Xi Zheng-Xiong, Gardner Eliot L
Neuropsychopharmacology Section, Chemical Biology Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
CNS Drug Rev. 2007 Summer;13(2):240-59. doi: 10.1111/j.1527-3458.2007.00013.x.
As a continuation of our work with SB-277011A, we have examined the effects of another highly elective dopamine (DA) D3 receptor antagonist, N-(4-[4-{2,3-dichlorophenyl}-1-piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904), in animal models of addiction. Our results indicate that by systemic administration, NGB 2904 inhibits intravenous cocaine self-administration maintained under a progressive-ratio (PR) reinforcement schedule, cocaine- or cocaine cue-induced reinstatement of cocaine-seeking behavior, and cocaine- or other addictive drug-enhanced brain stimulation reward (BSR). The action of NGB 2904 on PR cocaine self-administration was long-lasting (1-2 days) after a single injection, supporting its potential use in treatment of cocaine addiction. The effects of NGB 2904 in the BSR paradigm were dose-dependent for both NGB 2904 and cocaine; that is, only lower doses of NGB 2904 were effective, and their putative antiaddiction effect could be overcome by increasing the doses of cocaine or other addictive drugs. A dopamine-dependent mechanism is proposed to explain the effects of NGB 2904 on cocaine's actions in these animal models of drug addiction. The data reviewed in this paper suggest that NGB 2904 or other D3-selective antagonists may have potential in controlling motivation for drug-taking behavior or relapse to drug-seeking behavior, but may have a limited role in antagonizing the acute rewarding effects produced by cocaine or other addictive drugs. In addition, NGB 2904 may also act as a useful tool to study the role of D3 receptors in drug addiction.
作为我们对SB - 277011A研究工作的延续，我们研究了另一种高选择性多巴胺（DA）D3受体拮抗剂N -（4 - [4 - {2,3 - 二氯苯基}-1 - 哌嗪基]丁基）-2 - 芴基甲酰胺（NGB 2904）在成瘾动物模型中的作用。我们的结果表明，通过全身给药，NGB 2904可抑制在累进比率（PR）强化程序下维持的静脉注射可卡因自我给药、可卡因或可卡因线索诱导的可卡因寻求行为的恢复，以及可卡因或其他成瘾药物增强的脑刺激奖赏（BSR）。单次注射后，NGB 2904对PR可卡因自我给药的作用持久（1 - 2天），这支持了其在治疗可卡因成瘾方面的潜在用途。在BSR范式中，NGB 2904的作用对NGB 2904和可卡因均呈剂量依赖性；也就是说，只有较低剂量的NGB 2904有效，并且增加可卡因或其他成瘾药物的剂量可以克服其假定的抗成瘾作用。提出了一种多巴胺依赖性机制来解释NGB 2904对这些药物成瘾动物模型中可卡因作用的影响。本文综述的数据表明，NGB 2904或其他D3选择性拮抗剂在控制药物摄取行为的动机或恢复到药物寻求行为方面可能具有潜力，但在拮抗可卡因或其他成瘾药物产生的急性奖赏作用方面可能作用有限。此外，NGB 2904也可能作为研究D3受体在药物成瘾中作用的有用工具。
