CRF System and Methamphetamine Extinction

描述(申请人提供)：甲基苯丙胺(冰毒)是一种上瘾的精神刺激剂，复发率极高。治疗冰毒成瘾，特别是抗复发的有效药物疗法尚未开发出来。动物模型的研究表明，促肾上腺皮质激素释放因子(CRF)肽系统参与了精神刺激剂自我给药(SA)的消退和恢复机制。这些研究表明，CRF受体可能是治疗开发的重要靶点。CRF的多肽系统是复杂的，由CRF1和CRF2两种主要受体和CRF、Ucn1、Ucn2和Ucn3四种内源性配体组成。由于许多大脑区域由这些内源性配体中的几个支配，并且通常包含两个受体，CRF系统的单个组件对灭绝和复发的贡献很难用药理学方法解决。新近发展的基因敲除(KO)小鼠缺乏CRF系统的组件，它提供了一种新的方法，可以补充药理学研究，并阐明CRF系统组件在恢复药物寻找等行为中的作用。在这里，我们建议使用CRF1KO、CRF2KO和Ucn1KO来研究CRF系统的组成部分在冰毒SA消亡和恢复中的作用。我们假设CRF系统的不同组成部分将不同地参与药物和压力诱导的甲基苯丙氨酸的恢复。该项目将包括三个具体目标：(1)比较CRF1、CRF2和Ucn1 KO小鼠在手术静脉操作中的甲基苯丙酸率。我们假设CRF1 KO将表现出比其他基因型略慢的冰毒SA获取速度，但所有三种基因型最终都将达到相似的冰毒SA水平。(2)比较冰毒SA对CRF1、CRF2和Ucn1 KO小鼠的消失率。我们假设CRF2KO小鼠将表现出比其他基因型更快的消失率。(3)比较CRF1、CRF2和Ucn1 KO小鼠注射冰毒或暴露于应激(代谢和体力)后，冰毒SA的恢复情况。我们假设药物诱导的恢复在CRF1 KO小鼠中将减弱，但在CRF2或Ucn1 KO小鼠中不会，而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小鼠应激诱导的恢复的分析将进一步阐明这一行为是否由Ucn1与Ucn2或Ucn3肽介导。 与公共卫生相关：甲基苯丙胺(冰毒)是一种上瘾的精神刺激剂，复发率极高。治疗冰毒成瘾的有效药物疗法，特别是对抗复发的药物疗法，尚未开发出来。这项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)肽系统在消退和恢复冰毒行为机制中的作用。这些研究将确定CRF受体是否可能成为治疗开发的重要靶点。

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.