BRAIN CRF AND NOREPINEPHRINE AND STRESS

压力可能是导致和加剧 精神疾病。应激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) 轴心。这些系统被认为是互补的，但它们之间的关系 他们之间的关系鲜为人知。有确凿证据表明 严重抑郁症和焦虑症患者HPA轴异常，但 目前的治疗强调使用对去甲肾上腺素有效的药物， 5-羟色胺能和GABA能系统。 我们和其他人已经证明，脑内注射 促肾上腺皮质激素释放因子(CRF)可以模拟许多内分泌， 观察到自主神经、神经化学和焦虑样行为反应 在压力下。大脑CRF可能是其中一些的中介物 反应由脑内应用的能力提示 促肾上腺皮质激素释放激素拮抗剂，以预防或减弱它们。我们之前的研究已经 CRF和去甲肾上腺素能活动在应激相关 不同行为范式中的行为变化： 小鼠多室室与防御性撤退和冰冻 大鼠的行为。这些应激相关物质的药理学分析 变化表明，它们可能是由激活的 去甲肾上腺素能神经元通过以下途径激活含CRF细胞 α1受体。然而，独立的神经化学和 电生理证据表明，CRF的使用可以 激活去甲肾上腺素能神经元。因此，CRF和CRF之间的关系 大脑中的去甲肾上腺素系统可能要复杂得多。 拟议的实验将检验CRF与 含去甲肾上腺素能神经元。我们的工作假设是 下丘脑外CRF通过调节NE影响焦虑样行为 活动a蓝斑的水平。具体目标包括 慢性肾功能衰竭可引起行为反应的脑部位的识别 反应类似于在压力下观察到的反应。然后，我们将研究 促肾上腺皮质激素释放激素对去甲肾上腺素释放的影响 采用体内微渗析和体内伏安法进行评价。CRF 拮抗者将在同一地点接受测试，以确定他们是否有能力 拮抗观察到的行为和神经化学反应 对约束和慢性肾功能衰竭的反应。焦点将集中在蓝斑 (LC)因为这种结构与压力和焦虑有关 回应。中央杏仁核接受来自LC的输入和 在获得和表达恐惧和焦虑方面起作用的将是 第二个关注中心。如果大量CRF-NE相互作用是 大脑去甲肾上腺素能系统已确定的选择性损害将 被用来识别参与行为的神经元回路 对束缚和慢性肾功能衰竭的反应。这些实验应该有助于我们 了解CRF和去甲肾上腺素能之间的功能关系 神经元参与应激过程中观察到的行为反应。 这样的理解可能会对治疗该病产生影响。 抑郁症和焦虑症。

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.