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

项目摘要。 过量饮酒是世界范围内可预防的死亡的主要原因之一，并使美国 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。尽管有一致的人类流行病学证据，但在 实验模型压力并不总是会导致酒精消耗量增加。争议就出现了， 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 不为人知。 这一建议源于我们的初步结果显示，预先接触急性尼古丁或压力 在严格定义的实验条件下，增加酒精的自我给药。我们在老鼠身上展示了 尼古丁(就像压力一样)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 活动对于随后由于改变而引起的酒精自我给药的增加是必要的 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 纠正了中脑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，我们将从简单的急性接触尼古丁和压力转移到更多 生物上真实的实验情景。终生尼古丁和烟草的使用几乎总是始于 青春期、青少年吸烟和童年虐待都是高危因素 成年后的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 然后，尼古丁或压力让动物在分析饮酒行为之前变老，与 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- 接受治疗的大鼠确实会喝更多的酒。此外，更多的饮酒需要糖皮质激素的活动和 源于中脑GABA能回路的变化。我们将衡量青春期压力的后果 或尼古丁暴露在成年大鼠的酒精自我启动、维持、消退和重新陈述过程中 行政管理。 这些实验将继续研究酒精增加背后的一般电路机制 由青春期尼古丁或压力引起的自我管理。最初，我们将以我们最近的结果为指导 这表明，单一的、急性的尼古丁或压力暴露会导致酒精自我给药增加 通过改变中脑GABA能回路。然后，以我们的初步结果为指导，我们将防止或扭转 青少年压力或尼古丁通过分子和药物操作导致的饮酒增加 在中脑内。其目的是确定一个靶点并测试一种潜在的治疗药物，以帮助预防 饮酒。

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.