Sex Differences in the Cannabinoid Regulation of Feeding

描述(申请人提供)：大麻素对下丘脑对生殖和能量平衡等生物过程的控制具有深远的影响。这一提议的总体目标是更好地了解大麻素对食欲的调节，以及它们通过影响下丘脑弓状核阿片黑素皮质素原神经元的兴奋性来改变觅食行为的细胞机制(S)。基本的假设是，大麻类物质以一种性别依赖的方式调节食物摄入量。它们通过突触前抑制谷氨酸能神经传递来实现这一点，从而降低POMC神经元的兴奋性，这种方式与性别分化和性腺类固醇环境有关。将在豚鼠和转基因POMC缺陷小鼠中研究大麻对食欲的调节和谷氨酸能突触对厌食性POMC神经元的输入。在实验前一周，分别对雌性和雄性进行卵巢切除和雄性切除。在具体目标1中，我将通过评估CB1受体激动剂和拮抗剂在不同饮食和激励条件下分别增加和减少载体和性腺类固醇处理的雄性和雌性动物的摄食行为的能力，来评估大麻素对食欲的调节是否存在性别差异。在特定目标2中，目的是确定厌食性厌氧POMC神经元在性分化、大麻素诱导的吞噬亢进中的作用。具体地说，我将评估大麻类物质是否通过谷氨酸能突触输入的突触前衰减来抑制POMC神经元。我还将研究POMC神经元释放的内源性大麻素跨突触抑制冲击它们的谷氨酸能电流的可能性。这些研究将使用下丘脑片中充满生物细胞素的电极的全细胞膜片钳记录来完成。为了验证POMC神经元确实是大麻素调节食欲所必需的，我将评估CB1受体和阻断剂对POMC缺陷小鼠摄食行为的影响。这项建议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类药物对食物摄入量调节的性别差异，并将阐明相关的神经底物、细胞机制和性腺类固醇激素对食欲调节的影响，在大麻类药物滥用的早期参与食欲调节的急性干扰。公共卫生相关性大麻素调节摄食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度存在差异。这项研究产生的结果将对大麻类药物对男性和女性的治疗效果产生深远影响--从预防癌症和艾滋病相关的身体损耗到治疗肥胖症。

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.