Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates
Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates
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DOI：
10.1007/s00213-002-1365-y
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发表时间：
2003-07-01
影响因子：
3.4
通讯作者：
Spealman, RD
中科院分区：
文献类型：
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作者：
Khroyan, TV;Platt, DM;Spealman, RD
理由。多巴胺 D-1 受体激动剂和拮抗剂可减弱非人灵长类复发模型中可卡因寻求的恢复。这些不同类别的 D-1 受体药物对可卡因寻求产生类似作用的机制尚不清楚。目标。本研究调查了 D-1 受体激动剂和拮抗剂如何改变剂量反应函数的形状和位置，以恢复由可卡因引发剂诱导的药物寻求，同时恢复可卡因配对刺激。方法。松鼠猴在二阶固定间隔、固定比例的静脉注射方案下被给予了广泛的可卡因自我给药史。药物注射。然后，通过用媒介物替代可卡因并消除可卡因配对的刺激，从而消除了寻求毒品的行为。在随后的测试过程中，重新引入可卡因配对刺激，单独注射可卡因或与不同的 D-1 受体高效和低效激动剂和拮抗剂（SKF 82958、SKF 81297、SKF 83959、ecopipam；每种药物情况 n=3-4）联合注射可卡因，测试其恢复已熄灭的可卡因寻求的能力。结果。可卡因启动伴随着可卡因配对刺激的恢复诱导了药物寻求的剂量依赖性恢复。当与可卡因联合使用时，所有 D-1 受体激动剂和拮抗剂都会使可卡因剂量反应函数产生向右和向下的变化。然而，SKF81297（激动剂）和ecopipam（拮抗剂）的联合预处理对可卡因的抑制作用低于单独使用任何一种药物。结论。这些发现表明，D-1 受体高效和低效激动剂以及拮抗剂部分通过对常见 D-1 受体群体的药理学相反作用来减弱可卡因寻求的恢复。
Rationale. Dopamine D-1 receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D-1 receptor drugs produce these similar effects on cocaine seeking are unknown. Objectives. This study investigated how D-1 receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus. Methods. Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D-1 receptor high- and low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking. Results. Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D-1 receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually. Conclusions. These findings suggest that D-1 receptor high- and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D-1 receptors.