GCs, CRF and Stressor-Induced Relapse

GC、CRF 和压力源诱发的复发

• 批准号: 8212440
• 负责人: John R. Mantsch
• 金额: $ 28.91万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212440
• 关键词: Adrenalectomy; Anxiety; Behavior; Chronic; Cocaine; Cocaine Dependence; Corticosterone; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dependence; Development; Dopamine; Dopamine Antagonists; Drug Exposure; Drug usage; Glucocorticoid Receptor; Glucocorticoids; Goals; Hormones; Human; Individual; Infusion procedures; Injection of therapeutic agent; Intake; Mediating; Microdialysis; Modeling; Neural Pathways; Neurobiology; Neuronal Plasticity; Neuropeptides; Nucleus Accumbens; Operative Surgical Procedures; Pathway interactions; Pattern; Pharmaceutical Preparations; Plasma; Predisposition; Process; RNA Interference; RU-486; Rattus; Regulation; Relapse; Relative (related person); Reporting; Research; Role; Self Administration; Series; Stress; Testing; Time; Ventral Tegmental Area; Withdrawal; addiction; cocaine use; craving; design; dopaminergic neuron; driving behavior; drug relapse; drug seeking behavior; effective therapy; follow-up; footshock induced; in vivo; neurobiological mechanism; neurotransmission; osmotic minipump; prevent; public health relevance; receptor; receptor expression; research study; response; stressor; trafficking

DESCRIPTION (provided by applicant): For many cocaine addicts, drug use is a stress-driven behavior. Previous research has shown that stressor- induced cocaine seeking is mediated in part by corticotropin-releasing factor (CRF) stimulation of a neurobiological pathway involving dopamine (DA) neurons in the ventral tegmental area (VTA) that likely project to nucleus accumbens (NA). The regulation of this pathway by stressors and CRF appears to emerge as a consequence of prior cocaine use and therefore may be relevant to the onset of addiction. We have demonstrated that rats provided long access to cocaine for self-administration (SA) each day (LgA rats) display greater reinstatement in response to a stressor (electric footshock; EFS) or administration of CRF directly into the VTA, compared to rats provided shorter daily drug access (ShA rats). Furthermore, we have found that that the establishment of heightened stressor-induced reinstatement appears to require elevation of glucocorticoids (GCs) at the time of earlier LgA SA, suggesting that the induction of addiction-related neuroplasticity leading to heightened stressor-induced drug seeking following excessive patterns of cocaine use is a GC-dependent process. The goal of this proposal is to test the hypothesis that cocaine addiction is associated with an emergent or augmented CRF regulation of dopaminergic neurons projecting from the VTA to a subregion of the NA, the shell, that is attributable to increased VTA CRF receptor (CRF-R) expression or function and leads to a heightened susceptibility to stressor-induced craving and relapse. Furthermore, we hypothesize that the establishment of heightened CRF regulation is dependent upon elevated GCs and activation of GC receptors (GR) at the time of earlier drug exposure. These hypotheses will be tested in this proposal in three specific aims. In the first aim we will further investigate the relationship between augmented VTA CRF sensitivity and stressor-induced reinstatement through a series of experiments that examine the relative time-courses of altered CRF- and EFS-induced reinstatement as they relate to changes in CRF-R expression and trafficking and determine the involvement of CRF-R subtypes in the VTA in stressor-induced cocaine seeking through antagonist administration and receptor knockdown by RNA-interference. In the second aim we will examine the role of altered CRF actions in the VTA in the augmented stressor-induced regulation of NA DA and its involvement in stressor-induced cocaine seeking using in vivo microdialysis in and administration of DA receptor antagonists into the NA core and shell. In the final aim, we will examine the GC- dependence of the effects of LgA SA on stressor-induced cocaine seeking and NA DA neurotransmission and CRF-R expression/trafficking through a surgical adrenalectomy and diurnal GC replacement approach that eliminates evoked GC secretion while maintaining normal diurnal patterns of plasma GCs and through central infusion of the GR antagonist, RU-486 via osmotic minipump. Understanding the neurobiological processes through which stressor-induced regulation of cocaine use is established in cocaine addicts should facilitate the development of new and more effective treatment approaches, particularly for subpopulations of cocaine addicts whose drug use is stress-driven. PUBLIC HEALTH RELEVANCE: This project examines the neurobiological mechanisms through which susceptibility to drug relapse during periods of stress is heightened in cocaine addiction. The project focuses on neuroplasticity involving the regulation of neural pathways underlying drug use by corticotropin-releasing factor (CRF), a neuropeptide previously implicated in stress and anxiety. The ability of a rat model of excessive drug use to enhance CRF regulation of drug-seeking behavior in a manner that depends on secretion of glucocorticoid hormones will be tested.

描述（由申请人提供）：对于许多可卡因上瘾者，药物使用是一种压力驱动的行为。先前的研究表明，胁迫诱导的可卡因寻求部分是通过促肾上腺蛋白释放因子（CRF）刺激涉及腹侧段（da）神经元（VTA）的神经生物学途径（VTA）的刺激，这些途径可能会投射到Accumbens（NA）的核。压力源和CRF对这一途径的调节似乎是由于先前的可卡因使用而出现的，因此可能与成瘾的发作有关。我们已经证明，大鼠每天提供可卡因以进行自我管理（SA）（SA）（LGA大鼠），与应激源（电动脚印； EFS）或直接将CRF施用直接恢复到VTA中，与提供更短的日常药物通道（SHA大鼠）相比，CRF直接将CRF施用到VTA中。此外，我们发现，在早期LGA SA时，建立增强的压力剂诱导的恢复原状似乎需要升高糖皮质激素（GC），这表明与成瘾相关的神经塑性诱导导致良好的压力诱导的药物寻求药物的诱导性超高，这是GC依赖性依赖性的过程。 The goal of this proposal is to test the hypothesis that cocaine addiction is associated with an emergent or augmented CRF regulation of dopaminergic neurons projecting from the VTA to a subregion of the NA, the shell, that is attributable to increased VTA CRF receptor (CRF-R) expression or function and leads to a heightened susceptibility to stressor-induced craving and relapse.此外，我们假设建立增强的CRF调节取决于GC的升高和GC受体（GR）在较早的药物暴露时的激活。这些假设将以三个具体目标在该提案中进行检验。在第一个目的中，我们将进一步研究通过一系列实验，通过一系列实验来检查CRF和EFS诱导的改变的相对时间库之间的相对时间表，因为它们与CRF-R表达的变化，并确定CRF-R子类型的参与时，它们之间的相对时间表之间的关系，这些实验的相对时间表之间的相对时间表之间的关系，它们与CRF-R表达的变化相关，并确定CRF-R表达的变化，并确定它们与CRF-R表达的变化有关。 RNA干扰受体敲低。在第二个目标中，我们将研究CRF作用改变在VTA中的作用在增强压力诱导的Na DA的调控中及其参与压力诱导的可卡因寻求可卡因，从而在体内微透析中使用DA受体拮抗剂在Na核心中，并给药。 In the final aim, we will examine the GC- dependence of the effects of LgA SA on stressor-induced cocaine seeking and NA DA neurotransmission and CRF-R expression/trafficking through a surgical adrenalectomy and diurnal GC replacement approach that eliminates evoked GC secretion while maintaining normal diurnal patterns of plasma GCs and through central infusion of the GR antagonist, RU-486 via渗透微型。了解可卡因成瘾者在可卡因成瘾者中建立压力源诱导的可卡因使用调节的神经生物学过程，应促进开发新的，更有效的治疗方法，尤其是对于可卡因成瘾者的亚群，其吸毒是压力驱动的。 公共卫生相关性：该项目研究了神经生物学机制，通过这些机制，可卡因成瘾期间在压力期间对药物复发的敏感性提高。该项目着重于神经塑性，涉及促肾上腺素释放因子（CRF）的神经途径的调节，这是一种以前涉及压力和焦虑的神经肽。过度使用药物使用的大鼠模型以取决于糖皮质激素激素分泌的方式增强药物寻求行为的CRF调节的能力。