Interaction of Brain Norepinephrine/Galanin in Stress

大脑去甲肾上腺素/甘丙肽在压力下的相互作用

基本信息

批准号：
6887695
负责人：
David A Morilak
金额：
$ 18.06万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2007-04-30
项目状态：
已结题

项目摘要

Over the past two decades, obtaining a better understanding of the physiological significance of co- localization of neuropeptide and classical neurotransmitters such as norepinephrine (NE) in the brain has been an important yet elusive goal in neuroscientific research. NE modulates a variety of processes involved in the response to stress. However, several observations have suggested that NE interacts in important ways with other modulatory neurotransmitters with which it may be co-localized, for the full manifestation of this modulatory influence. In this project, we propose using a multidisciplinary strategy of pharmacological, physiological, behavioral, neurochemical and anatomical approaches to investigate the functional interaction of NE and galanin (GAL), a neuropeptide with which it is prominently co-localized. It is thought that NE acts in limbic forebrain regions, such as central amygdala (CeA) and lateral bed nucleus of the stria terminalis (BSTL), to facilitate neuroendocrine and behavioral components of the stress response. We hypothesize that under conditions of intense activation of the noradrenergic system, GAL is released along with NE in the CeA and BSTL, and acts to buffer the modulatory effects of NE on these affective and hormonal components of the stress response. These hypotheses will be tested by exposing rats to acute immobilization stress, and selectively amplifying the stress-induced activation of the noradrenergic system by pretreatment with yohimbine. The first two aims are pharmacological investigations. In Aim 1, a GAL antagonist will be microinjected, alone or with an adrenergic antagonist, directly into CeA or BSTL of rats to test the hypothesis that GAL attenuates the facilitatory effect of NE on stress-induced ACTH secretion when stress-induced activation of the NE system is amplified by yohimbine. Similarly, Aim 2 tests the hypothesis that GAL attenuates the facilitatory influence of NE on stress-induced anxiety, as measured on the social interaction test and the elevated plus maze test. The last two aims are to investigate the neural mechanisms and substrates underlying these interactions. Aim 3 addresses the neurochemical substrates underlying these interactions by measuring GAL release in CeA and BSTL using microdialysis. Finally, in Aim 4, immunocytochemistry and in situ hybridization will be used io reveal the anatomical substrates for these interactions, by identifying cells in CeA and BSTL that are activated by stress and also express post-synaptic receptors for NE and GAL. In sum, the experiments outlined in this proposal represent a multidisciplinary investigation of the interaction of the neuropeptide GAL with the classic monoaminergic neurotransmitter NE, in modulating hormonal and affective components of the stress response in CeA and BSTL. By providing a basic neurobiological context within which to better understand the functional and regulatory interactions between monoamines and neuropeptides, these results may guide the future development of novel or more effective therapeutic strategies for the treatment of stress- related psychiatric disorders such as depression, anxiety or PTSD.

在过去的二十年中，对神经肽和经典神经递质（例如大脑中的去甲肾上腺素（NE））的共同定位的生理意义有了更好的了解，这在神经科学研究中是一个重要但难以捉摸的目标。 NE调节应力反应中涉及的各种过程。但是，几种观察结果表明，NE与其他调节性神经递质的相互作用可以与之共定位，以完全表现出这种调节作用。在这个项目中，我们建议使用药理学，生理，行为，神经化学和解剖方法的多学科策略研究NE和Galanin（GAL）的功能相互作用，NE和Galanin（GAL）是一种神经肽，它与之显着地共同定位。人们认为，NE在边缘前脑区域作用，例如中央杏仁核（CEA）和脊柱末端的侧床核（BSTL），以促进胁迫反应的神经内分泌和行为成分。我们假设在去甲肾上腺素能系统激活的条件下，GAL与CEA和BSTL中的NE一起释放，并起作用，以缓解NE对压力反应的这些情感和激素成分的调节作用。这些假设将通过将大鼠暴露于急性固定应力，并通过用Yohimbine预处理来测试急性固定应力，并选择性地扩增应激诱导的甲肾上腺素能系统的激活。前两个目的是药理研究。在AIM 1中，GAL拮抗剂将单独或与肾上腺素能拮抗剂进行显微注射，直接进入CEA或BSTL大鼠的BSTL，以检验以下假设，即当Yohohimbine放大了应激诱导的NE系统激活时，GAL会减弱NE对压力诱导的ACTH分泌的促进作用。同样，AIM 2检验了GAL减弱NE对压力引起的焦虑的促进影响的假设，如社交互动测试和升高的迷宫测试所测量的那样。最后两个目的是研究这些相互作用的神经机制和底物。 AIM 3通过使用微透析在CEA和BSTL中测量GAL释放来解决这些相互作用的神经化学底物。最后，在AIM 4中，通过鉴定由应激激活的CEA和BSTL中的细胞，并表达NE和GAL的突触后受体，将使用免疫细胞化学和原位杂交来揭示这些相互作用的解剖底物。总而言之，该提案中概述的实验代表了对神经肽GAL与经典的单胺能神经递质NE的相互作用的多学科研究，以调节CEA和BSTL中应力反应的激素和情感成分。通过提供基本的神经生物学环境，在该环境中，这些结果可以更好地了解单胺与神经肽之间的功能和调节性相互作用，这些结果可以指导新型或更有效的治疗策略的未来发展，以治疗抑郁症，焦虑或PTSD等应激相关的精神疾病。