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越来越确定。因此，CRH拮抗剂作为药物滥用的潜在药物疗法，无论是当它单独发生时，还是当它被应激刺激改变时，都引起了相当大的兴趣。直到最近，还没有显著活性的CRH拮抗剂可用于研究。随着最近小分子拮抗剂和新的、有效的肽拮抗剂的合成，探测这些问题的手段更加可用，并且研究和治疗潜力更加令人兴奋。本提案的目的是表征一种新的小分子CRH 1受体拮抗剂antalarmin、一种“超新”小分子CRH 1受体拮抗剂R 121919和一种新的肽CRH 1/CRH 2受体拮抗剂astressin B。这些表征将在大鼠中使用五种应激措施进行：CRH静脉内给药、CRH R1激动剂EG 12114静脉内给药、足电击、社交失败和食物剥夺。首先，将确定每种应激源对ACTH和皮质酮水平的影响。然后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。接下来将测试拮抗剂在无压力大鼠中改变食物、可卡因和瑞芬太尼自我给药的速率和模式的能力。将使用抵抗应激剂直接作用的强化时间表来评估一些应激源对食物和药物自我给药的速率和模式的影响，并将确定每种拮抗剂改变应激诱导的药物摄入改变的能力。最后，将确定应激源恢复对食物和药物的熄灭反应的能力，并评价拮抗剂对应激的这种作用的影响。这些实验的目的是表征CRH拮抗剂，然后测试他们的能力，以修改药物自我管理，无论是作为修改的压力，或在没有明显的压力，和他们的能力，修改压力诱导的恢复。这可能提供有关药物滥用的病因学的信息，以及关于正常或特别是应激个体中药物滥用的潜在治疗的数据。

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.