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（由适用提供）：已知生命早期接触尼古丁和乙醇会在青少年期间增加这些药物的使用，从而导致依赖性。两种药物引起的这些行为障碍在子宫内暴露尤其深远，并且与奖励和依赖性有关的中唇脑脑区域的神经化学变化相似。我们最近在成年动物的研究揭示了药物使用与富含脂肪的饮食的消费之间的积极关系，以及它们对脑系统的影响，尤其是阿片类药物Enkephalin（ENK），在药物奖励和成瘾中具有重要作用。他们还表明，在子宫内暴露于饮食中，脂肪脂肪显着升高了循环脂肪酸，可以刺激神经发生，增殖和分化 后代下丘脑旁脑室核（PVN）中的ENK神经元的同时，同时增强了随后对脂肪的偏爱。在此证据的基础上，我们建议在这里测试一个新的想法，即，即使在短时间内，大量富含脂肪的饮食也对脂质敏感的转录因子，过氧化物体增殖物激活受体（PPAR）具有潜在的刺激效果，在胚胎大脑中，在ENK系统中诱导ENK系统持续的过度依赖性和依赖性和依赖性和依赖性对持续性和依赖性，并对其进行了依赖的依赖性。我们的初步结果证明了这一假设，这是第一次暴露于富含脂肪的饮食会增加尼古丁和乙醇的消耗，刺激ENK神经元在Occumbens（NAC）（NAC）（NAC）以及PVN的神经发生和表达，以及PPAR的表达，具体是PPAR的表达，具体是这些领域。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。在AIM 1中，我们计划表征产前脂肪暴露引起的变化，并确定后代对自我管理的倾向以及依赖尼古丁和乙醇的倾向是否与出生，分化和扩散有关 神经元在NAC和PVN中共表达ENK和PPAR。基于我们的其他新发现，即体外和体内脂肪酸可以刺激胚胎前脑和下丘脑中的ppar€ /€和ENK表达，并且PPAR» /pPAR€又刺激了前脑ENK，我们计划在AIM 2中提供更直接的直接测试，以实现这种基于Lipid的机械性机械性，使NIC型效应的效果效应效应，使Pripid nic效应效应效应，使PRENATIS IN NIC效起来效应。自我管理和依赖。首先，我们将研究几天的脂肪饮食是否恰恰是在NAC或PVN中的神经发生峰值足以刺激ENK和PPAR€ /ppar€ /¿随着近几十年来美国饮食的脂肪含量的增加，了解大脑发育的早期变化越来越重要，因为它们与后代的行为灾难相关，然后采取初步步骤来测试和开发可能抵消这些变化的方法。 公共卫生相关性：当前赠款申请的目的是研究以下思想：在怀孕期间，肥胖饮食的消耗会导致大脑发育的深刻变化，后来促进了对尼古丁和酒精的使用和依赖。拟议的研究将检验以下特定假设，即母亲的循环脂质升高 Diet activate a fat-sensitive signal in the fetal brain, which in turn stimulates the development o oopioid neurons that later enhanced drug intake in adolescent offspring.这些研究的结果应提供新的信息和新的研究方向，以通过富含脂肪的饮食在子宫内编程的机制进行研究，这不仅可能导致暴饮暴食和肥胖，而且会增加尼古丁和酒精共依赖性的风险。