Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A
Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A
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DOI：
10.1038/sj.npp.1300148
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发表时间：
2003-02-01
影响因子：
7.6
通讯作者：
Everitt, BJ
中科院分区：
文献类型：
--
作者：
Di Ciano, P;Underwood, RJ;Everitt, BJ
条件刺激（CS）以前与滥用药物配对可以引起人类的渴望，复发药物使用，也可以加强人类和动物的药物寻求行为，这些事件被认为部分是通过激活中脑边缘多巴胺系统来实现的。汇聚解剖学，药理学和行为学的证据暗示多巴胺D-3受体的机制线索控制的行为。因此，本研究的目的是研究一种新的D-3受体拮抗剂SB-277011-A对可卡因寻求行为的影响，SB-277011-A对D-3多巴胺受体的选择性是D-2多巴胺受体的100倍。我们以前已经建立了二阶强化时间表提供了一个动物模型的线索控制药物寻求之前和之后的可卡因已经自我管理。SB-277011-A在第一个无药物间隔和可卡因自我给药后，通过可卡因相关条件反射维持的可卡因觅药呈剂量依赖性降低。在较高剂量下，SB-277011-A还增加了接受首次CS呈现和可卡因输注的潜伏期，从而减少了在二级强化方案下自我给药的可卡因输注次数。在任何试验剂量下，SB-277011-A对FR-I强化方案下的可卡因摄入量或二阶强化方案下的蔗糖反应均无影响。因此，这些结果表明，D-3多巴胺受体可能是至关重要的线索控制的药物寻求行为独立的任何相互作用与可卡因本身的强化作用，因此可能提供一个治疗目标，在治疗复发可卡因使用诱导的CS。
Conditioned stimuli (CS) previously paired with drugs of abuse can elicit cravings in humans, relapse to drug use, and can also reinforce drug-seeking behavior in both humans and animals, events that are believed to be subserved in part by activation of the mesolimbic dopamine system. Converging anatomical, pharmacological, and behavioral evidence implicates dopamine D-3 receptors in the mechanisms underlying cue-controlled behaviors. The purpose of the present study was therefore to investigate the effects on cocaine-seeking behavior of a novel D-3 receptor antagonist, SB-277011-A, which is 100-fold more selective for D-3 over D-2 dopamine receptors. We have established previously that second-order schedules of reinforcement provide an animal model of cue-controlled drug-seeking both prior to and after cocaine has been self-administered. SB-277011-A dose-dependently decreased cocaine-seeking maintained by a cocaine-associated conditioned reinforcer in both the first, drug-free interval and also following self-administration of cocaine. At higher doses, SB-277011-A also increased the latency to receive the first CS presentation and cocaine infusion, thereby decreasing the number of cocaine infusions self-administered under the second-order schedule of reinforcement. SB-277011-A had no effect on cocaine intake under an FR-I schedule of reinforcement, or on responding for sucrose under a second-order schedule of reinforcement, at any dose tested. These results therefore suggest that D-3 dopamine receptors may be critically involved in cue-controlled drug-seeking behavior independently of any interaction with the reinforcing effects of cocaine itself, and may therefore provide a therapeutic target in the treatment of relapse to cocaine use induced by CSs.