MECHANISMS OF OPIATE AND STIMULANT DRUG REINFORCEMENT

描述：（申请人摘要） 该项目的主要长期目标是采用行为 药理学方法来研究neura 1底物的基础 滥用阿片类药物和兴奋剂。 朝着这个 最后，三个具体的目标，其中每一个都是为了建立 在此基础上，并延长在前九年完成的工作， 项目 这些是：1）继续调查假定的 多巴胺拮抗剂药物对阿片类药物的奖赏衰减作用， 兴奋剂强化行为; 2）进一步研究的作用， 药物自我给药和药物复发中的药物配对刺激;以及3） 继续研究长期服用可卡因的焦虑副作用。 推动这项工作的假设是，中枢多巴胺能（DA）系统 负责鸦片剂和兴奋剂的强化特性 毒品 虽然这一立场并不独特， 在这个项目中采取的是新颖的在一些方面：我），而传统的 压力测试程序检查了麻醉动物的行为， 维持他们的药物血浆水平，目前的项目检查IV药物 使用操作性跑道进行强化，其中动物仅接受一种药物 每天注射。 在这种情况下，Ss穿越 药物加固的通道在操作上提供了一个可靠的指标， 未受破坏动物获得许可证的动机; ii）通过测试 每天只有一次试验，所产生的数据缺乏潜在的 药物致敏剂产生的混杂和非特异性效应 （三）使用响应恢复测试来检查 导致跑道操作行为恢复的因素， 长期禁欲，因此作为一个可行的模型， 药物复发;和iv）在每项研究中，假定的 同时评估拮抗剂药物的减毒作用 当药物的直接药理作用不再存在时（即， 在第一次治疗后试验中注射后24小时）。 这允许 关于拮抗剂对操作行为的影响的结论， 被这些试验药物的镇静和运动副作用所混淆。 总之，本申请中提出的工作旨在提供 重要的新信息的性质和神经生物学的两个 积极和消极因素共同决定了 人类自我给药行为。

DESCRIPTION: (Applicant's Abstract) The primary long-term goal of this project is to employ behavioral pharmacological methods to investigate neura1 substrates underlying the self-administration of opiate and stimulant drugs of abuse. Toward this end, three specific aims are described each of which is intended to build upon and extend the work completed during the first nine years of this project. These are; 1) to continue investigations of the putative reward-attenuating actions of dopamine antagonist drugs on opiate- and stimulant-reinforced behaviors; 2) to further examine the role of drug-paired stimuli in drug self-administration and drug relapse; and 3) to continue investigations of the anxiogenic side effects of chronic cocaine. The hypothesis driving this work is that central dopaminergic (DA) systems are responsible for the reinforcing properties of both opiate and stimulant drugs. While this position is hardly unique, the methodological approach taken in this project is novel in a number of ways: I) while traditional lever-press procedures examine the behavior of drugged animals working to maintain their drug plasma levels, the current project examines IV drug reinforcement using an operant runway where animals received only one drug injection per day. In this context, the speed with which Ss traverse the alley for drug reinforcement has operationally provided a reliable index of the undrugged animals' motivation to obtain the reinforcer; ii) by testing only one trial per day, the resulting data are devoid of potential confounding and nonspecific effects produced by the drug reinforcers themselves; iii) a response reinstatement test is used to examine the factors that result in the reinstatement of operant runway behavior after a prolonged period of abstinence, and hence serves as a viable model of human drug relapse; and iv) in each of the studies, the putative reinforcement-attenuating actions of antagonist drugs are assessed at a time when the drug's direct pharmacological effects are no longer present (i.e., on the first post-treatment trial 24 hrs post-injection). This permits conclusions about antagonist effects on operant behavior that are not confounded by the sedative arrd motoric side-effects of these test agents. In summary, the work proposed in this application is intended to provide important new information about the nature and neurobiology of both the positive and negative factors that together determine the nature and extent of human drug self-administration behaviors.