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: 8438408
• 负责人: SARAH F LEIBOWITZ
• 金额: $ 18.72万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438408
• 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.

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对这些药物的使用，导致依赖。这两种药物引起的行为障碍在子宫内暴露时尤为严重，并且与涉及奖励和依赖的中脑边缘区域类似的神经化学变化有关。我们最近对成年动物的研究揭示了药物使用与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的影响的相似性，特别是阿片类脑啡肽（ENK），它在药物奖励和成瘾中起着重要作用。他们还表明，在子宫内暴露于饮食脂肪，显著提高循环脂肪酸，可以刺激神经发生，增殖和分化