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。 过度使用饮酒是全球可预防死亡的主要原因之一，并使美国损失 每年超过2230亿美元。压力和尼古丁（来自烟草）是大量酒精的众所周知的风险因素 消费和饮酒障碍。尽管有人类的流行病学证据一致 实验模型压力并不总是会增加饮酒量。引起争议， 部分是因为压力，尼古丁和酒精之间相互作用的神经机制仍然存在 明显未知。 该提议来自我们的初步结果，表明前暴露于急性尼古丁或压力 在严格定义的实验条件下，可以增加酒精的自我管理。我们在老鼠中表明 尼古丁（如压力）可以提高大鼠的皮质酮水平。尼古丁或应力诱导的糖皮质激素受体 随后由于改变而产生的酒精自我给药的增加是必需的 中脑GABA能电路。当我们抑制尼古丁/应力诱导的糖皮质激素信号传导或 校正的中脑GABA能功能障碍，然后酒精自我给予控制水平。 在拟议的研究中，我们将从简单的急性暴露转变为尼古丁，并压力更多 生物学上现实的实验情况。终身尼古丁和烟草的使用几乎总是开始 青春期和青春期吸烟和儿童虐待都是增加的高风险因素 成年后的饮酒和饮酒障碍。因此，我们将使青少年大鼠暴露于 与尼古丁或压力相比 控制大鼠。我们对青少年尼古丁治疗的初步结果表明，在生活中，青少年 - 治疗的大鼠确实喝更多的酒精。此外，饮酒增加需要糖皮质激素活性，并且 来自中脑GABA能电路的变化。我们将衡量青少年压力的后果 在起始，维持，灭绝和重新加入酒精时，成年大鼠的尼古丁暴露 行政。 实验将继续研究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管理。最初，我们将受到我们最近的结果的指导 表明单一的急性暴露于尼古丁或压力会导致酒精自给自足的增加 通过改变中脑GABA能电路。然后，在我们的初步结果的指导下，我们将防止或扭转 通过分子和药理学操纵而由青少年压力或尼古丁引起的饮酒增加 在中脑。一个目的是识别靶标并测试潜在的治疗药物以帮助增加 饮酒。