性。将 D1 样或 D2 受体拮抗剂注入 NAc 中，并与 VTA 中的胃饥饿素微注射结合，以研究这种阻断是否会减弱胃饥饿素引起的食物奖励行为。VTA 注射胃饥饿素可显著增加食物动机/奖励行为，如蔗糖诱导的渐进比率操作性条件反射和进食量。NAc 中预先注射 D1 样或 D2 受体拮抗剂可完全阻断胃饥饿素的奖励作用，而不影响进食量。我们还发现，该回路可能与内源性释放的胃饥饿素的作用有关，因为两种拮抗剂均降低了禁食（高循环胃饥饿素水平的状态）时蔗糖驱动的行为，但不增加摄食量。总之，我们的数据确定 VTA 到 NAc 的多巴胺能投射，以及 NAc 中的 D1 样和 D2 受体，是控制食物奖励行为的胃饥饿素反应回路的基本要素。有趣的是，结果还表明，食物奖励行为和简单的进食量由不同的回路控制，其中 NAc 多巴胺在食物奖励中起重要作用，但在进食中不起作用。
