Opioids:Relative Reinforcing Strength and Dependence

描述（由申请人提供）：在理解阿片类药物依赖的生理和行为方面已经付出了相当大的努力，但关于阿片类药物依赖如何改变海洛因的强化效应却知之甚少。自1968年首次证明动物开始自我给药不需要事先依赖以来，很少有研究调查阿片类药物依赖受试者的自我给药行为。拟议的研究旨在解决阿片类药物的强化效应是否以及如何作为依赖的函数而改变的问题，包括由确定的海洛因成瘾药物治疗（例如丁丙诺啡）引起的依赖。我们开发了创新的自我给药程序，可以迅速确定静脉注射海洛因的相对强化强度的全部剂量效应功能。在这些新颖的选择过程中，受试者学会在整个过程中根据可用于自我注射的静脉注射溶液和可选择的强化物（食物）的相对强化强特征来分配他们的行为。这些程序是专门设计用来将药物的强化作用与其他行为效应分离开来的。在拟议的研究中，将在不同的反应成本条件下确定海洛因和其他阿片类激动剂的自我给药，以评估环境对相对强化强度的影响。接下来，我们将研究吗啡样药物的急性治疗和慢性治疗如何调节海洛因的相对强化强度。初步数据表明，海洛因在非依赖性受试者中的强化强度可以通过其他阿片类药物治疗或反应成本的变化而可预测地改变，这证实了这些程序在研究自我给药海洛因的相对强化强度方面的效用。在完成这些研究之后，海洛因强化强度的改变将与慢性治疗期间产生的耐受性和依赖性有关。最后，计划中的实验将解决非阿片类药物，特别是GABA-A激动剂对海洛因强化效应的修饰。这些研究旨在从经验上解决阿片类药物成瘾人群中苯二氮卓类药物滥用率高所带来的问题。总的来说，拟议的研究将为评估海洛因在非依赖和阿片类药物依赖个体中的增强强度的环境或药理学改变提供重大进展。这些研究的结果将提高我们评估基于激动剂的药物对抗其成瘾性的有效性的能力。

DESCRIPTION (provided by applicant): Considerable effort has been dedicated to understanding physiological and behavioral aspects of opioid dependence, yet little is known regarding how opioid dependence alters the reinforcing effects of heroin. Since 1968, when it was first demonstrated that prior dependence is not required for animals to initiate self-administration of abused drugs, very few studies have examined self-administration behavior in opioid-dependent subjects. The proposed research is designed to address questions of whether and how reinforcing effects of opioids are altered as a function of dependence, including dependence that results from identified pharmacotherapies for heroin addiction, e.g., buprenorphine. We have developed innovative self-administration procedures in which full dose-effect functions for the relative reinforcing strength of IV heroin can be rapidly determined. In these novel choice procedures, subjects learn to distribute their behavior throughout the session on the basis of the relative reinforcing strong features of an IV solution that is available for self-injection and an alternative reinforcer (food). These procedures are especially designed to divorce the reinforcing strength of drugs from other behavioral effects. In proposed studies, the self-administration of heroin and other opioid agonists will be determined under varying conditions of response cost to evaluate contextual influences on relative reinforcing strength. Next, studies will be conducted to determine how the relative reinforcing strength of heroin is modulated by acute treatment and chronic treatment with morphine-like drugs. Preliminary data indicate that the reinforcing strength of heroin in nondependent subjects can be predictably altered by treatment with other opioids or by changes in response cost, confirming the utility of these procedures for studies of the relative reinforcing strength of self-administered heroin. Following completion of these studies, alteration in the reinforcing strength of heroin will be gauged in relation to aspects of tolerance and dependence that develop during chronic treatment. Lastly, planned experiments will address the modification of heroin's reinforcing effects by nonopioid drugs, specifically GABA-A agonists. These studies are designed to empirically address questions raised by high rates of benzodiazepine abuse by opioid-addicted populations. Overall, the proposed studies will provide significant advances for evaluating contextual or pharmacological modifications of the reinforcing strength of heroin in nondependent and opioid-dependent individuals. Results of these studies will improve our ability to assess the effectiveness with which agonist-based medications may combat its addictive power.