Sex Differences in the Cannabioid Regulation of Energy Homeostasis

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。这项建议的总体目标是更好地了解大麻素对食欲、核心体温、代谢的调节，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这些作用的细胞机制(S)。基本的假设是，大麻类物质以一种性别依赖的方式调节能量平衡，这种方式可能会受到性腺类固醇激素的不同影响。它们通过1)突触前改变兴奋性+和抑制性神经传递之间的平衡和2)增强突触后K电流，从而以一种有性分化和性腺类固醇环境依赖的方式降低POMC神经元的活动。将使用豚鼠动物模型研究大麻类物质对能量稳态的调节以及突触对食欲抑制的POMC神经元的传递。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，我将通过评估雄激素和雌激素如何影响1)CB1受体激动剂和拮抗剂改变食物摄入量、进食模式、核心体温、O2消耗、二氧化碳和代谢热产生的能力，2)内源性大麻素的产生以及随后对兴奋性谷氨酸和抑制性GABA能突触输入到POMC神经元的突触前抑制，以及3)在不同的饮食和激励条件下，关键的能量感受酶的活性和表达，来评价雄激素和雌激素对大麻素调节能量平衡的不同调节机制。在具体目标2中，目标是确定受体亚型(S)，雌激素通过该亚型减弱大麻素对能量平衡的调节。具体地说，我将评估GQ偶联的膜雌激素受体m(ER)、ER？、ER？和/或GPR30的激动剂是否能减少大麻素引起的能量摄入和支出的变化，以及突触前谷氨酸能传入POMC神经元的抑制。这项建议描述了一种综合的方法来研究性别差异和性腺类固醇激素对能量平衡的调节，并将阐明相关的细胞机制，这些机制预先决定了男性和女性在滥用大麻类药物的早期对能量摄入和支出的急性扰动的敏感性。

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, core body temperature, metabolism, and the cellular mechanism(s) by which they affect the excitability of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus to alter these actions. The fundamental hypothesis is that cannabinoids modulate energy balance in a sex-dependent fashion that can be differentially influenced by gonadal steroid hormones. They do so by 1) presynaptically altering the balance between excitatory + and inhibitory neurotransmission and 2) augmenting postsynaptic K currents, thereby reducing POMC neuronal activity in a manner that is sexually differentiated and dependent on the gonadal steroid milieu. Cannabinoid regulation of energy homeostasis and synaptic transmission onto appetite-suppressing POMC neurons will be studied using a guinea pig animal model. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively. In Specific Aim 1, I will evaluate the mechanisms through which androgens and estrogens differentially modulate the cannabinoid regulation of energy balance by assessing how they influence 1) the capability of CB1 receptor agonists and antagonists to alter food intake, meal pattern, core body temperature, O2 consumption, CO2 and metabolic heat production, 2) endogenous cannabinoid production and subsequent presynaptic inhibition of excitatory glutamatergic and inhibitory GABAergic synaptic input onto POMC neurons, and 3) the activity and expression of critical energy-sensing enzymes, under different dietary and motivational conditions. In Specific Aim 2, the objective is to determine the receptor subtype(s) through which estrogens attenuate the cannabinoid modulation of energy balance. Specifically, I will evaluate whether agonists for the Gq-coupled membrane estrogen receptor m(ER), ER¿, ER¿ and/or GPR30 diminish cannabinoid-induced changes in energy intake and expenditure, as well the presynaptic inhibition of glutamatergic input onto POMC neurons. This proposal describes an integrated approach to study sex differences in, and gonadal steroid hormonal on, the cannabinoid regulation of energy balance, and will elucidate the relevant cellular mechanisms that predetermine the sensitivity of males and females to the acute perturbation of energy intake and expenditure very early in cannabinoid abuse.