Nonhuman Primate Neuroimaging and Cocaine Medication Development
Nonhuman Primate Neuroimaging and Cocaine Medication Development
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DOI：
10.1037/a0014196
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发表时间：
2008-12-01
影响因子：
2.3
通讯作者：
Howell, Leonard L.
中科院分区：
文献类型：
--
作者：
Howell, Leonard L.
鉴于多巴胺转运体（DAT）在可卡因成瘾特性中的重要作用，针对DAT的化合物的开发和使用代表了可卡因滥用药物治疗的合理方法。本报告描述了在非人类灵长类动物中进行的一系列研究，这些研究评估了DAT抑制剂在减少可卡因自我给药方面的有效性。此外，药物替代研究评估了DAT抑制剂的滥用风险。正电子发射断层扫描神经成像研究量化了行为相关剂量下的DAT占用，表征了脑内药物摄取的时间过程，并记录了药物引起的脑血流变化作为脑激活的模型。选择性DAT抑制剂在减少可卡因使用方面是有效的，但高（约70%）的DAT占用水平与可卡因自我给药的显著减少有关。选择性DAT抑制剂是可靠的自我施用，但即使在较高的DAT占用水平下，应答率也低于可卡因维持的应答率。脑内缓慢的药物摄取速率伴随着细胞外多巴胺的逐渐增加，这可能是DAT抑制剂增强效果有限的原因。选择性血清素转运体（SERT）抑制剂在减少可卡因使用和阻断可卡因诱导的大脑激活和细胞外多巴胺增加方面也有效。SERT抑制剂与选择性DAT抑制剂联合使用比单独使用DAT抑制剂更有效，即使在DAT占用水平相当的情况下也是如此。结果表明，联合抑制DAT和SERT可能是治疗可卡因成瘾的可行方法。
Given the important role of the dopamine transporter (DAT) in the addictive properties of cocaine, the development and use of compounds that target the DAT represents a reasonable approach for the pharmacological treatment of cocaine abuse. The present report describes a series of studies conducted in nonhuman primates that evaluated the effectiveness of DAT inhibitors in reducing cocaine self-administration. In addition, drug substitution studies evaluated the abuse liability of the DAT inhibitors. Positron emission tomography neuroimaging studies quantified DAT occupancy at behaviorally relevant doses, characterized the time-course of drug uptake in brain, and documented drug-induced changes in cerebral blood flow as a model of brain activation. Selective DAT inhibitors were effective in reducing cocaine use but high (>70%) levels of DAT occupancy were associated with significant reductions in cocaine self-administration. The selective DAT inhibitors were reliably self-administered but rates of responding were lower than those maintained by cocaine even at higher levels of DAT occupancy. A profile of slow rate of drug uptake in brain accompanied by a gradual increase in extracellular dopamine may account for the more limited reinforcing effectiveness of the DAT inhibitors. Selective serotonin transporter (SERT) inhibitors were also effective in reducing cocaine use and blocked cocaine-induced brain activation and increases in extracellular dopamine. Coadministration of SERT inhibitors with a selective DAT inhibitor was more effective than the DAT inhibitor administered alone, even at comparable levels of DAT occupancy. The results indicate that combined inhibition of DAT and SERT may be a viable approach to treat cocaine addiction.