CRH Antagonists for Treatment of Drug Abuse

描述(由申请人提供)：压力和CRH激活在药物滥用的获得、维持和恢复中的作用正在变得更加确定。因此，CRH拮抗剂作为药物滥用的潜在药物疗法是相当有兴趣的，无论是当药物滥用单独发生时，还是当它被应激刺激改变时。直到最近，还没有明显有效的CRH拮抗剂可供研究。随着最近合成的小分子拮抗剂和新型、有效的多肽拮抗剂，探索这些问题的手段变得更加可用，研究和治疗潜力也更加令人兴奋。本研究的目的是鉴定一种新的小分子CRH_1受体拮抗剂Analarmin、一种“超新”小分子CRH_1受体拮抗剂R_(121919)和一种新的多肽CRH_1/CRH_2受体拮抗剂Astressin B。CRH的管理，静脉注射。CRH R1激动剂EG12114的应用，足休克，社会失败和食物匮乏。首先，将确定每种应激源对ACTH和皮质酮水平的影响。然后，将测量拮抗剂阻断应激诱导的ACTH和皮质酮水平增加的能力，并记录这种拮抗作用的持续时间。接下来，这些拮抗剂将接受测试，以确定它们是否有能力改变无应激大鼠的食物、可卡因和瑞芬太尼自我给药的频率和模式。一些应激源对食物和药物自我给药的速度和模式的影响将使用抵抗增强剂直接影响的强化时间表进行评估，并将确定每个拮抗剂改变应激诱导的药物摄入变化的能力。最后，将确定应激源恢复对食物和药物的熄灭反应的能力，并评估拮抗剂对这一应激效果的影响。这些实验旨在确定CRH拮抗剂的特征，然后测试它们在被应激或在没有明显应激的情况下修改药物自我给药的能力，以及它们修改应激诱导的恢复的能力。这可能提供关于药物滥用的病因的信息，以及关于正常人群，特别是有压力的个人的潜在药物滥用治疗的数据。

DESCRIPTION (provided by applicant): A role for stress and CRH activation in acquisition, maintenance, and reinstatement of drug abuse is becoming more established. CRH antagonists are therefore of considerable interest as potential pharmacotherapies for drug abuse, both when it occurs alone, and when it is modified by stressful stimuli. Until recently, there were no significantly active CRH antagonists available for study. With the recent synthesis of small molecule antagonists and of novel, potent peptide antagonists, the means to probe these questions are much more available, and the research and therapeutic potential much more exciting. The purpose of this proposal is to characterize one new small molecule CRH1 receptor antagonist, antalarmin, one "ultra-new" small molecule CRH1 receptor antagonist, R 121919 and one new peptide CRH1/CRH2 receptor antagonist, astressin B. These characterizations will be done in rats using five measures of stress: i.v. administration of CRH, i.v. administration of the CRH R1 agonist EG12114, footshock, social defeat, and food deprivation. Initially, the effect of each stressor on ACTH and corticosterone levels will be determined. Then the ability of the antagonists to block the stress-induced increases in ACTH and corticosterone levels will be measured and the duration of this antagonism recorded. The antagonists will next be tested for their ability to modify rates and patterns of food, cocaine and remifentanil self-administration in unstressed rats. The effects of some of the stressors on rates and pattern of food and drug self-administration will be evaluated using a schedule of reinforcement that is resistant to the direct effects of the reinforcers, and the ability of each of the antagonists to modify stress-induced alterations in drug intake will be determined. Finally, the ability of the stressors to reinstate extinguished responding for food and drug will be determined and the effects of the antagonists on this effect of stress evaluated. These experiments are designed to characterize the CRH antagonists, and then to test their ability to modify drug self-administration, either as it is modified by stress, or in the absence of overt stress, and their ability to modify stress-induced reinstatement. This may provide information about the etiology of drug abuse, as well as data on the potential treatment of drug abuse in normal, or particularly, in stressed individuals.