Departments of Pharmacology (D.R.M., L.R.G., C.P.F.) and Psychiatry (C.P.F.), the University of Texas Health Science Center at San Antonio, San Antonio, Texas.
J Pharmacol Exp Ther. 2013 Dec;347(3):557-63. doi: 10.1124/jpet.113.208355. Epub 2013 Sep 16.
Drug abuse can be conceptualized as excessive choice of drug over other reinforcers, and factors that affect drug taking can be examined experimentally using choice procedures. This study examined the impact of reinforcer delay on self-administration of the μ-opioid receptor agonist remifentanil in rhesus monkeys (n = 4) lever pressing under a concurrent fixed-ratio 30 schedule. Responding on either lever delivered an intravenous infusion of either remifentanil or saline. Dose-effect curves were first determined when responding on one lever delivered remifentanil and responding on a second lever delivered saline. Monkeys then chose between two doses of remifentanil, and delay to delivery of the large dose was varied systematically. Responding for remifentanil (0.01-1.0 µg/kg/infusion) increased dose-dependently when the alternative was saline or a dose of remifentanil. Delaying delivery of the large dose of remifentanil by 30, 60, 120, or 240 seconds increased responding for smaller, immediately available doses (0.01-0.1 µg/kg/infusion) and, in some cases, increased responding for doses of remifentanil that did not maintain responding when the alternative was saline. These data demonstrate that delaying the delivery of an opioid receptor agonist can significantly affect its reinforcing effectiveness. The imposition of a delay reduces the effectiveness of large doses of drug to maintain responding and increases the effectiveness of immediately available commodities, including smaller doses of drug. Increased reinforcing effectiveness of smaller doses of drug in the context of other delayed reinforcers might contribute to the development and maintenance of opioid abuse.
药物滥用可以被概念化为对药物的过度选择，而其他强化物，影响药物摄入的因素可以使用选择程序进行实验性地检查。本研究使用恒比 30 程序检验了强化物延迟对恒速输注 μ-阿片受体激动剂瑞芬太尼自身给药的影响。在恒比 30 程序中，猴子（n=4）通过按压杠杆进行操作，每按压一次杠杆都会进行静脉输注瑞芬太尼或生理盐水。当按压一个杠杆时，药物为瑞芬太尼，而按压另一个杠杆时，药物为生理盐水，首先确定了剂量-效应曲线。然后，猴子在两种瑞芬太尼剂量之间进行选择，大剂量的给药时间被系统地延迟。当替代物为生理盐水或瑞芬太尼的剂量时，瑞芬太尼（0.01-1.0μg/kg/输注）的反应剂量依赖性地增加。将大剂量瑞芬太尼的给药时间延迟 30、60、120 或 240 秒，会增加对小剂量（0.01-0.1μg/kg/输注）药物的反应，在某些情况下，还会增加对生理盐水替代物时不能维持反应的瑞芬太尼剂量的反应。这些数据表明，延迟阿片受体激动剂的给药会显著影响其强化效果。延迟会降低大剂量药物维持反应的效果，并增加即时可得的商品的效果，包括较小剂量的药物。在其他延迟强化物的背景下，较小剂量药物的强化效果增加可能导致阿片类药物滥用的发生和维持。
