赖氨酸右旋苯丙胺作为可卡因成瘾激动剂候选药物的临床前评估：对经训练能在可卡因与食物选择程序中辨别可卡因或自行服用可卡因的恒河猴的影响。
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.
作者信息
Banks Matthew L, Hutsell Blake A, Blough Bruce E, Poklis Justin L, Negus S Stevens
机构信息
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough)
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA (Drs Banks, Hutsell, Negus, and Mr Poklis); Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA (Drs Banks and Negus); Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC (Dr Blough).
出版信息
Int J Neuropsychopharmacol. 2015 Jan 24;18(8):pyv009. doi: 10.1093/ijnp/pyv009.
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 = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.
RESULTS
In the cocaine-discrimination procedure, lisdexamfetamine (0.32-3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032-0.32mg/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 (0-0.1mg/kg/injection, i.v.) and food (1g 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 (0.32-3.2mg/kg/day, i.m.) or d-amphetamine (0.032-0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/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.
背景
在临床前和人体实验室研究以及临床试验中，长期使用苯丙胺治疗可减少可卡因的摄入量。赖右苯丙胺是一种苯丙胺前体药物，其中L-赖氨酸与d-苯丙胺的末端氮结合。由于起效较慢和作用持续时间较长，前体药物相对于其活性代谢物可能具有优势；然而，赖右苯丙胺治疗在减少可卡因摄入量方面的疗效尚不清楚。
方法
本研究使用两种行为程序比较了赖右苯丙胺和d-苯丙胺对恒河猴的影响：（1）可卡因辨别程序（训练剂量 = 0.32mg/kg可卡因，肌肉注射）；（2）可卡因与食物选择自我给药程序。
结果
在可卡因辨别程序中，赖右苯丙胺（0.32 - 3.2mg/kg，肌肉注射）替代可卡因时，其效力低于d-苯丙胺（0.032 - 0.32mg/kg，肌肉注射），起效较慢，作用持续时间较长。与赖右苯丙胺作为苯丙胺无活性前体药物的功能一致，赖右苯丙胺作用的时间进程通过逆时针滞后环与d-苯丙胺血浆水平相关。在选择程序中，可卡因（0 - 0.1mg/kg/注射，静脉注射）和食物（1g香蕉味颗粒）同时可用，并且在基线条件下，可卡因维持了可卡因选择的剂量依赖性增加。连续7天用赖右苯丙胺（0.32 - 3.2mg/kg/天，肌肉注射）或d-苯丙胺（0.032 - 0.1mg/kg/小时，静脉注射）治疗，在可卡因剂量 - 效应曲线中产生了类似的剂量依赖性右移，并降低了对0.
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