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: 10453734
• 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/10453734
• 关键词: Acute; Adolescence; Adolescent; Adrenal Glands; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohols; Animals; Behavior; Child Abuse and Neglect; Corticosterone; Cues; Development; Down-Regulation; Elderly; Epidemiology; Experimental Models; Exposure to; Extinction (Psychology); 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; Pharmacology; 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 abstinence; alcohol seeking behavior; alcohol use disorder; antagonist; base; behavior test; biological adaptation to stress; chloride-cotransporter potassium; cost; drinking; drinking behavior; experience; experimental study; functional status; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; high risk; hypothalamic-pituitary-adrenal axis; in vivo; incentive salience; neuromechanism; neuronal circuitry; nicotine exposure; nicotine treatment; nicotine use; prevent; preventable death; relating to nervous system; response; 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。 过量饮酒是全球可预防死亡的主要原因之一，美国为此付出了巨大代价 每年超过 2230 亿美元。压力和尼古丁（来自烟草）是众所周知的酗酒风险因素 消费和酒精使用障碍。尽管人类流行病学证据一致， 实验模型压力并不总是导致饮酒量增加。争议由此产生， 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 显着未知。 该提议源于我们的初步结果，该结果表明，预先暴露于急性尼古丁或压力 在严格规定的实验条件下增加酒精的自我管理。我们在老鼠身上证明了 尼古丁（如压力）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 活动对于随后因改变而引起的自我饮酒增加是必要的 中脑 GABA 能电路。当我们抑制尼古丁/压力诱导的糖皮质激素信号传导或 纠正了中脑 GABA 能功能障碍，然后自我饮酒恢复到控制水平。 在拟议的研究中，我们将从简单的急性暴露于尼古丁和压力转向更多 生物学上真实的实验情境。一生中尼古丁和烟草的使用几乎总是开始于 青春期、青少年吸烟和儿童期虐待都是增加患病率的高危因素 成年期的饮酒和酒精使用障碍。因此，我们将让青春期大鼠暴露于 然后，尼古丁或压力让动物变老，然后再分析它们的饮酒行为，并将其与对照组进行比较。 控制老鼠。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，增加饮酒需要糖皮质激素活性和 源于中脑 GABA 电路的变化。我们将衡量青少年压力的后果 或成年大鼠在酒精自我恢复过程中的尼古丁暴露、维持、消除和恢复过程中的尼古丁暴露 行政。 实验将继续研究酒精增加背后的一般电路机制 由青少年尼古丁或压力引起的自我给药。最初，我们将以最近的结果为指导 表明单次急性接触尼古丁或压力会导致自我饮酒量增加 通过改变中脑 GABAergic 电路。然后，根据我们的初步结果，我们将阻止或扭转这种情况 通过分子和药理学操作，青少年压力或尼古丁导致饮酒增加 中脑内。目的是确定目标并测试潜在的治疗药物，以帮助对抗增加的 饮酒量。