Effects of Negative Consequences on Drug Self Administration in Rats

描述（由申请人提供）：拟议研究的主要目的是开发一种自我给药（SA）的啮齿动物模型，其中药物消费延迟了负面后果。在自我给药程序中，动物做出反应，通过静脉注射药物得到加强，这一程序被广泛使用，可能是最令人信服的非人类药物滥用动物模型。然而，非人类动物SA模型可能无法模拟人类药物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，因为人们不顾与药物使用相关的负面（通常是延迟的）结果而吸毒。相比之下，SA的标准实验动物模型没有与药物SA相关的明确负面结果。由于目前还没有纳入负面后果的SA模型，负面结果的影响通常没有纳入目前关于药物滥用的潜在行为和神经生物学机制的观点。本应用程序的实验1的目标是确定具有等效强化功效的可卡因剂量和水量。在这种应用中，钢筋效能是用钢筋的递进比率表来测量的。在递进比率计划中，强化效能在操作上被定义为断点（BP），它表示动物对给定强化物的递进比率计划将做出的最大反应数。确定具有同等功效的可卡因剂量和水的量将确保在实验2和3中使用具有同等功效的可卡因和水增强剂。实验2将采用递进强化比例表来确定即刻休克对药物和天然强化剂的强化效果是否有不同的影响。在实验1和2的基础上，实验3将确定延迟刺激对可卡因/刺激和水/刺激增强剂增强效果的影响。这些研究将通过确定惩罚或延迟惩罚是否对药物（可卡因）和具有同等强化效果的自然（水）强化剂有相似（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“惩罚”SA模型是否是一个有价值的工具，用于研究药物滥用的负面后果的行为和认知调节。公共卫生相关性：拟议研究的主要目的是开发一种自我给药（SA）的啮齿动物模型，其中药物消费延迟了负面后果。毫无疑问，非人类动物SA程序模拟了人类服药的重要方面；然而，在某些方面，该模型在实验室的典型应用并没有模拟人类成瘾者吸毒的重要方面。根据《精神疾病诊断与统计手册》（APA, 1994），人类吸毒成瘾的一个重要特征是不顾有害后果继续吸毒。然而，目前的非人类药物滥用动物模型并没有解决这一重要问题。因此，负面结果的影响通常没有纳入目前关于潜在的行为和神经生物学机制介导药物滥用的想法。我们认为，人类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。一个包含负面后果的非人类SA模型的发展将加强对“冲动相关因素”的研究，这是戒断药物所必需的。

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.