Sex Differences in the Cannabinoid Regulation of Feeding

大麻素喂养调节的性别差异

• 批准号: 7515807
• 负责人: EDWARD J WAGNER
• 金额: $ 22.5万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7515807
• 关键词: AIDS related cancer; Acute; Address; Affect; Agonist; Animal Model; Animals; Appetite Depressants; Appetite Regulation; Behavior; Behavioral; Biological; Biological Process; Body Weight; CNR1 gene; Cannabinoids; Cavia; Cells; Condition; Desire for food; Eating; Electrodes; Endocannabinoids; Feeding behaviors; Female; Food; Food Intake Regulation; Frequencies; Glutamates; Goals; Gonadal Steroid Hormones; Homeostasis; Hormonal; Hyperphagia; Hypothalamic structure; Molecular; Mus; Neurons; Obesity; Pro-Opiomelanocortin; Public Health; Receptor Activation; Regulation; Reproduction; Research; Role; Sex Characteristics; Slice; Structure of nucleus infundibularis hypothalami; Synapses; Techniques; Testing; Transgenic Organisms; Week; Woman; attenuation; biocytin; biological adaptation to stress; cancer prevention; cannabinoid receptor; feeding; increased appetite; interdisciplinary approach; male; men; neuronal excitability; neurotransmission; obesity treatment; patch clamp; presynaptic; relating to nervous system; sex; therapeutic effectiveness; wasting

DESCRIPTION (provided by applicant): Cannabinoids exert a profound impact on the hypothalamic control of biological processes such as reproduction and energy homeostasis. The overall goal of this proposal is to gain a better understanding of the cannabinoid regulation of appetite, and the cellular mechanism(s) by which they affect the excitability of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus to alter food seeking behavior. The fundamental hypothesis is that cannabinoids modulate food intake in a sex-dependent fashion. They do so by presynaptically inhibiting glutamatergic neurotransmission, thereby reducing POMC neuronal excitability in a manner that is sexually differentiated and dependent on the gonadal steroid milieu. Cannabinoid regulation of appetite and glutamatergic synaptic input onto anorexigenic POMC neurons will be studied both in the guinea pig and in transgenic, POMC-deficient mice. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively. In Specific Aim 1, I will evaluate whether sex differences exist in the cannabinoid regulation of appetite by assessing the capability of CB1 receptor agonists and antagonists to respectively increase and decrease feeding behavior in vehicle- and gonadal steroid-treated male and female animals under different dietary and motivational conditions. In Specific Aim 2, the objective is to determine the role of anorexigenic POMC neurons in the sexually differentiated, cannabinoid-induced hyperphagia. Specifically, I will evaluate whether cannabinoids inhibit POMC neurons via the presynaptic attenuation of glutamatergic synaptic input. I will also investigate the potential for endogenous cannabinoids released from POMC neurons to transynaptically inhibit the glutamatergic currents impinging upon them. These studies will be accomplished using whole-cell patch clamp recordings with biocytin-filled electrodes in hypothalamic slices. To verify that POMC neurons are indeed integral to the cannabinoid modulation of appetite, I will evaluate the effects of CB1 receptor and blockade on feeding behavior in POMC-deficient mice. This proposal describes an integrated approach using two different animal models to study sex differences in the cannabinoid regulation of food intake, and will elucidate the relevant neural substrates, cellular mechanisms and gonadal steroid hormonal influences involved in the acute perturbation of appetite regulation very early in cannabinoid abuse. PUBLIC HEALTH RELEVANCE Sex differences in the cannabinoid regulation of feeding means that there are differences between males and females in their sensitivity to the appetite-stimulating and appetite suppressing effects of cannabinoid receptor agonists and antagonists. The findings generated from this research will have profound implications for the therapeutic effectiveness of cannabinoids in men and women - from the prevention of cancer - and AIDS-related body wasting to the treatment of obesity.

描述（由申请人提供）：大麻素对生殖和能量稳态等生物过程的下丘脑控制产生深远影响。该提案的总体目标是更好地了解大麻素对食欲的调节，以及它们影响下丘脑弓状核中阿黑皮素原（POMC）神经元兴奋性以改变觅食行为的细胞机制。基本假设是大麻素以性别依赖的方式调节食物摄入。他们这样做，通过突触前抑制多巴胺能神经传递，从而降低POMC神经元兴奋性的方式是性分化和依赖于性腺类固醇环境。大麻素调节食欲和神经元的突触输入到apoxigenic POMC神经元将研究在豚鼠和转基因，POMC缺陷小鼠。分别在实验前一周切除雌性动物的卵巢和切除雄性动物的卵巢。在具体目标1中，我将通过评估CB 1受体激动剂和拮抗剂在不同饮食和动机条件下分别增加和减少溶媒和性腺类固醇治疗的雄性和雌性动物的摄食行为的能力，评估大麻素对食欲的调节是否存在性别差异。在具体目标2中，目的是确定性分化的，大麻素诱导的摄食过多中的促性腺激素性POMC神经元的作用。具体来说，我将评估大麻素是否通过突触前衰减的神经元突触输入抑制POMC神经元。我还将研究从POMC神经元释放的内源性大麻素的潜力，以跨突触抑制对它们的刺激电流。这些研究将使用下丘脑切片中生物胞素填充电极的全细胞膜片钳记录完成。为了验证POMC神经元确实是大麻素调节食欲的组成部分，我将评估CB 1受体和阻断剂对POMC缺陷小鼠摄食行为的影响。该提案描述了一种综合的方法，使用两种不同的动物模型来研究大麻素调节食物摄入的性别差异，并将阐明相关的神经底物，细胞机制和性腺类固醇激素的影响，参与急性扰动的食欲调节非常早期大麻素滥用。 大麻素对摄食调节的性别差异意味着男性和女性对大麻素受体激动剂和拮抗剂的食欲刺激和食欲抑制作用的敏感性存在差异。这项研究的结果将对大麻素在男性和女性中的治疗效果产生深远的影响-从预防癌症和艾滋病相关的身体消瘦到治疗肥胖。