Delay discounting: effects of drug dependence and withdrawal

描述（由申请人提供）：冲动，即未经思考或深思熟虑就采取行动的倾向增加，在精神疾病中很常见，经常在药物滥用者中观察到。虽然冲动性可能是一种促成药物滥用发展的诱发特征，但也可能是吸毒的结果，从而促进持续滥用和可能复发。研究考察了急性给药如何影响冲动性;然而，大多数药物滥用涉及重复给药，通常会产生身体依赖性，但很少有研究考察冲动性如何受到长期给药及其停药的影响。冲动是多方面的，已经开发了几个程序来研究冲动的不同但同样重要的维度;在一个程序中，延迟折扣，受试者在没有延迟的情况下提供的较小的折扣和延迟后提供的较大的折扣之间进行选择。对较小的、立即可用的刺激物的反应增加被认为反映了更大的冲动性。本申请中的研究检查了急性和慢性阿片类药物治疗及其停药对动物延迟折扣的影响，因为人类延迟折扣对阿片类药物治疗及其停药敏感。来自人类的数据表明，冲动导致药物滥用，药物滥用增加冲动;延迟折扣也可能因不同的药物而异（例如，金钱与毒品）。拟议的研究建立在初步数据的基础上，这些数据表明，延迟折扣受到每天服用非常小剂量吗啡的影响，这表明即使是小剂量药物的滥用（例如，处方阿片类药物）可以显着增加冲动。这些研究检查了用原型5阿片受体激动剂（吗啡）的急性和慢性治疗以及停止治疗如何影响成年雄性恒河猴的延迟折扣。AIM 1项下的研究建立在初步研究的基础上，并比较了对非药物治疗有反应的猴子中延迟折扣的急性药物效应与对药物治疗有反应的猴子中的效应;这些研究测试了当通过不同的药物维持反应时延迟折扣是否发生差异性改变，并测试了这些药物效应的药理学选择性。AIM 2使用相同的猴子，评估了吗啡长期治疗及其停药如何改变非药物和药物强化程序下的延迟折扣;这些研究检查了每日治疗对延迟折扣的影响，是否对这些影响产生耐受性，停药如何改变延迟折扣，以及这种冲动性测量的变化时间过程如何与戒断指数相关。这些研究检查了未探索的可能性，即滥用即使是小剂量的阿片类药物也会增加可能持久的冲动;冲动的增加可能会导致持续的药物滥用，复发和其他高风险行为，在药物戒断后很长时间内不再明显。

DESCRIPTION (provided by applicant): Impulsivity, an increased tendency to act without thought or deliberation, is common in psychiatric disorders and often is observed in drug abusers. Although impulsivity might be a predisposing trait that contributes to the development of substance abuse, it might also be a result of drug use, thereby promoting ongoing abuse and possibly relapse. Studies have examined how acute administration of drugs affects impulsivity; however, most drug abuse involves repeated drug administration and often the development of physical dependence, yet few studies have examined how impulsivity is affected by chronic drug administration and its discontinuation. Impulsivity is multidimensional and several procedures have been developed for studying different but equally important dimensions of impulsivity; in one procedure, delay discounting, subjects choose between a smaller reinforcer that is delivered without delay and a larger reinforcer that is delivered after a delay. Increased responding for the smaller, immediately available reinforcer is thought to reflect greater impulsivity. Studies in this application examine effects of acute and chronic opioid treatment, and its discontinuation, on delay discounting in animals because in humans delay discounting is sensitive to opioid treatment and its discontinuation. Data from humans suggest that impulsivity contributes to drug abuse and that drug abuse increases impulsivity; delay discounting might also vary across different reinforcers (e.g., money versus drug). Proposed studies build on preliminary data showing that delay discounting is affected by daily administration of very small doses of morphine, suggesting that abuse of even small doses of drugs (e.g., prescription opioids) could significantly increase impulsivity. These studies examine how acute and chronic treatment with a prototypic 5 opioid receptor agonist (morphine), as well as discontinuation of treatment, impact delay discounting in adult male rhesus monkeys. Studies under AIM 1 build on preliminary studies and compare acute drug effects on delay discounting in monkeys responding for a non-drug reinforcer to effects in monkeys responding for a drug reinforcer; these studies test whether delay discounting is differentially altered when responding is maintained by different reinforcers and also test the pharmacologic selectively of these drug effects. Using the same monkeys, AIM 2 evaluates how chronic treatment with morphine and its discontinuation alter delay discounting under the non-drug and drug reinforced procedures; these studies examine the effects of daily treatment on delay discounting, whether tolerance develops to those effects, how discontinuation modifies delay discounting, and how the time course of changes in this measure of impulsivity correlates with indices of withdrawal. These studies examine the unexplored possibility that abuse of even small doses of opioids increases impulsivity that can be enduring; increased impulsivity might contribute to ongoing drug abuse, relapse, and other high risk behavior long after drug withdrawal is no longer evident.