Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys
Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys
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DOI：
10.1124/jpet.116.236307
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发表时间：
2016-12-01
影响因子：
3.5
通讯作者：
France, Charles P.
中科院分区：
文献类型：
--
作者：
Gerak, Lisa R.;Collins, Gregory T.;France, Charles P.
兴奋剂滥用是一个严重的公共卫生问题，目前尚无有效的药物治疗方法。血清素 (2C) [5-羟色胺 (2C) (5-HT2C)] 受体激动剂氯卡色林可减少猴子中可卡因滥用的一些影响，并可能有助于治疗兴奋剂滥用。目前的研究调查了氯卡色林减少自我服用可卡因或甲基苯丙胺以及可卡因引起的已消失反应恢复的有效性。四只恒河猴按照渐进比例（PR）方案做出反应，其中每次可卡因输注（32-320μg/kg/输注）后响应要求增加。另一组四只猴子按照可卡因固定比例（FR）方案（32μg/kg/输注）做出反应，并在给予非偶然输注可卡因（0.1-1mg/kg）并结合药物相关刺激的反应相关表现后检查已消失的反应的恢复情况。最后，三只猴子在 FR 方案下对甲基苯丙胺（0.32-100 μg/kg/输注）做出反应。氯卡色林（3.2 mg/kg）显着降低了猴子在 PR 计划下做出反应的最终完成比率（即降低了断点），并减少了非偶然输注可卡因后对药物相关刺激的反应恢复；当每天服用氯卡色林时，这些作用似乎没有改变。相同剂量的氯卡色林降低了三只猴子中的两只对甲基苯丙胺的反应，并且在每日施用氯卡色林期间维持了这种效果；急性给予较大剂量（10-17.8 mg/kg）显着降低对甲基苯丙胺的反应，尽管这种作用在每日氯卡色林给药期间并未持续。总之，这些结果表明氯卡色林可能有效减少可卡因和甲基苯丙胺滥用以及至少在某些个体中的可卡因复发。
Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin(2C) [5-hydroxytryptamine(2C) (5-HT2C)] receptor agonist lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive-ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32-320 mu g/kg/infusion). A separate group of four monkeys responded under a fixed-ratio (FR) schedule for cocaine (32 mu g/kg/infusion) and reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.1-1 mg/kg) that were combined with response-contingent presentations of the drug-associated stimuli. Finally, three monkeys responded under a FR schedule for methamphetamine (0.32-100 mu g/kg/infusion). Lorcaserin (3.2 mg/kg) significantly decreased the final ratio completed (i.e., decreased break point) in monkeys responding under the PR schedule and reduced the reinstatement of responding for drug-associated stimuli following a noncontingent infusion of cocaine; these effects did not appear to change when lorcaserin was administered daily. The same dose of lorcaserin decreased responding for methamphetamine in two of the three monkeys, and the effect was maintained during daily lorcaserin administration; larger doses given acutely (10-17.8 mg/kg) significantly decreased responding for methamphetamine, although that effect was not sustained during daily lorcaserin administration. Together, these results indicate that lorcaserin might be effective in reducing cocaine and methamphetamine abuse and cocaine relapse at least in some individuals.