Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure
Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure
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DOI：
10.1093/ijnp/pyv009
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发表时间：
2015-06-01
影响因子：
4.8
通讯作者：
Negus, S. Stevens
中科院分区：
文献类型：
--
作者：
Banks, Matthew L.;Hutsell, Blake A.;Negus, S. Stevens
背景：慢性安非他明治疗在临床前和人体实验室研究以及临床试验中减少可卡因的消耗。利地安非他明是一种安非他明前药，其中l -赖氨酸与d-安非他明的末端氮结合。由于起效较慢和作用持续时间较长，前药相对于其活性代谢物可能是有利的；然而，利地安非他明治疗在减少可卡因消费方面的功效尚不清楚。方法：采用两种行为程序比较利地安非他明和d-安非他明对恒河猴的影响：(1)可卡因辨别程序（训练剂量= 0.32 mg/kg可卡因，i.m）；(2)可卡因与食物选择的自我管理程序。结果：在可卡因鉴别过程中，利地安非他明（0.32 ~ 3.2 mg/kg, i.m）比d-安非他明（0.032 ~ 0.32 mg/kg, i.m）替代可卡因的效价更低、起效更慢、作用时间更长。利地安非他明作为非活性前药的作用，利地安非他明作用的时间过程与d-安非他明血浆水平呈逆时针的滞后环相关。在选择过程中，可卡因（0-0.1 mg/kg/静脉注射）和食物（1 g香蕉味颗粒）同时可用，在基线条件下，可卡因的选择保持剂量依赖性增加。连续7天服用利地安非他明（0.32-3.2 mg/kg/天，静脉注射）或d-安非他明（0.032-0.1 mg/kg/h，静脉注射），在可卡因剂量效应曲线上产生了类似的剂量依赖右移，并且0.032 mg/kg/注射可卡因的偏好降低。结论：利地安非他明比安非他明起效更慢，作用时间更长，但在恒河猴中保留了安非他明减少可卡因选择的功效。这些结果支持进一步考虑利地安非他明作为一种激动剂为基础的药物候选可卡因成瘾。
Background: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment's efficacy in decreasing cocaine consumption is unknown.Methods: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32 mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2 mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32 mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0-0.1 mg/kg/injection, i.v.) and food (1 g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32-3.2 mg/kg/day, i.m.) or d-amphetamine (0.032-0.1 mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032 mg/kg/injection cocaine.Conclusions: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine's efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist- based medication candidate for cocaine addiction.