The role of CREB in stress-induced reinstatement

CREB 在应激诱导恢复中的作用

基本信息

批准号：
7804995
负责人：
LISA A BRIAND
金额：
$ 5.05万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7804995
关键词：
Acute Amygdaloid structure Animal Model Animals Behavior Behavioral Brain region Cells Chronic stress Cocaine Cocaine Dependence Corticotropin-Releasing Hormone Cyclic AMP-Responsive DNA-Binding Protein Exhibits Experimental Designs Exposure to Gene Activation Goals Grant Hippocampus (Brain)Human Hypothalamic structure Immunohistochemistry Infusion procedures Injection of therapeutic agent Label Lead Molecular Mus Mutant Strains Mice Neurobiology Neurons Nucleus Accumbens Pattern Pharmaceutical Preparations Pharmacological Treatment Prefrontal Cortex Public Health Relapse Research Resistance Rewards Rodent Model Role Stimulus Stress Structure of terminal stria nuclei of preoptic region Swimming System Ventral Tegmental Area Work classical conditioning cohort coping drug discovery drug relapse experience mutant neural circuit neurochemistry new therapeutic target preference response restraint restraint stress stressor

项目摘要

DESCRIPTION (provided by applicant): Although cocaine addiction is a major public health problem, currently no effective pharmacological treatment options exist. With relapse rates estimated at around 40-60%, developing a better understanding of the mechanisms underlying relapse could provide us with the means to develop better treatment options. Stress has been shown to elicit relapse to cocaine seeking in human addicts and reinstatement of drug seeking in animals models; however, the molecular mechanisms by which stress leads to relapse is unknown. Recent work in our lab has demonstrated that cAMP response element binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned place preference using mice with a constitutive deletion of CREB. Currently, it is unclear which aspects of the neural circuitry depend on CREB to drive stress-induced reinstatement of cocaine seeking. Utilizing behavioral, immunohistochemical, and neuropharmacological approaches, this grant aims to examine the role of CREB in stress-induced reinstatement of cocaine conditioned place preference. Initially, we will examine the role of behavioral coping strategies in response to stress will be examined by examining the ability of stressors that do not engage altered behavioral responding in CREB deficient mice to lead to resinstatement of conditioned reward. Additionally, we will examine differences between both naive and cocaine-experienced wildtype and CREB deficient mice in the ability of stress to engage neurobiological circuitry implicated in stress-induced reinstatement. Finally, interactions between CREB and corticotropin-releasing factor (CRF) will be elucidated by local infusions of CRF into the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA) prior to reinstatement. The goal of this research is to gain a better understanding of how stressful experiences can lead to drug relapse. By investigating the role of CREB in both the behavioral responses to stress as well as the molecular mechanisms underlying the interactions between stress and drug seeking we can identify new therapeutic targets for drug discovery

描述（由申请人提供）：尽管可卡因成瘾是一个主要的公共卫生问题，但目前尚无有效的药理治疗选择。由于估计约40-60％的复发率，对复发的机制有了更好的了解，可以为我们提供开发更好治疗选择的方法。已显示压力会引起人类成瘾者的可卡因寻求以及在动物模型中恢复毒品的恢复。但是，应力导致复发的分子机制尚不清楚。我们实验室中的最新工作表明，使用与可卡因诱导的恢复有条件的位置优先型的cAMP响应元件结合蛋白（CREB）是必要的，使用具有构型CREB的缩写。目前，尚不清楚神经回路的哪些方面取决于CREB推动应力引起的可卡因寻求恢复。该赠款利用行为，免疫组织化学和神经药理学方法，旨在检查CREB在应力引起的可卡因调节位置偏好中的作用。最初，我们将通过检查不参与CREB缺乏小鼠的行为反应的压力源的能力来检查行为应对策略对压力的作用，从而导致对条件奖励进行研究。此外，我们将研究幼稚和可卡因经验丰富的野生型和CREB缺乏小鼠的差异，这是压力参与与压力引起的恢复有关的神经生物学回路的能力。最后，CREB和促肌激素释放因子（CRF）之间的相互作用将通过CRF局部输注到恢复原状之前的局部输注（BNST）（BNST）（BNST）（BNST）和腹侧段区域（VTA）。这项研究的目的是更好地了解压力体验如何导致药物复发。通过研究CREB在压力的行为反应中的作用以及压力与寻求药物之间相互作用的分子机制，我们可以识别出用于药物发现的新的治疗靶标