Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys
Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys
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DOI：
10.1017/s146114571300059x
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发表时间：
2013-10-01
影响因子：
4.8
通讯作者：
Mello, Nancy K.
中科院分区：
文献类型：
--
作者：
Kohut, Stephen J.;Fivel, Peter A.;Mello, Nancy K.
具有不同选择性的多巴胺(DA)/去甲肾上腺素(DA)和5-羟色胺(5-HT)释放的单胺释放剂是治疗可卡因滥用的潜在药物。尽管DA选择性单胺释放剂有效地减少了可卡因的滥用，但它们的临床用途受到滥用倾向的限制。假设增加5-羟色胺的神经传递可以减少DA释放剂的滥用相关作用，但最佳的DA：5-羟色胺释放量比例仍有待确定。这项在恒河猴身上的研究比较了两种不同效力的化合物对5-羟色胺释放的影响。美卡西酮和3-氯-美卡西酮(PAL-434)对DA的释放量相同，但PAL-434对5-羟色胺的释放量比PAL-434高10倍。在药物辨别研究中，训练猴子辨别可卡因(0.4毫克/公斤肌肉注射)。在两个关键的食物强化程序中从生理盐水中脱脂。在药物自我给药研究中，另一组猴子被训练对可卡因[0.01毫克/公斤/注射(INJ)]和食物(1克颗粒)做出反应，强化的二级时间表[Fr2(VR16：S)]。反应稳定时，给予美卡西酮(0.1-0.56 mg/kg)。HIV.)或PAL-434(0.32-1.8 mg/kg.HIV.)在辨别研究中，两种化合物均呈剂量依赖性地增强类可卡因反应，但效力不同(可卡因=美卡西酮；PAL-434)。长期使用美卡西酮或PAL-434可剂量依赖性和选择性地减少可卡因的自我给药。PAL-434在减少可卡因-食物维持反应方面的效力约为4倍，美卡西酮约为1.6倍。这些数据表明，对DA具有中等选择性的化合物与5-羟色胺释放(8-15倍)相比，可能对治疗可卡因依赖有效。
Monoamine releasers with varying selectivity for dopamine (DA)/norepinephrine and serotonin (5-HT) release are potential treatment medications for cocaine abuse. Although DA-selective monoamine releasers effectively reduce cocaine abuse, their clinical usefulness is limited by abuse liability. It is hypothesized that increasing 5-HT neurotransmission may reduce the abuse-related effects of DA releasers, but the optimal DA: 5-HT release ratio remains to be determined. This study in rhesus monkeys compared the effects of two compounds with differing potency for 5-HT release. Methcathinone and 3-Cl-methcathinone (PAL-434) have equal potency for DA release, but PAL-434 has 10-fold higher potency for 5-HT release. In drug discrimination studies, monkeys were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline in a two-key, food-reinforced procedure. In drug self-administration studies, a separate group of monkeys was trained to respond for cocaine [0.01 mg/kg/injection (inj)] and food (1 g pellets) under a second order schedule of reinforcement [FR2(VR16:S)]. When responding was stable, methcathinone (0.1-0.56 mg/kg. h i.v.) or PAL-434 (0.32-1.8 mg/kg. h i.v.) was administered chronically (one injection every 20 min for 23 h/d) for 7-10 d. In discrimination studies, both compounds dose-dependently increased cocaine-like responding but with different potencies (cocaine=methcathinone>PAL-434). Chronic treatment with methcathinone or PAL-434 dose-dependently and selectively reduced cocaine self-administration. PAL-434 was about 4-fold and methcathinone about 1.6-fold more potent at decreasing cocaine-over food-maintained responding. These data suggest that compounds with moderate selectivity for DA vs. 5-HT release (8-15-fold) may be effective for the treatment of cocaine dependence.