CRH Antagonists for Treatment of Drug Abuse

点击翻译按钮获取中文摘要

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.