CRH Antagonists for Treatment of Drug Abuse

描述（由申请人提供）：应激和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具有相当大的兴趣，无论是当它单独发生时，还是当它被应激刺激修饰时。直到最近，还没有明显活性的CRH拮抗剂可用于研究。随着近年来小分子拮抗剂和新型强效肽拮抗剂的合成，探索这些问题的手段更加可行，研究和治疗潜力也更加令人兴奋。本研究的目的是表征一种新的小分子CRH1受体拮抗剂antalarmin，一种“超新型”小分子CRH1受体拮抗剂r121919和一种新的肽CRH1/CRH2受体拮抗剂应激素b。这些表征将在大鼠中使用五种应激措施：静脉给药CRH，静脉给药CRH R1激动剂EG12114，脚部休克，社会失败和食物剥夺。首先，将确定每种应激源对促肾上腺皮质激素和皮质酮水平的影响。然后测量拮抗剂阻断应激诱导的促肾上腺皮质激素和皮质酮水平升高的能力，并记录这种拮抗剂的持续时间。接下来将测试这些拮抗剂是否有能力改变无压力大鼠的食物、可卡因和瑞芬太尼自我给药的速率和模式。一些应激源对食物和药物自我给药的速率和模式的影响将通过一种对增强剂的直接作用有抵抗性的强化表来评估，并且每种拮抗剂对应激诱导的药物摄入改变的能力将被确定。最后，确定应激源恢复对食物和药物已消失的反应的能力，并评估拮抗剂对这种应激效应的影响。这些实验旨在描述CRH拮抗剂的特性，然后测试它们改变药物自我给药的能力，无论是在压力下还是在没有明显压力的情况下，以及它们改变压力诱导的恢复的能力。这可能提供有关药物滥用的病因的信息，以及在正常情况下，特别是在压力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.