CRF System and Methamphetamine Extinction

描述（由申请人提供）：甲基苯丙胺（冰毒）是一种上瘾的精神兴奋剂，复发率极高。治疗冰毒成瘾的有效药物疗法，特别是防止复发的药物疗法尚未开发出来。动物模型研究提示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）消退和恢复的机制。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，包括两种主要受体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）。由于许多大脑区域受几种内源性配体的支配，并且通常含有两种受体，因此很难用药理学方法解决CRF系统中单个组分对消失和复发的贡献。最近开发的敲除（KO）小鼠，缺乏CRF系统的成分，提供了一种新的方法，可以补充药理学研究，并阐明CRF系统成分在恢复药物寻找等行为中的作用。在这里我们建议使用CRF1KO CRF2 KO和Ucn1 KO研究组件的角色CRF系统的灭绝,和恢复SA的冰毒。我们假设CRF系统的不同组成部分将不同地参与药物诱导与应激诱导的甲基安非他明SA恢复。该项目将包括3个具体目标：(1)通过手术静脉注射手术比较CRF1、CRF2和Ucn1 KO小鼠中甲基安非他明SA的发生率。我们假设CRF1 KO的甲基苯丙胺SA获得率略低于其他基因型，但所有三种基因型最终都将达到相似的甲基苯丙胺SA水平。(2)比较CRF1、CRF2和Ucn1小鼠对甲基安非他明SA的灭绝率。我们假设，与其他基因型相比，CRF2 KO小鼠从甲基安非他明SA中灭绝的速度更快。(3)比较甲基安非他明启动剂量或暴露于应激（代谢和物理）后，CRF1、CRF2和Ucn1小鼠甲基安非他明SA的恢复情况。我们假设药物诱导的恢复在CRF1 KO中会减弱，但在CRF2或Ucn1 KO小鼠中不会减弱，而应激诱导的恢复在CRF2 KO小鼠中会减弱，这表明它涉及内源性尿皮质素。对应激诱导的Ucn1 KO小鼠恢复的分析将进一步阐明这种行为是否由Ucn1、Ucn2或Ucn3肽介导。

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.