The role of CREB in stress-induced reinstatement

CREB ​​在应激诱导恢复中的作用

• 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
• 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

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）：虽然可卡因成瘾是一个重大的公共卫生问题，但目前没有有效的药物治疗选择。复发率估计在40-60%左右，更好地了解复发的机制可以为我们提供更好的治疗方案。在人类成瘾者中，压力已被证明会导致可卡因寻求的复发，在动物模型中，压力会导致药物寻求的恢复；然而，应激导致复发的分子机制尚不清楚。我们实验室最近的工作表明，cAMP反应元件结合蛋白（CREB）是应激所必需的，但不是可卡因诱导的条件性位置偏好的恢复。目前，尚不清楚神经回路的哪些方面依赖CREB来驱动压力诱导的可卡因寻求恢复。利用行为学、免疫组织化学和神经药理学方法，该资助旨在研究CREB在应激诱导的可卡因条件位置偏好恢复中的作用。首先，我们将检查行为应对策略在应激反应中的作用，并通过检查应激源的能力来检查，这些应激源不会改变CREB缺陷小鼠的行为反应，从而导致条件奖励的恢复。此外，我们将研究幼稚和有可卡因经验的野生型和CREB缺陷小鼠在应激参与与应激诱导恢复有关的神经生物学回路的能力方面的差异。最后，CREB和促肾上腺皮质激素释放因子（CRF）之间的相互作用将通过在恢复前向终纹床核（BNST）和腹侧被盖区（VTA）局部输注CRF来阐明。这项研究的目的是为了更好地理解压力经历是如何导致药物复发的。通过研究CREB在应激行为反应中的作用以及应激与药物寻求之间相互作用的分子机制，我们可以为药物发现找到新的治疗靶点