Ghrelin and Reward

说明(申请人提供)：Ghrelin是一种具有多种作用的激素，其中研究最多的是它对体重动态平衡的影响。例如，胃促生长素水平随着饥饿和禁食的增加而升高。此外，Ghrelin刺激食物摄取，减少能量消耗，当浓度较高时会导致肥胖。Ghrelin的作用是通过与其受体，生长激素促分泌素受体(GHSR；Ghrelin受体)的相互作用来介导的，Ghrelin受体在大脑中具有明确的、离散的表达模式。这包括大脑腹侧被盖区(VTA)中含有多巴胺的神经元的高度表达。由于这些多巴胺能VTA神经元参与大脑奖赏回路，例如与成瘾有关的回路，因此受到高度研究。目前的应用提供了一系列研究，旨在增加我们对Ghrelin参与促进奖赏寻求行为的了解，以及VTA在Ghrelin作用中的作用。特别是，将调查Ghrelin在旨在获得食物奖励和可卡因的动机行为中所起的作用。要做到这一点，将使用独特的小鼠模型，在该模型中，ghrelin受体的表达已经被删除，或者ghrelin受体的功能已经被特定的拮抗剂给药阻断。这些小鼠将接受一系列测试，这些测试将使我们能够确定基因和药物阻断Ghrelin信号通路对食物强化和可卡因强化的奖赏行为的影响。此外，还将使用一种独特的小鼠模型，在该模型中，ghrelin受体可以选择性地靶向多巴胺能VTA神经元，以研究ghrelin参与这些特定神经元对奖励行为和体重的作用的充分性。这种选择性靶向将涉及最先进的神经解剖学和转基因技术。人们希望这些研究将产生新的靶向疗法，以治疗某些形式肥胖的无情寻食行为，如Prader-Willi综合征，以及其他适应不良的奖励行为，如与成瘾有关的行为。公共卫生相关性本研究中提出的实验旨在调查Ghrelin在旨在获得食物奖励和可卡因等成瘾药物的动机行为中所起的作用。人们希望，这些研究最终将产生新的靶向疗法，以治疗某些形式肥胖的无情寻食行为，如Prader-Willi综合征，以及其他适应不良的奖励行为，如与成瘾有关的行为。

DESCRIPTION (provided by applicant): Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight homeostasis. For instance, ghrelin levels rise in association with hunger and fasting. Also, ghrelin stimulates food intake, decreases energy expenditure, and induces obesity when present in high concentrations. Ghrelin's actions are mediated by interaction with its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), which has a well-defined, discrete pattern of expression within the brain. This includes a high degree of expression in dopamine-containing neurons within a part of the brain known as the ventral tegmental area (VTA). These dopaminergic VTA neurons have been highly studied due to their involvement in brain reward circuits, such as those associated with addiction. The current application provides a series of studies designed to increase our understanding of the involvement of ghrelin in promoting reward- seeking behaviors and the role of the VTA in ghrelin action. In particular, the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and cocaine will be investigated. To accomplish this, unique mouse models in which either expression of the ghrelin receptor has been deleted or the functioning of the ghrelin receptor has been blocked by the administration of a specific antagonist will be used. These mice will be subjected to a battery of tests that will allow us to determine the effect of genetic and pharmacological blockade of ghrelin signaling pathways on food-reinforced and cocaine-reinforced reward-seeking behaviors. Also, a unique mouse model in which ghrelin receptor expression can be selectively targeted to dopaminergic VTA neurons will be used in order to investigate the sufficiency of ghrelin's engagement of these particular neurons for its actions on reward behaviors and body weight. This selective targeting will involve state-of-the- art neuroanatomical and transgenic techniques. It is hoped that these studies will result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction. PUBLIC HEALTH RELVANCE The experiments proposed in this study have been designed to investigate the role ghrelin plays in motivated behaviors aimed at obtaining both food rewards and addictive drugs such as cocaine. It is hoped that these studies will eventually result in new targeted therapies to treat the unrelenting food-seeking behaviors characteristic of certain forms of obesity, such as Prader-Willi Syndrome, as well as other maladaptive reward behaviors, such as those associated with addiction.