Delay discounting: effects of drug dependence and withdrawal

描述(由申请人提供)：冲动，一种未经思考或深思熟虑而采取行动的增加的倾向，在精神障碍中很常见，通常在吸毒者中观察到。尽管冲动可能是导致药物滥用的诱因，但它也可能是药物使用的结果，从而促进持续的滥用和可能的复发。已有研究考察了急性用药对冲动的影响；然而，大多数药物滥用涉及重复用药，而且往往是身体依赖的形成，但很少有研究考察长期用药和停药对冲动的影响。冲动性是多维的，已经开发了几种程序来研究冲动性的不同但同样重要的维度；在一种名为延迟贴现的程序中，受试者在无延迟交付的较小增强剂和延迟交付后交付的较大增强剂之间进行选择。对于较小的、可立即获得的增强剂的响应增加被认为反映了更大的冲动。这项应用中的研究考察了急性和慢性阿片类药物治疗及其停止对动物延迟折扣的影响，因为在人类中，延迟折扣对阿片类药物治疗及其停止很敏感。来自人类的数据表明，冲动导致药物滥用，滥用药物会增加冲动；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，延迟折扣会受到每天服用非常小剂量的吗啡的影响，这表明滥用即使是小剂量的药物(如处方阿片类药物)也可能显著增加冲动。这些研究考察了典型的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，并比较了对非药物增强剂反应的猴子和对药物增强剂反应的猴子的延迟折扣的急性药物效应；这些研究测试了不同的增强剂维持反应时延迟折扣是否有差异地改变，并测试了这些药物效果的药理学选择性。使用相同的猴子，AIM 2评估了在非药物和药物强化程序下，长期使用吗啡及其停药如何改变延迟折扣；这些研究检查了日常治疗对延迟折扣的影响，耐受性是否发展为这些影响，停药如何修改延迟折扣，以及这种冲动指标的变化过程如何与戒断指数相关。这些研究考察了一种未知的可能性，即滥用即使是小剂量的阿片类药物也会增加可以持续的冲动；增加的冲动可能会导致持续的药物滥用、复发和其他高风险行为，在戒毒很长一段时间后不再明显。

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.