Adolescent Exposure to Stress or Nicotine Increases Rodent Alcohol Self-Administration

青少年接触压力或尼古丁会增加啮齿动物的自我饮酒

• 批准号: 10671050
• 负责人: John A. Dani
• 金额: $ 48.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671050
• 关键词: Abstinence; Acute; Adolescence; Adolescent; Adrenal Glands; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Behavior; Child Abuse and Neglect; Corticosterone; Cues; Development; Down-Regulation; Drug usage; Elderly; Epidemiology; Experimental Models; Exposure to; Extinction; Functional disorder; Glucocorticoid Receptor; Glucocorticoids; Home; Human; Hypothalamic structure; Life; Life Experience; Link; Literature; Longevity; Maintenance; Measures; Mediating; Midbrain structure; Modeling; Molecular; Motivation; Neurons; Nicotine; Pathologic; Pharmaceutical Preparations; Physiology; Pituitary Gland; Rattus; Research; Risk; Risk Factors; Rodent; Safety; Self Administration; Signal Transduction; Slice; Smoking; Stimulus; Stress; Stressful Event; System; Testing; Therapeutic; Time; Tobacco; Tobacco use; addiction; adolescent smoking; alcohol seeking behavior; alcohol use disorder; antagonist; behavior test; biological adaptation to stress; comparison control; cost; drinking; drinking behavior; experience; experimental study; functional status; glucocorticoid-induced orphan receptor; high risk; hypothalamic-pituitary-adrenal axis; in vivo; incentive salience; neural; neuromechanism; neuronal circuitry; nicotine exposure; nicotine treatment; nicotine use; pharmacologic; prevent; preventable death; response; symporter; therapeutic target; vulnerable adolescent

Project Summary. Excessive alcohol use is among the leading causes of preventable death worldwide and costs the USA over $223 billion a year. Stress and nicotine (from tobacco) are well-known risk factors for heavy alcohol consumption and alcohol use disorders. Despite the consistent human epidemiological evidence, in experimental models stress does not always produce increased alcohol consumption. The controversy arises, in part, because the neural mechanisms underlying the interactions among stress, nicotine, and alcohol remain significantly unknown. This proposal arose from our preliminary results showing that pre-exposure to acute nicotine or stress under strictly defined experimental conditions increases alcohol self-administration. We showed in rats that nicotine (like stress) boosts corticosterone levels in rats. Nicotine- or stress-induced glucocorticoid receptor activity is necessary for the subsequent increase in alcohol self-administration that arises owing to altered midbrain GABAergic circuitry. When we inhibited the nicotine/stress-induced glucocorticoid signaling or corrected midbrain GABAergic dysfunction, then alcohol self-administration returned to control levels. In the proposed studies, we will move from the simple acute exposures to nicotine and stress to more biologically realistic experimental situations. Lifetime nicotine and tobacco use almost always begins during adolescence, and adolescent smoking and childhood maltreatment are both high risk factors for increased alcohol consumption and alcohol use disorders in adulthood. Therefore, we will expose adolescent rats to nicotine or stress then allow the animals to age before analyzing their alcohol drinking behavior compared to control rats. Our preliminary results with adolescent nicotine treatments show that later in life, the adolescent- treated rats do drink more alcohol. Furthermore, the increased drinking requires glucocorticoid activity and arises from changes in midbrain GABAergic circuitry. We will measure the consequences of adolescent stress or nicotine exposure in adult rats during initiation, maintenance, extinction, and re-instatement of alcohol self- administration. The experiments will go on to investigate general circuit mechanisms underlying the increase in alcohol self-administration induced by adolescent nicotine or stress. Initially, we will be guided by our recent results indicating that a single, acute exposure to nicotine or stress induces an increase in alcohol self-administration by altering midbrain GABAergic circuitry. Then, guided by our preliminary results we will prevent or reverse the increased drinking caused by adolescent stress or nicotine via molecular and pharmacological manipulations within the midbrain. An aim is to identify a target and test a potential therapeutic drug to aid against increased alcohol consumption.

项目摘要。 过度饮酒是全球可预防死亡的主要原因之一， 超过2230亿美元。压力和尼古丁（来自烟草）是众所周知的酗酒的危险因素 消费和酒精使用障碍。尽管有一致的人类流行病学证据， 实验模型压力并不总是导致酒精消费增加。争议出现了， 部分原因是压力、尼古丁和酒精之间相互作用的神经机制仍然存在， 意义不明。 这一建议源于我们的初步结果，表明预先暴露于急性尼古丁或压力， 在严格限定的实验条件下，增加了酒精自我给药。我们在老鼠身上发现， 尼古丁（像压力一样）会提高大鼠的皮质酮水平。尼古丁或应激诱导的糖皮质激素受体 活动是必要的，随后增加酒精自我管理，这是由于改变 中脑GABA能回路当我们抑制尼古丁/应激诱导的糖皮质激素信号或 纠正中脑GABA能功能障碍，然后酒精自我给药恢复到对照水平。 在拟议的研究中，我们将从简单的尼古丁和压力的急性暴露转移到更多 生物学上真实的实验环境。一生中尼古丁和烟草的使用几乎总是从 青少年吸烟和儿童期虐待都是增加吸烟的高危因素。 酒精消费和酒精使用障碍。因此，我们将把青春期的老鼠暴露在 尼古丁或压力，然后让动物年龄之前，分析他们的饮酒行为相比， 对照组大鼠。我们对青少年尼古丁治疗的初步结果表明，在以后的生活中，青少年- 接受治疗的老鼠确实喝了更多的酒。此外，增加的饮酒需要糖皮质激素活性， 是由中脑GABA能回路的变化引起的。我们将衡量青少年压力的后果 或尼古丁暴露在成年大鼠在启动，维持，消退，并恢复酒精自我， 局 实验将继续调查酒精增加的一般电路机制 青少年尼古丁或压力引起的自我给药。最初，我们将以我们最近的结果为指导 表明单次急性暴露于尼古丁或压力诱导酒精自我给药增加 通过改变中脑GABA能回路然后，根据我们的初步结果，我们将防止或扭转 青少年压力或尼古丁通过分子和药理学操作引起的饮酒增加 在中脑内。目的是确定一个目标，并测试一种潜在的治疗药物，以帮助对抗增加的 酒精消费。