Alcohol and Stress: Interactive Effects

酒精和压力：互动效应

• 批准号: 6630831
• 负责人: JOANNE WEINBERG
• 金额: $ 26.52万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630831
• 关键词: autoradiography; corticosteroids; corticosterone; embryo /fetus toxicology; estradiol; ethanol; fetal alcohol syndrome; gender difference; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; immunocytochemistry; in situ hybridization; laboratory rat; neuropharmacology; prenatal stress; progesterone; radioimmunoassay; sex hormones; steroids; stimulus /response; stress; stressor; testosterone; western blottings

DESCRIPTION (provided by applicant): The ability to respond to stress is an important basic adaptive mechanism, and hypothalamic-pituitary-adrenal (HPA) activation is a central component of this response. In the short term, stress-induced increases in corticosteroids (CORT) enable the organism to respond to and cope with the stressor. However, prolonged HPA activation can result in adverse physiological and behavioral consequences that can compromise health and even survival. Therefore, early life events that result in greater reactivity to stress and a lifetime of increased levels of CORT can increase the vulnerability to illnesses later in life. Our data demonstrate that 1) prenatal ethanol (E) exposure reprograms the fetal HPA axis and the central components that regulate HPA activity such that HPA tone is increased throughout life; 2) the change in set point of HPA activity appears to be mediated by alterations at multiple levels of the axis and under both basal and stress conditions; 3) E males and females show different patterns of response to stressors, indicating a marked sexual dimorphism in fetal ethanol effects and a possible role for the gonadal steroids in mediating HPA hyperresponsiveness. It appears that the balance between HPA drive and feedback is differentially altered in E males and females. A change in the balance between drive and feedback impairs the ability to maintain homeostasis, and progressively creates a condition of disturbed neuroendocrine regulation and behavioral adaptation. In turn, these changes have implications for vulnerability to illnesses, as noted, and for the development of secondary disabilities such as mental health and behavior problems in children with FAS. The proposed research will continue our study of the mechanisms underlying HPA dysregulation in E animals, and will extend our focus to an examination of mechanisms underlying the sex differences observed. The Specific Aims are: 1) to investigate further the mechanisms underlying the increased HPA responsiveness and altered HPA regulation observed in E animals; and 2) to investigate the modulatory influences of the gonadal steroids in the differential HPA responsiveness of E males and females compared to their control counterparts. The data from these studies will significantly advance our understanding of the long term and far reaching consequences of prenatal ethanol exposure on health and well-being, and will have important implications for the development of interventions and treatments.

描述（由申请人提供）：对压力的反应能力是一种重要的基本适应机制，下丘脑-垂体-肾上腺（HPA）激活是这种反应的核心组成部分。在短期内，应激诱导的皮质类固醇（CORT）增加使生物体能够应对和科普应激源。然而，长时间的HPA激活会导致不良的生理和行为后果，从而危及健康甚至生存。因此，早期生活事件导致对压力的更大反应和一生中CORT水平的增加，会增加以后生活中对疾病的脆弱性。我们的数据表明，1）产前乙醇（E）暴露重新编程胎儿HPA轴和调节HPA活性的中心成分，使HPA张力在整个生命过程中增加; 2）HPA活性设定点的变化似乎是由轴的多个水平以及基础和应激条件下的改变介导的;（3）雌雄性对应激反应的模式不同，表明乙醇对胎儿的影响存在明显的性别差异，性腺激素可能在调节HPA高反应中起作用。看来，HPA驱动和反馈之间的平衡是差异改变E男性和女性。驱力和反馈之间平衡的改变会损害维持体内平衡的能力，并逐渐造成神经内分泌调节和行为适应紊乱的状况。反过来，这些变化也会影响疾病的易感性，正如所指出的那样，并影响患有胎儿酒精综合症的儿童的心理健康和行为问题等继发性残疾的发展。拟议的研究将继续我们的研究机制的HPA失调在E动物，并将我们的重点扩大到检查机制的性别差异观察。具体目标是：1）进一步研究在E动物中观察到的HPA反应性增加和HPA调节改变的潜在机制;和2）研究性腺类固醇在E雄性和雌性与其对照对应物相比的差异HPA反应性中的调节影响。这些研究的数据将大大促进我们对产前乙醇暴露对健康和福祉的长期和深远影响的理解，并将对干预和治疗的发展产生重要影响。