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（甲基苯丙胺）是一种令人上瘾的心理刺激剂，复发率极高。尚未开发出有效治疗甲基成瘾的有效药物治疗，尤其是针对反复发的药物疗法。动物模型中的研究暗示了皮质激素释放因子（CRF）肽系统在灭绝和恢复精神刺激性自我给药（SA）的机制中。这些研究表明，CRF受体可能是治疗发育的重要靶标。 CRF肽系统是复杂的，由两种主要类型的受体CRF1和CRF2组成，以及四个内源配体CRF，CRF，尿素素1（UCN1），UCN1），尿果素2（UCN2）和尿果素3（UCN3）。由于许多大脑区域被这些内源性配体中的几种支配并经常包含受体，因此很难使用药理学方法解决CRF系统各个组件对灭绝和复发的贡献。最近开发的敲除小鼠（KO）小鼠缺乏CRF系统的组成部分，提供了一种新颖的方法，可以补充药理学研究并阐明CRF系统组成部分在诸如恢复药物寻求药物之类的行为中的作用。在这里，我们建议使用CRF1KO，CRF2 KO和UCN1 KO研究CRF系统的组成部分在灭绝和恢复甲基甲基苯丙胺中的作用。我们假设CRF系统的不同组成部分将差异化参与药物与压力诱导的甲基甲基苯丙胺的恢复。该项目将包括3个具体目标：（1）使用操作静脉内程序比较CRF1，CRF2和UCN1 KO小鼠中甲基甲基甲基苯丙胺的速率。我们假设CRF1 KO比其他基因型的甲基甲基甲基苯甲烷SA采集率略慢，但是所有三种基因型最终都将达到类似水平的甲基甲基甲基甲基苯丙胺SA。 （2）比较CRF1，CRF2和UCN1 KO小鼠中甲基SA的消光率。我们假设与其他基因型相比，CRF2 KO小鼠将显示出甲基SA的灭绝速度更快。 （3）比较在CRF1，CRF2和UCN1 KO小鼠中恢复甲基甲基苯丙胺或抗压力（代谢和物理）后的CRF2和UCN1 KO小鼠。我们假设在CRF1 KO中会减弱药物诱导的恢复原状，但不会在CRF2或UCN1 KO小鼠中减弱，并且在CRF2 KO小鼠中，应减轻压力诱导的恢复原状，这表明它涉及内源性尿素蛋白酶。分析UCN1 KO小鼠中应力诱导的恢复原状，将进一步描述该行为是由UCN1与UCN2与UCN3肽介导的。 公共卫生相关性：甲基苯丙胺（METH）是一种令人上瘾的心理刺激剂，复发率极高。尚未开发出有效治疗甲基成瘾的药物治疗，尤其是针对反复发的药物疗法。这项研究将使用一种甲基自加入的动物模型来检查皮质激素释放因子（CRF）肽系统的参与，以灭绝和恢复寻求甲基甲基甲基苯酚的行为。这些研究将确定CRF受体是否可以成为治疗发育的重要目标。