Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys
Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys
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DOI：
10.1016/j.pbb.2005.01.004
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发表时间：
2005-03-01
影响因子：
3.6
通讯作者：
Howell, LL
中科院分区：
文献类型：
--
作者：
Ginsburg, BC;Kimmel, HL;Howell, LL
靶向多巴胺转运蛋白（DAT）的药物已被提议作为治疗可卡因滥用的药物疗法。因此，了解可卡因和DAT抑制剂之间的药理学相互作用至关重要。本研究的特点可卡因和几个DAT抑制剂（RTI-177，FECNT，RTI-112），不同的选择性单胺转运体的操作行为和在体内神经化学在松鼠猴之间的急性相互作用。RTI-177和FECNT是两种对去甲肾上腺素转运蛋白（NET）具有低亲和力的DAT抑制剂，对由刺激终止的固定间隔时间表维持的行为产生剂量依赖性刺激作用。与可卡因相比，RTI-177和FECNT起效较慢，作用持续时间较长。清醒猴子尾状核的体内微透析证实了细胞外多巴胺的剂量依赖性增加，对应于行为效应。在表征的药物中，据报道RTI-112对DAT、NET和5-羟色胺转运体（SERT）的结合选择性最低。有趣的是，RTI-112未能产生显着的行为刺激作用，其对细胞外多巴胺的影响在受试者之间差异很大。结果表明，DAT抑制剂的药理学特征可能受到多种单胺转运蛋白作用的影响。重要的是，当可卡因与行为刺激剂量的DAT抑制剂联合给药时，几乎没有证据表明行为或神经化学措施具有相加作用。(c)2005年爱思唯尔公司All rights reserved.
Drugs that target the dopamine transporter (DAT) have been proposed as pharmacotherapies to treat cocaine abuse. Accordingly, it is paramount to understand pharmacological interactions between cocaine and DAT inhibitors. The present study characterized acute interactions between cocaine and several DAT inhibitors (RTI-177, FECNT, RTI-112) that differed in selectivity for monoamine transporters on operant behavior and in vivo neurochemistry in squirrel monkeys. RTI-177 and FECNT, two DAT inhibitors with low affinity at norepinephrine transporters (NET), produced dose-dependent stimulant effects on behavior maintained by a fixed-interval schedule of stimulus termination. Compared to cocaine, RTI-177 and FECNT had a slower onset and longer duration of action. In vivo microdialysis in the caudate nucleus of awake monkeys confirmed dose-dependent increases in extracellular dopamine that corresponded to behavioral effects. Among the drugs characterized, RTI-112 is reportedly the least selective for binding to DAT, NET, and serotonin transporters (SERT). Interestingly, RTI-112 failed to produce significant behavioral-stimulant effects, and its effects on extracellular dopamine were highly variable across subjects. The results indicate that the pharmacological profile of DAT inhibitors may be influenced by actions at multiple monoamine transporters. Importantly, there was little evidence of additivity on behavioral or neurochemical measures when cocaine was administered in combination with behavioral-stimulant doses of the DAT inhibitors. (c) 2005 Elsevier Inc. All rights reserved.