CRF System and Methamphetamine Extinction

CRF 系统和甲基苯丙胺灭绝

• 批准号: 7835581
• 负责人: GREGORY P MARK
• 金额: $ 19.24万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835581
• 关键词: Affinity; Alcohol consumption; Animal Model; Attenuated; Behavior; Binding; Brain region; C57BL/6 Mouse; CRF receptor type 1; CRF receptor type 2; Complement; Complex; Coping Behavior; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dose; Exhibits; Exposure to; Extinction (Psychology); Genotype; Individual; Intravenous; Knock-out; Knockout Mice; Ligands; Mediating; Metabolic stress; Methamphetamine; Methamphetamine dependence; Modeling; Mus; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Relapse; Research; Role; Self Administration; Stress; System; Testing; base; drug of abuse; novel strategies; psychostimulant; public health relevance; receptor; therapeutic development; urocortin

DESCRIPTION (provided by applicant): Methamphetamine (METH) is an addictive psychostimulant with extremely high relapse rates. Effective pharmacotherapies to treat METH addiction, and in particular to counter relapse have not yet been developed. Research in animal models implicates the corticotropin releasing factor (CRF) peptide system in the mechanisms of extinction and reinstatement of psychostimulant self- administration (SA). These studies suggest CRF receptors could be an important target for therapeutic development. The CRF peptide system is complex, consisting of two main types of receptors, CRF1 and CRF2, and four endogenous ligands, CRF, urocortin 1 (Ucn1), urocortin 2 (Ucn2) and urocortin 3 (Ucn3). Since many brain regions are innervated by several of these endogenous ligands and often contain both receptors, the contribution of individual components of the CRF system to extinction and relapse is difficult to resolve using pharmacological approaches. Recently developed knockout (KO) mice, deficient in components of the CRF system, provide a novel approach that can complement pharmacological studies and clarify the role of components of the CRF system in behaviors such as reinstatement of drug-seeking. Here we propose using CRF1KO, CRF2 KO and Ucn1 KO to study the role of components of the CRF system in extinction from, and reinstatement of SA of METH. We hypothesize that different components of the CRF system will be differentially involved in drug- versus stress-induced reinstatement of METH SA. The project will include 3 Specific Aims: (1) to compare rates of METH SA in CRF1, CRF2 and Ucn1 KO mice using operant intravenous procedures. We hypothesize that CRF1 KO will show slightly slower acquisition rates of METH SA than other genotypes, but that all three genotypes will ultimately reach a similar level of METH SA. (2) To compare rates of extinction from METH SA in CRF1, CRF2 and Ucn1 KO mice. We hypothesize that CRF2 KO mice will show faster rates of extinction from METH SA compared to other genotypes. (3) To compare reinstatement of METH SA in CRF1, CRF2 and Ucn1 KO mice following a priming dose of METH or exposure to stress (metabolic and physical). We hypothesize that drug-induced reinstatement will be attenuated in CRF1 KO, but not in CRF2 or Ucn1 KO mice, and that stress-induced reinstatement will be attenuated in CRF2 KO mice suggesting that it involves endogenous urocortins. Analysis of stress- induced reinstatement in Ucn1 KO mice will further delineate whether this behavior is mediated by Ucn1 versus Ucn2 or Ucn3 peptides. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) is an addictive psychostimulant with extremely high relapse rates. Effective pharmacotherapies to treat METH addiction, and in particular to counter relapse, have not yet been developed. This research will use an animal model of METH self-administration to examine the involvement of the corticotropin releasing factor (CRF) peptide system in the mechanisms of extinction and reinstatement of METH-seeking behavior. These studies will determine if CRF receptors could be an important target for therapeutic development.

描述（由申请人提供）：甲基苯丙胺（METH）是一种成瘾性精神兴奋剂，复发率极高。治疗冰毒成瘾，特别是防止复发的有效药物疗法尚未开发出来。动物模型研究表明促肾上腺皮质激素释放因子（CRF）肽系统参与精神兴奋剂自我给药（SA）的消失和恢复机制。这些研究表明 CRF 受体可能成为治疗开发的重要靶点。 CRF肽系统很复杂，由两种主要类型的受体CRF1和CRF2以及四种内源性配体CRF、尿皮质素1 (Ucn1)、尿皮质素2 (Ucn2)和尿皮质素3 (Ucn3)组成。由于许多大脑区域受到其中几种内源性配体的神经支配，并且通常包含两种受体，因此使用药理学方法很难解决 CRF 系统的各个成分对灭绝和复发的贡献。最近开发的缺乏 CRF 系统组件的基因敲除 (KO) 小鼠提供了一种新方法，可以补充药理学研究并阐明 CRF 系统组件在恢复药物寻求等行为中的作用。在这里，我们建议使用 CRF1KO、CRF2 KO 和 Ucn1 KO 来研究 CRF 系统组件在 METH 的 SA 灭绝和恢复中的作用。我们假设 CRF 系统的不同组成部分将不同地参与药物与应激诱导的 METH SA 恢复。该项目将包括 3 个具体目标：(1) 比较使用操作性静脉注射操作的 CRF1、CRF2 和 Ucn1 KO 小鼠中的 METH SA 率。我们假设 CRF1 KO 将表现出比其他基因型稍慢的 METH SA 获取率，但所有三种基因型最终将达到相似的 METH SA 水平。 (2)比较CRF1、CRF2和Ucn1 KO小鼠中METH SA的灭绝率。我们假设与其他基因型相比，CRF2 KO 小鼠会因 METH SA 而表现出更快的灭绝速度。 (3) 比较 CRF1、CRF2 和 Ucn1 KO 小鼠在给予 METH 初始剂量或暴露于压力（代谢和身体）后 METH SA 的恢复情况。我们假设药物诱导的恢复在 CRF1 KO 小鼠中会减弱，但在 CRF2 或 Ucn1 KO 小鼠中不会减弱，并且应激诱导的恢复在 CRF2 KO 小鼠中会减弱，这表明它涉及内源性尿皮质素。对 Ucn1 KO 小鼠应激诱导的恢复的分析将进一步阐明这种行为是否是由 Ucn1 与 Ucn2 或 Ucn3 肽介导的。 公共卫生相关性：甲基苯丙胺 (METH) 是一种成瘾性精神兴奋剂，复发率极高。治疗冰毒成瘾，特别是防止复发的有效药物疗法尚未开发出来。本研究将使用冰毒自我给药的动物模型来研究促肾上腺皮质激素释放因子（CRF）肽系统在冰毒寻求行为的消失和恢复机制中的作用。这些研究将确定 CRF 受体是否可以成为治疗开发的重要靶点。