Hormone-neurotransmitter interactions in the control of food intake.

描述（由申请人提供）：卵巢激素雌二醇对大多数（如果不是全部）神经系统有深远的影响。因此，雌二醇影响多种生理功能，从而影响行为。在其多种作用中，雌二醇对食物摄入有强有力的抑制作用，这种抑制作用在包括人类在内的多种物种中都有表达。近年来，人们发现雌二醇的这种作用与饮食失调的发展、食欲增加和体重增加有关，这在雌二醇缺乏的绝经后妇女中经常观察到。了解雌二醇如何导致上述两种情况的关键第一步是确定它如何影响健康动物的食物摄入控制。现有证据表明，雌二醇对食物摄入的抑制作用是通过其增加饱腹感信号系统中其他关键元素强度的能力来介导的。在此，我们拟探讨雌二醇和5-羟色胺（5-HT）这种饱腹感信号在雌性大鼠食物摄入控制中的可能相互作用的几个基本问题。行为学、药理学、解剖学和分子技术的结合将用于研究我们的中心假设，即5-羟色胺神经传递的增加介导雌二醇在雌性大鼠中的厌食作用。在具体目标1和2中，我们将建立对食物摄入的雌激素抑制既必要又充分的大脑区域。在Specific Aim 3中，我们将确定突触后5-HT2C受体激活的增加是否有助于食物摄入的雌激素抑制。在Specific Aim 4中，我们将确定雌二醇是否与中脑中脑系统一起作用，以增加与控制食物摄入有关的特定大脑区域内5-羟色胺的释放和/或周转。这些研究的成功完成将扩大我们对雌二醇厌食作用的行为和神经生物学机制的理解。由于我们提出的研究重点是雌二醇和5-羟色胺在控制食物摄入中的相互作用，并且已经在神经性厌食症女性中发现了5-羟色胺能功能异常，因此完成这项工作有可能揭示雌二醇如何作为饮食相关疾病的危险因素。因此，该提案针对一个具有明确临床相关性的重要研究问题。

DESCRIPTION (provided by applicant): The ovarian hormone estradiol has profound effects on most, if not all, of the nervous system. As a result, estradiol influences a variety of physiological functions and, therefore, behavior. Among its varied actions, estradiol exerts a potent inhibitory effect on food intake that is expressed in a variety of species, including humans. In recent years, this action of estradiol has been linked to the development of eating disorders, as well as the increase in appetite and weight gain that is often observed in estradiol-deficient, postmenopausal women. A crucial first step in understanding how estradiol may contribute to either of these conditions is to determine how it affects the controls of food intake in healthy animals. Available evidence suggests that the inhibitory effect of estradiol on food intake is mediated by its ability to increase the strength of other key elements within the satiety-signaling system. Here, we propose to investigate several fundamental questions regarding the possible interaction of estradiol and serotonin (5-HT), 1 such satiety signal, in the control of food intake in the female rat. A combination of behavioral, pharmacological, anatomical, and molecular techniques will be used to investigate our central hypothesis, which is that an increase in 5-HT neurotransmission mediates the anorectic effect of estradiol in the female rat. In Specific Aims 1 and 2, we will establish brain regions that are both necessary and sufficient for the estrogenic inhibition of food intake. In Specific Aim 3, we will determine whether increased activation of postsynaptic 5-HT2C receptors contributes to the estrogenic inhibition of food intake. In Specific Aim 4, we will determine whether estradiol acts with the midbrain raphe system to increase the release and/or turnover of 5-HT within specific brain regions implicated in the control of food intake. Successful completion of these studies will broaden our understanding of the behavioral and neurobiological mechanisms underlying the anorectic effect of estradiol. Because our proposed studies focus on an interactive effect of estradiol and 5-HT in the control of food intake, and abnormalities in serotonergic function have been identified in women with anorexia nervosa, completion of this work has the potential to reveal how estradiol may function as a risk factor for eating-related disorders. Thus, this proposal targets an important research question with clear clinical relevance.