Delay discounting: effects of drug dependence and withdrawal

描述（由申请人提供）：冲动，一种不经思考或考虑就采取行动的倾向，在精神疾病中很常见，经常在药物滥用者身上观察到。虽然冲动可能是导致药物滥用的一个易感特征，但它也可能是药物使用的结果，从而促进持续滥用和可能复发。研究已经检验了急性用药是如何影响冲动的；然而，大多数药物滥用涉及重复用药和经常发展的身体依赖，但很少有研究调查冲动性如何受到长期用药和停药的影响。冲动性是多维的，已经开发了几种方法来研究冲动性的不同但同样重要的维度；在一个过程中，延迟折扣，受试者在一个没有延迟的较小的强化物和一个延迟后交付的较大的强化物之间做出选择。对较小的、立即可用的强化物的反应增强被认为反映了更大的冲动性。本应用的研究考察了急性和慢性阿片类药物治疗及其停药对动物延迟贴现的影响，因为人类延迟贴现对阿片类药物治疗及其停药敏感。来自人类的数据表明，冲动会导致药物滥用，而药物滥用会增加冲动；延迟折扣也可能因不同的强化因素而异（例如，金钱与药物）。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，这表明滥用即使是小剂量的药物（例如处方阿片类药物）也会显著增加冲动。这些研究考察了典型阿片受体激动剂（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贴现。AIM 1下的研究建立在初步研究的基础上，比较了对非药物强化剂反应的猴子对延迟折扣的急性药物效应和对药物强化剂反应的猴子的效应；这些研究测试了当反应被不同的强化物维持时，延迟折扣是否会有不同的改变，并测试这些药物作用的药理学选择性。使用相同的猴子，AIM 2评估慢性吗啡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；这些研究考察了日常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。这些研究考察了一种未被探索的可能性，即即使是小剂量的阿片类药物滥用也会增加持久的冲动性；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，即使在停药后很长一段时间也不再明显。

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. PUBLIC HEALTH RELEVANCE: Impulsivity puts you at risk for drug abuse, but might also be caused by it, although little is known about how drug use, especially chronic drug use, impacts impulsivity. This grant examines the effects of chronic drug administration and its discontinuation (withdrawal) on delay discounting to determine how common drugs of abuse affect impulsivity.