Translational Approach to Models in Relapse

描述（由申请人提供）：药物滥用是一种慢性复发性疾病。实验动物的药物恢复和人类的药物复发之间存在关键差异。本提案的第一个目标是在寻求未经治疗的人类可卡因滥用者和非人类灵长类动物中建立平行的复发实验室模型。我们将近似于临床情况，即吸毒率开始高（基线），然后变低（治疗），然后又经常变高（复发），通过使用行为偶然性来产生低可卡因摄入量。我们将通过为参与者提供在药物和替代强化物之间进行选择的机会来模拟个体在治疗中做出的选择。一旦我们确定了产生低吸毒率所需的行为偶然性，第二个目标是检查单次自我服用可卡因对可卡因选择的影响，即可卡因诱导的复发。与治疗一样，与传统的恢复模型不同，在所有的测试过程中，人类和非人类灵长类动物都可以使用可卡因，而不是安慰剂。目标1：确定一组行为偶然性，这将有效地减少选择自我管理可卡因。我们将通过增加获得一剂可卡因的工作量来增加选择可卡因的成本，我们将通过增加人类在机会游戏中赚钱的概率来增加替代可卡因的强化物的价值，并通过增加非人类灵长类动物的首选食物来增加替代可卡因的价值。我们假设：1)可卡因的选择将随着可卡因成本的增加和可卡因使用替代品价值的增加而减少；2)在选择环节之前立即自我服用一剂“免费”可卡因（免费或无替代品）将以剂量依赖的方式增加可卡因的选择水平，即可卡因诱发复发。目标2：通过确定维持莫达非尼对可卡因选择和可卡因诱导复发的影响，为新模型提供“概念证明”。莫达非尼是一种已被证明在治疗可卡因滥用方面具有临床效用的警示剂。我们假设维持莫达非尼会减少可卡因的选择和可卡因诱导的复发。我们将模拟复发的基本方面：寻求非治疗的人类和非人类灵长类动物将根据他们必须为药物努力的程度以及他们必须放弃非药物替代品的程度来决定是否开始使用药物。人类和非人类灵长类动物的平行设计将使我们能够同时完善目前的临床前实验动物和人类复发模型，从而提高我们开发更有效的策略来减少药物复发的能力。

DESCRIPTION (provided by applicant): Drug abuse is a chronic relapsing disorder. Key differences exist between drug reinstatement in laboratory animals and drug relapse in humans. The first objective of this proposal is to develop parallel laboratory models of relapse in non-treatment seeking human cocaine abusers and in nonhuman primates. We will approximate the clinical situation, where rates of drug taking start off high (baseline), then become low (treatment) and then often become high again (relapse), by using behavioral contingencies to produce low rates of cocaine intake. We will model the choices made by individuals in treatment to take drug by providing participants opportunities to choose between drug and an alternative reinforcer. Once we have established the behavioral contingencies needed to produce a low rate of drug taking, the second objective is to examine the effect of a single self-administered dose of cocaine on cocaine choice, i.e., cocaine- induced relapse. As in treatment, and in contrast to traditional reinstatement models, both humans and non- human primates will have access to cocaine, not placebo, during all test sessions. Aim 1: Determine a set of behavioral contingencies that will be effective in decreasing the choice to self- administer cocaine. We will increase the cost of choosing cocaine by increasing the work requirement to obtain a dose, and we will increase the value of the alternative reinforcer to cocaine by increasing the probability of earning money in a game of chance in humans, and a preferred food treat in nonhuman primates. We hypothesize that 1) cocaine choice will decrease with increasing cocaine cost and with increasing value of the alternative to cocaine use; and 2) a single dose of "free" cocaine (available without cost or alternatives) self-administered immediately before the choice session will increase the level of cocaine choice in a dose-dependent manner, i.e., cocaine-induced relapse. Aim 2: Provide "proof of concept" for the new model by determining the effect of maintenance on modafinil, an alerting agent that has demonstrated clinical utility in treating cocaine abuse, on cocaine choice and cocaine-induced relapse. We hypothesize that maintenance on modafinil will decrease cocaine choice and cocaine-induced relapse. We will model essential aspects of relapse: non-treatment seeking humans and nonhuman primate's will make decisions to initiate drug use based on how hard they will have to work for drug and how much they will have to forego in non-drug alternatives. The parallel design for humans and nonhuman primates will allow us to simultaneously refine current preclinical laboratory animal and human models of relapse, and thereby improve our ability to develop more effective strategies for decreasing relapse to drug use.