Mechanisms of nicotine and alcohol use: Focus on in utero exposure to dietary fat

尼古丁和酒精使用的机制：关注子宫内膳食脂肪的暴露

• 批准号: 8303789
• 负责人: SARAH F LEIBOWITZ
• 金额: $ 24.37万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303789
• 关键词: Adolescence; Adolescent; Adult; Affect; Age; Agonist; Alcohol consumption; Alcohols; American; Animals; Applications Grants; Area; Behavioral; Birth; Brain; Brain region; Cell Nucleus; Clinical Research; Consumption; Dependence; Development; Diet; Dietary Fats; Dietary Fatty Acid; Dopamine; Drug Addiction; Drug abuse; Drug usage; Embryo; Enkephalins; Ethanol; Ethanol dependence; Exposure to; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Goals; Hyperphagia; Hypothalamic structure; In Vitro; Intake; Lead; Life; Lipids; Mediating; Methods; Modeling; Mothers; Neurons; Nicotine; Nicotine Dependence; Nucleus Accumbens; Obesity; Opioid; Opioid Peptide; Perinatal Exposure; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Predisposition; Pregnancy; Prosencephalon; Proteins; Psychological reinforcement; Puberty; Rattus; Research; Rewards; Risk; Role; Self Administration; Self-Administered; Signal Transduction; Sprague-Dawley Rats; System; Techniques; Testing; Time; Tobacco use; adolescent offspring; alcohol exposure; base; cholinergic; density; design; drug reward; fetal; fetal programming; in utero; in vivo; mature animal; neurochemistry; neurogenesis; neuron development; novel; offspring; overexpression; paraventricular nucleus; postnatal; preference; prenatal; prenatal exposure; programs; research study; transcription factor

DESCRIPTION (provided by applicant): Exposure to nicotine and ethanol early in life is known to increase the use of these drugs during adolescence, leading to dependence. These behavioral disturbances induced by both drugs are particularly profound with in utero exposure and are associated with similar neurochemical changes in mesolimbic brain regions involved in reward and dependence. Our recent studies in adult animals are revealing positive relationships between drug use and the consumption of a diet rich in fat and also similarities in their effects on brain systems, notably the opioid enkephalin (ENK), which has an important role in drug reward and addiction. They also show that in utero exposure to dietary fat, which markedly elevates circulating fatty acids, can stimulate the neurogenesis, proliferation and differentiation of ENK neurons in the hypothalamic paraventricular nucleus (PVN) of the offspring, while enhancing subsequent preference for fat. Building on this evidence, we propose to test here the novel idea that maternal consumption of a fat-rich diet, even for a short period, has a potent stimulatory effect on the lipid-sensitive transcription factor, peroxisome proliferator-activated receptor (PPAR), in the embryonic brain, which then reprograms the ENK system to induce persistent overexpression and increased use and dependence on nicotine and ethanol in the adolescent offspring. This hypothesis is supported by our preliminary results showing, for the first time, that prenatal exposure to a fat-rich diet increases the consumption of both nicotine and ethanol, stimulates neurogenesis and expression of ENK neurons in the nucleus accumbens (NAc) as well as PVN, and potentiates the expression specifically of PPAR ¿/¿ in these same areas. To test this hypothesis, we propose to conduct six experiments in the following two aims. In Aim 1, we plan to characterize the changes induced by prenatal fat exposure and determine if the offspring's predisposition to self-administer and become dependent on nicotine and ethanol can be related to the birth, differentiation and proliferation of neurons co-expressing ENK and PPAR ¿/¿ in the NAc and PVN. Building on our additional new findings that fatty acids in vitro and in vivo can stimulate both PPAR ¿/¿ and ENK expression in embryonic forebrain and hypothalamus and that PPAR ¿/¿ in turn stimulates forebrain ENK, we plan in Aim 2 to provide a more direct test of the importance of this lipid-based mechanism in mediating the effect of prenatal fat exposure on nicotine and ethanol self-administration and dependence. We will examine, first, whether a few days of exposure to the fat-rich diet, precisely when neurogenesis peaks in the NAc or PVN, is sufficient to stimulate ENK and PPAR ¿/¿ neurogenesis and drug abuse during adolescence and, second, whether PPAR ¿/¿ in the brain is, in fact, essential to the phenomenon of enhanced ENK expression. With the increase in fat content of the American diet in recent decades, it is becoming increasingly important to understand early changes in brain development as they relate to behavioral disturbances in the offspring and then take initial steps toward testing and developing methods that may counteract these changes. PUBLIC HEALTH RELEVANCE: The goal of the current grant application is to examine the idea that maternal consumption of a fat-rich diet during pregnancy produces profound changes in brain development that later promote the use and dependence on nicotine and alcohol. The proposed studies will test the specific hypothesis that circulating lipids elevated by the mother's diet activate a fat-sensitive signal in the fetal brain, which in turn stimulates the development o opioid neurons that later enhance drug intake in adolescent offspring. The results of these studies should provide new information and a new direction of research for investigating mechanisms programmed in utero by a fat-rich diet, which may lead not only to overeating and obesity but also to increased risk for nicotine and alcohol co-dependence.

描述（由申请人提供）：已知在生命早期接触尼古丁和乙醇会增加青春期期间对这些药物的使用，导致依赖性。这两种药物引起的行为障碍在子宫内接触时尤其严重，并与类似的相关。我们最近对成年动物的中脑边缘区域的神经化学变化揭示了吸毒和摄入富含脂肪的饮食之间的积极关系，以及它们对大脑系统影响的相似性，这是值得注意的。阿片类脑啡肽（ENK）在药物奖赏和成瘾中发挥着重要作用。他们还表明，在子宫内暴露于膳食脂肪会显着升高循环脂肪酸，从而刺激神经发生、增殖和分化。 后代下丘脑室旁核（PVN）中的 ENK 神经元的数量增加，同时增强了随后对脂肪的偏好。基于这一证据，我们建议在此测试母亲食用富含脂肪的饮食（即使是短期）的新想法。 ，对胚胎大脑中的脂质敏感转录因子过氧化物酶体增殖物激活受体 (PPAR) 具有有效的刺激作用，然后重新编程 ENK 系统，诱导持续过度表达并增加对 ENK 的使用和依赖我们的初步结果支持了这一假设，该结果首次表明，产前接触富含脂肪的饮食会增加尼古丁和乙醇的消耗，刺激神经发生和 ENK 神经元的表达。伏隔核 (NAc) 以及 PVN，并增强 PPAR 的特异性表达 ¿ /¿为了检验这一假设，我们建议在以下两个目标中进行六个实验，我们计划描述产前脂肪暴露引起的变化，并确定后代是否倾向于自我管理并变得依赖。尼古丁和乙醇的产生、分化和增殖可能与 共表达 ENK 和 PPAR 的神经元 ¿ /¿基于我们的额外新发现，脂肪酸在体外和体内都可以刺激 PPAR ¿ /¿和 ENK 在胚胎前脑和下丘脑中的表达以及 PPAR ¿ /¿反过来刺激前脑 ENK，我们计划在目标 2 中提供更直接的测试，以证明这种基于脂质的机制在调节产前脂肪暴露对尼古丁和乙醇自我给药和依赖性的影响方面的重要性。接触富含脂肪的饮食几天，恰好在 NAc 或 PVN 神经发生达到顶峰时，是否足以刺激 ENK 和 PPAR ¿ /¿青春期期间的神经发生和药物滥用，第二，PPAR 是否存在 ¿ /¿事实上，随着近几十年来美国饮食中脂肪含量的增加，了解大脑发育的早期变化变得越来越重要，因为它们与行为障碍有关。后代，然后采取初步措施测试和开发可能抵消这些变化的方法。 公共健康相关性：当前拨款申请的目标是检验母亲在怀孕期间食用富含脂肪的饮食会对大脑发育产生深刻的变化，从而促进对尼古丁和酒精的使用和依赖。拟议的研究将进行测试。母亲的血液循环导致血脂升高的具体假设 饮食激活胎儿大脑中的脂肪敏感信号，进而刺激阿片类神经元的发育，从而增加青少年后代的药物摄入量。这些研究的结果应该为研究编程机制提供新的信息和新的研究方向。子宫内富含脂肪的饮食不仅可能导致暴饮暴食和肥胖，而且还会增加尼古丁和酒精相互依赖的风险。