Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: Studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys
Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: Studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys
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DOI：
10.1124/jpet.106.107383
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Rothman, R. B.
中科院分区：
文献类型：
--
作者：
Negus, S. S.;Mello, N. K.;Rothman, R. B.
单胺释放剂是正在调查的一类药物，作为治疗可卡因滥用的候选药物。苯丙胺与5-羟色胺相比，在释放多巴胺/去甲肾上腺素方面具有很高的选择性，已经取得了良好的临床前和临床结果。然而，安非他明作为一种药物疗法的使用因其高度的滥用潜力而变得复杂。最近的临床前研究表明，非选择性单胺释放剂或5-羟色胺选择性释放剂具有较低的滥用倾向，可能值得作为苯丙胺的替代品进行评估。为了解决这个问题，本研究评估了五种单胺释放剂在恒河猴可卡因辨别和可卡因自我给药试验中的效果。释放物从多巴胺/去甲肾上腺素选择性到5-羟色胺选择性[间氟苯丙胺(PAL-353)、甲基苯丙胺、间甲基苯丙胺(PAL-314)、1-萘基-2-氨基丙烷(PAL-287)、芬氟拉明]。在药物辨别研究中，研究人员训练恒河猴区分生理盐水和可卡因(0.4毫克/公斤肌肉注射)。在两个关键的，食物强化的药物歧视程序中。可卡因的替代与多巴胺/去甲肾上腺素的选择性与5-羟色胺的释放呈正相关。在药物自我给药研究中，恒河猴对可卡因(0.01和0.032 mg/kg/针)和食物(1-g颗粒)的反应按二级固定比例2(可变比例16：S)进行。总体而言，单胺释放剂导致可卡因自身给药的剂量依赖性和持续性减少。然而，多巴胺/去甲肾上腺素选择性释放剂减少了可卡因的自我给药，对食物维持的反应影响很小，而更多的5-羟色胺选择性释放者在可卡因和食物维持的反应中都产生了非选择性的减少。这些结果与以下结论一致，即多巴胺/去甲肾上腺素选择性释放剂保留了类似于可卡因滥用的相关效应，但也可能能够相对选择性地减少可卡因的增强效应。
Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin- selective [ m- fluoroamphetamine ( PAL- 353), methamphetamine, m- methylamphetamine ( PAL- 314), 1-napthyl- 2- aminopropane ( PAL- 287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine ( 0.4 mg/ kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/ norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food ( 1-g pellets) under a second- order fixed- ratio 2 ( variable-ratio 16: S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/ norepinephrine-selective releasers decreased cocaine self- administration with minimal effects on food-maintained responding, whereas the more serotonin- selective releasers produced nonselective reductions in both cocaine-and food-maintained responding. These results are consistent with the conclusion that dopamine/ norepinephrine- selective releasers retain cocaine- like abuse- related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.