BRAIN CRF AND NOREPINEPHRINE AND STRESS

大脑 CRF 和去甲肾上腺素与压力

• 批准号: 2460356
• 负责人: Adrian John Dunn
• 金额: $ 16.81万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460356
• 关键词: amygdala; behavioral /social science research tag; corticotropin releasing factor; high performance liquid chromatography; hormone inhibitor; hormone receptor; hypothalamic pituitary axis; laboratory rat; locus coeruleus; neurochemistry; neuropharmacology; norepinephrine; parabrachial nucleus; paraventricular nucleus; psychological stressor

Stress can be an important factor precipitating and exacerbating in mental illness. Stressful stimuli activate catecholaminergic systems (the sympathetic nervous system, the adrenal medulla, and cerebral catecholamines), and the hypothalamo-pituitary-adrenocortical (HPA) axis. These systems are regarded as complementary, but the relationships between them are poorly understood. There is substantial evidence for abnormalities of the HPA axis in major depression and anxiety, but current treatments emphasize the use of drugs active on noradrenergic, serotonergic and GABAergic systems. We and others have demonstrated that intracerebral injections of corticotropin-releasing factor (CRF) can mimic many of the endocrine, autonomic, neurochemical and anxiety-like behavioral responses observed in stress. That cerebral CRF may be a mediator of some of these responses is suggested by the ability of intracerebral application of CRF antagonists to prevent or attenuate them. Our previous studies have implicated both CRF and noradrenergic activity in the stress-related behavioral changes in different behavioral paradigms: the multicompartment chamber in mice, and defensive withdrawal and freezing behavior in rats. Pharmacological analyses of these stress-related changes suggests that they may be mediated by activation of noradrenergic neurons which in turn activate CRF-containing cells via alpha1-receptors. However, independent neurochemical and electrophysiological evidence indicates that CRF administration can activate noradrenergic neurons. Thus, the relationships between CRF and noradrenergic systems in the brain may be considerably more complex. The proposed experiments will examine the relationships between CRF- containing and noradrenergic neurons. Our working hypothesis is that extrahypothalamic CRF affects anxiety-like behavior by modulating NE activity a the level of the locus coeruleus. Specific objectives include the identification of the brain sites in which CRF can elicit behavioral responses resembling those observed in stress. We will then study the effects of CRF injected into these sites on norepinephrine release assessed by in vivo microdialysis and in vivo voltammetry. CRF antagonists will be tested in the same sites for their ability to antagonize the behavioral and neurochemical responses observed in response to restraint and CRF. The focus will be on the locus coeruleus (LC) because this structure has been implicated in stress and anxiety responses. The central amygdala that receives input from the LC and plays a role in acquiring and expression of fear and anxiety will be the second center of attention. If substantial CRF-NE interactions are established, selective lesions of cerebral noradrenergic systems will be used to identify neuronal circuits involved in the behavioral responses to restraint and CRF. These experiments should help us to understand the functional relationships between CRF and noradrenergic neurons involved in the behavioral responses observed during stress. Such an understanding may have implications for the treatment of depression and anxiety disorders.

压力可能是沉淀和加剧的重要因素 精神疾病。压力刺激激活儿茶酚胺能系统 （交感神经系统，肾上腺髓质和大脑 儿茶酚胺）和下丘脑 - 垂体 - 肾上腺皮质（HPA） 轴。这些系统被认为是互补的，但是关系 他们之间的理解很少。有大量证据表明 HPA轴异常在严重抑郁和焦虑中，但 当前的治疗强调使用活跃于去甲肾上腺素的药物， 血清素能和GABA能系统。 我们和其他人已经证明了脑内注射 皮质激素释放因子（CRF）可以模仿许多内分泌， 观察到的自主，神经化学和焦虑样行为反应 在压力下。脑CRF可能是其中一些的中介者 通过脑内应用的能力提出了响应 CRF拮抗剂预防或衰减。我们以前的研究有 与应力有关 不同行为范式的行为变化： 小鼠中的多班门室，防御性​​戒断和冻结 大鼠的行为。这些与应力有关的药理分析 变化表明它们可能是通过激活来介导的 去甲肾上腺素能神经元又通过 α1受体。但是，独立的神经化学和 电生理证据表明，CRF给药可以 激活去甲肾上腺素能神经元。因此，CRF与 大脑中的去肾上腺素能系统可能更为复杂。 提出的实验将检查CRF-之间的关系 含有和去甲肾上腺素能神经元。我们工作的假设是 通过调节NE会影响偏肌外CRF会影响焦虑样行为 活性a基因座的水平。具体目标包括 CRF可以引起行为的大脑位点的识别 反应类似于在压力下观察到的反应。然后我们将研究 将CRF注射到这些位点上对去甲肾上腺素释放的影响 通过体内微透析和体内伏安法评估。 CRF 对抗者将在同一地点进行测试，以了解其能力 与观察到的行为和神经化学反应对抗 对约束和CRF的响应。焦点将放在基因座上 （LC）因为这种结构与压力和焦虑有关 回答。从LC和 在获取和表达恐惧和焦虑方面发挥作用将是 第二个关注中心。如果实质性的CRF-NE相互作用是 脑去甲肾上腺素能系统的已建立的选择性病变将 用于识别行为涉及的神经元电路 对约束和CRF的反应。这些实验应该帮助我们 了解CRF和去甲肾上腺素能之间的功能关系 在压力期间观察到的行为反应的神经元。 这样的理解可能对治疗 抑郁症和焦虑症。