CRF System and Methamphetamine Extinction

CRF 系统和甲基苯丙胺灭绝

• 批准号: 7576945
• 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/7576945
• 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; Modeling; Mus; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Relapse; Research; Role; Self Administration; Stress; System; Testing; addiction; 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。尚未开发出有效的药物疗法来治疗METH成瘾，特别是对抗复发。动物模型的研究表明促肾上腺皮质激素释放因子（CRF）肽系统参与了精神兴奋剂自我给药（SA）的消退和恢复机制。这些研究表明CRF受体可能是治疗发展的重要靶点。CRF肽系统是复杂的，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（Ucn 1）、尿皮质素2（Ucn 2）和尿皮质素3（Ucn 3）组成。由于许多脑区域受这些内源性配体中的几种的支配，并且通常包含两种受体，因此CRF系统的各个组分对消退和复发的贡献难以使用药理学方法来解决。最近开发的基因敲除（KO）小鼠，缺乏CRF系统的组成部分，提供了一种新的方法，可以补充药理学研究，并澄清CRF系统的组成部分在行为中的作用，如恢复药物寻求。在这里，我们建议使用CRF1 KO，CRF2 KO和Ucn1 KO研究CRF系统的组成部分在METH SA的消退和恢复中的作用。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个特定目的：（1）使用操作性静脉内程序比较CRF1、CRF2和Ucn1 KO小鼠中METH SA的发生率。我们假设CRF1 KO将显示比其他基因型稍慢的METH SA获得率，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的消退率。我们假设CRF2 KO小鼠与其他基因型相比，METH SA的灭绝速度更快。(3)比较METH预激剂量或暴露于应激（代谢和身体）后CRF1、CRF2和Ucn1 KO小鼠中METH SA的恢复情况。我们假设药物诱导的恢复将在CRF1 KO中减弱，但在CRF2或Ucn1 KO小鼠中不会减弱，并且应激诱导的恢复将在CRF2 KO小鼠中减弱，这表明它涉及内源性尿皮质素。对Ucn1 KO小鼠中应激诱导的恢复的分析将进一步阐明这种行为是否由Ucn1相对于Ucn2或Ucn3肽介导。 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。尚未开发出有效的药物疗法来治疗甲基苯丙胺成瘾，特别是对抗复发。本研究将使用METH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METH寻求行为消退和恢复机制中的参与。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。