Adolescent alcohol exposure and altered adult HPA axis activity

青少年酒精暴露和成人 HPA 轴活性改变

• 批准号: 8032645
• 负责人: SOON O LEE
• 金额: $ 46.2万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032645
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adrenal Glands; Adrenergic Agents; Adult; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Attention; Behavior; Brain; Brain Stem; Breeding; Catecholamines; Control Animal; Correlative Study; Corticotropin; Corticotropin-Releasing Hormone; Data; Dependence; Development; Embryo; Endocrine; Epidemiology; Epinephrine; Ethanol; Exhibits; Exposure to; FOS gene; Female; Future; Gene Expression; Gene Proteins; Glucocorticoids; Heavy Drinking; Human; Hypothalamic structure; Individual; Intake; Life; Link; Maintenance; Measures; Mediating; Memory impairment; Modeling; Mood Disorders; Neurologic; Neurons; Pharmaceutical Preparations; Pituitary Gland; Plasma; Play; Population; Principal Investigator; Probability; Puberty; Rattus; Relapse; Risk; Rodent; Role; Self Administration; Signal Transduction; Sprague-Dawley Rats; Staging; Stress; Testing; Therapeutic; Time; United States National Institutes of Health; adolescent alcohol exposure; adrenergic; alcohol exposure; alcohol response; base; binge drinking; cost; craving; drinking; falls; hypothalamic-pituitary-adrenal axis; indexing; male; novel; paraventricular nucleus; postnatal; protein expression; public health relevance; research study; response; sexual dimorphism; stressor; underage drinking; vapor

DESCRIPTION (provided by applicant): Adolescent drinking has been linked to increased alcohol abuse in adults. Despite the high societal cost of this phenomenon, the mechanisms responsible for it remain mostly unknown. In view of the importance of the hypothalamic-pituitary-adrenal (HPA) axis in alcohol abuse and relapse per se, as well as in affective disorders thought to be linked to abuse/relapse, we propose to test the hypothesis that alcohol exposure during adolescence, in a model called Adolescent Intermittent Alcohol (AIE), alters the adult rat's HPA axis activity. Currently, there is no available detailed information regarding the time-course over which alcohol upregulates parameters of the HPA axis in adolescent rats, or the magnitude of this response. However, this information is critical for the development of the AIE model. We will first explore the ability of intermittent alcohol vapors to activate the HPA axis in male and female rats. Parameters measured will include plasma ACTH levels, c-fos signaling as an index of neuronal activation of corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) of the hypothalamus, and PVN CRF gene expression. Particular emphasis will be put on the potential presence of sexual dimorphism in HPA axis activity. As both humans and outbred rodents often fall into a low- or a high-responder group regarding a variety of stress-induced responses, and as this may have important consequences for the long-term consequences of AIE, we will also determine whether we can identify these two groups in our model. If we identify low- and high-responders, we will then test the hypothesis that these differential HPA axis responses to AIE correspond to similar differences in adults. We will then explore the mechanisms through which AIE alters the adult rats' HPA axis. We recently observed that alcohol upregulates hypothalamic and brain stem catecholaminergic circuits, and that this (nor)adrenergic activation plays an important role in mediating the rat HPA axis response to alcohol. We will therefore focus on the hypothesis that the brain catecholaminergic circuitry of adult rats exposed to AIE, differs from that of control animals; that the ability of (nor)epinephrine, which is released by alcohol in the brain, to activate the HPA axis, is also altered by AIE; and that the role played by catecholamines in modulating the consequences of AIE might be sexually dimorphic. Collectively, these results will provide novel and important information regarding the long-term influence of adolescent alcohol exposure on the adult HPA axis. This will then pave the way for future correlative studies that explore potential functional links between adult alcohol self-administration induced by pubertal exposure to the drug, and HPA axis activity. PUBLIC HEALTH RELEVANCE: This Project tests the hypothesis that in the rat, exposure to alcohol during adolescence induces long-term changes in the hypothalamic-pituitary-activity of the adults, with emphasis on the possible presence of sexual dimorphism. This will pave the way for future experiments that investigate functional links between this adult altered endocrine activity and the increased alcohol abuse known to take place in adults exposed to alcohol when juvenile.

描述（由申请人提供）：青少年饮酒与成人酗酒的增加有关。尽管这种现象的社会成本很高，但对此的造成的机制仍未知。鉴于下丘脑 - 垂体 - 肾上腺（HPA）轴对酒精滥用和复发本身以及被认为与滥用/复发有关的情感障碍，我们建议在青春期中的酒精暴露在一个被称为青少年间歇性酒精（AIE）的模型中，Alters the Alters HPA axkis axkis axkis axkis axkis axkis axkis axkis axgias axkis axkis axkis axkis axkis axkis axgias axkis axkis axkis axkis axkis axkis axkis axkis axkis axkis的假设当前，尚无有关在青少年大鼠中上调HPA轴参数或此反应的大小的时间课程的可用详细信息。但是，此信息对于AIE模型的开发至关重要。我们将首先探讨间歇性酒精蒸气激活男性和雌性大鼠HPA轴的能力。测得的参数将包括血浆ACTH水平，C-FOS信号作为在下丘脑的旁脑核（PVN）中皮质激素释放因子（CRF）神经元激活的指数和PVN CRF基因表达。特别重点将放在HPA轴活动中性二态性的潜在存在上。由于人类和近亲啮齿动物经常属于有关各种应力引起的反应的低响应者或高响应者组，并且由于这可能会对AIE的长期后果产生重要影响，因此我们还将确定我们是否可以在模型中识别这两个组。如果我们确定了低反应者和高响应者，我们将测试以下假设：这些差异HPA轴对AIE的响应对应于成年人的类似差异。然后，我们将探索AIE改变成年大鼠HPA轴的机制。我们最近观察到，酒精上调下丘脑和脑干儿茶酚胺能回路，并且这种（NOR）肾上腺素能激活在介导大鼠HPA轴对酒精的反应中起着重要作用。因此，我们将关注以下假设：成年大鼠暴露于AIE的脑儿茶酚胺能回路与对照动物的不同。 AIE也改变了（NOR）肾上腺素激活HPA轴的（NOR）肾上腺素激活HPA轴的能力；儿茶酚胺在调节AIE后果中所扮演的角色可能是性二态的。总的来说，这些结果将提供有关青少年酒精暴露对成人HPA轴的长期影响的新颖和重要信息。然后，这将为未来的相关研究铺平道路，探索因青春期暴露于该药物而引起的成人酒精自我给药与HPA轴活动之间的潜在功能联系。 公共卫生相关性：该项目检验了以下假设：在大鼠中，青春期暴露于酒精会导致成年人下丘脑垂体活性的长期变化，重点是可能存在性二态性。这将为将来的实验铺平道路，这些实验研究了这种成年人的内分泌活性改变与少年时暴露于酒精的成年人中已知的酗酒量之间的功能联系。