Effects of Negative Consequences on Drug Self Administration in Rats

描述（由申请方提供）：拟定研究的主要目的是开发一种啮齿动物自我给药（SA）模型，其中药物消耗具有延迟的负面后果。自我管理程序，其中动物作出的反应，加强了静脉注射药物被广泛使用，也许是最令人信服的非人类动物模型的药物滥用。然而，非人动物SA模型可能无法模拟人药物SA的重要方面。在人类中，冲动被认为是药物滥用的一个重要组成部分，因为尽管知道与药物使用相关的负面（通常是延迟的）结果，但个人仍然服用药物。相比之下，SA的标准实验室动物模型没有与药物SA相关的明确的负面结果。由于目前没有SA模型，包括负面后果，负面结果的影响一般不纳入目前的想法有关的行为和神经生物学机制介导的药物滥用。本申请的实验1的目的是确定具有等同强化功效的可卡因剂量和水量。在本申请中，使用增强的渐进比率时间表来测量增强功效。在渐进比率计划中，强化功效在操作上被定义为断点（BP），其指示动物将对给定强化剂的渐进比率计划做出的最大响应次数。确定具有等效功效的可卡因剂量和水的量将确保在实验2和3中使用具有等效增强功效的可卡因和水稀释剂。实验2将使用强化的渐进比率时间表来确定即时休克是否对药物和天然增强剂的强化功效具有不同的影响。在实验1和2的基础上，实验3将确定延迟休克对可卡因/休克和水/休克抑制剂的增强功效的影响。这些研究将通过确定惩罚或延迟惩罚是否对具有同等强化功效的药物（可卡因）和天然（水）兴奋剂具有相似（或不同）的影响，从而促进我们对药物滥用的理解。这些结果将有助于确定，如果一个“惩罚”SA模型是一个有价值的工具，调查药物滥用的行为和认知调节的负面后果。公共卫生相关性：本研究的主要目的是建立一种啮齿类动物自我给药（SA）模型，在该模型中，药物消耗延迟了负面后果。毫无疑问，非人类动物SA程序模拟了人类吸毒的重要方面;然而，在某些方面，该模型在实验室中的典型应用并没有模拟人类成瘾者吸毒的重要方面。根据《精神疾病诊断和统计手册》（阿帕，1994年），人类药物成瘾的一个重要特征是尽管有有害后果，但仍持续摄入药物。然而，目前的非人类药物滥用动物模型并没有解决这个重要的问题。因此，负面结果的影响通常没有被纳入目前关于介导药物滥用的潜在行为和神经生物学机制的想法。我们认为，人类的药物滥用是两个独立过程的功能，“奖励”对药物的积极情感反应和“冲动相关”因素，或通常抑制或限制药物使用的影响。开发一个非人类的SA模型，并纳入负面影响，将加强对药物戒断所必需的“冲动相关因素”的研究。

DESCRIPTION (provided by applicant): The primary objective of the proposed research is to develop a rodent model of self administration (SA) in which drug consumption has delayed negative consequences. Self administration procedures in which the animals make responses that are reinforced by IV drug injections are widely used and are perhaps the most convincing non-human animal models of drug abuse. Non-human animal SA models, however, may not model important aspects of human drug SA. In humans, impulsivity is considered an important component of drug abuse because individuals take drugs despite the knowledge of negative (often delayed) outcomes associated with drug use. In contrast, standard laboratory animal models of SA have no explicit negative outcomes associated with the SA of the drug. Because there are currently no SA models that incorporate negative consequences, the impact of negative outcomes is not generally incorporated into current ideas about the underlying behavioral and neurobiological mechanisms mediating drug abuse. The goal of the Experiment 1 of this application is to determine a dose of cocaine and an amount of water that have equivalent reinforcing efficacy. In this application reinforcing efficacy is measured using progressive ratio schedules of reinforcement. In progressive ratio schedules, reinforcement efficacy is operationally defined as the break point (BP) which indicates the maximum number of responses an animal will make on a progressive ratio schedule of reinforcement for a given reinforcer. Determination of a dose of cocaine and an amount of water that have equivalent efficacy will insure that cocaine and water reinforcers of equivalent reinforcing efficacy are used In Experiments 2 and 3. Experiment 2 will determine if immediate shock has different effects on the reinforcing efficacy of drug and natural reinforcers using the progressive ratio schedule of reinforcement. Building upon Experiments 1 and 2, Experiment 3 will determine the effects of delaying the shock on the reinforcing efficacy of the cocaine/shock and water/shock reinforcers. These studies will advance to our understanding of drug abuse by determining if punishment or delays to punishment have similar (or dissimilar) effects on drug (cocaine) and natural (water) reinforcers of equivalent reinforcing efficacy. These results will help to determine if a "punished" SA model is a valuable tool with which to investigate the behavioral and cognitive regulation of drug abuse by negative consequences. PUBLIC HEALTH RELEVANCE: The primary objective of the proposed research is to develop a rodent model of self administration (SA) in which drug consumption has delayed negative consequences. There is little doubt that non-human animal SA procedures model important aspects of drug taking in humans; however in some respects the typical application of this model in the laboratory does not model important aspects of drug consumption by human addicts. According to the Diagnostic and Statistical Manual of Mental Disorders (APA, 1994) an important characteristics of human drug addiction is continued drug intake despite harmful consequences. However, current non human animal models of drug abuse do not address this important issue. Consequently, the impact of negative outcomes is not generally incorporated into current ideas about the underlying behavioral and neurobiological mechanisms mediating drug abuse. We believe that drug abuse in humans is a function of two separate processes, "rewarding" positive affective responses to the drug and "impulsivity-related" factors, or influences that normally inhibit or limit the use of drugs. Development of a non human SA model that incorporates negative consequences will enhance research into "impulsivity-related factors" that are necessary for drug abstinence.