Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在2007年10月1日至2008年9月30日期间，该研究项目取得了重大进展。 我们发现，新型多巴胺D3受体拮抗剂NGB 2904对脑多巴胺D3受体的阻断在很大程度上模拟了我们以前用我们的主要概念验证多巴胺D3受体拮抗剂SB 277011 A所看到的推定的抗成瘾、抗渴望和抗复发效果。 具体地说，我们发现NGB 2904减弱了递增比（PR）强化下静脉内可卡因自我给药（降低PR断点），减弱可卡因寻求行为的复发（使用恢复动物模型）由可卡因本身和环境线索触发（景象，声音），这些都是以前与可卡因服用行为有关的，并显著减弱由可卡因、尼古丁和海洛因产生的药物增强的脑奖赏（如通过电脑刺激奖赏电生理学技术所评估的）。 与我们研究的其他选择性D3受体拮抗剂一样，NGB 2904在低努力高回报固定比例强化下不会改变可卡因自我给药。 与SB 277011 A一样，NGB 2904本身对脑电刺激奖励没有影响-这是一个非常有希望的发现，可能最终人类使用这些候选抗成瘾药物。 这些发现进一步增加了我们以前的建议，高选择性多巴胺D3受体拮抗剂可能是有用的，在治疗广泛的药物成瘾的重量。 我们进一步发现，我们的两种高选择性D3受体拮抗剂-SB 277011 A和NGB 2904-显著减弱甲基苯丙胺增强的大脑奖励（通过电脑刺激奖励评估）。 这一发现构成了多巴胺D3脑受体参与甲基苯丙胺依赖和成瘾的第一个证据，以及高选择性多巴胺D3受体拮抗剂在治疗甲基苯丙胺依赖和成瘾中可能具有治疗益处的第一个证据。 我们进一步比较了SB 277011 A和NGB 2904与BP 897对甲基苯丙胺增强的脑奖励的作用，并得出结论，SB 277011 A和NGB 2904的抗甲基苯丙胺作用可能归因于选择性D3受体拮抗作用，而观察到的BP 897的作用可能归因于D3和D2受体拮抗作用的组合。 我们继续研究了SB 277011 A在口服乙醇自我给药模型中的抗成瘾作用，并证实了我们先前的发现，即SB 277011 A显著减弱了实验室小鼠的乙醇自我给药和乙醇寻求行为的恢复。 我们继续研究了新型抗成瘾化合物左旋四氢巴马汀（l-THP）对可卡因奖赏效应的影响，并证实l-THP显著减弱可卡因自我给药和可卡因增强的脑刺激奖赏。 在一系列神经化学实验中，我们发现l-THP可能通过突触后机制起作用，并且似乎非选择性地拮抗多巴胺D1、D2和D3受体。 此外，我们发现SB 277011 A阻断脑多巴胺D3受体可显著减弱实验室啮齿动物对可卡因的渴望。 这是第一次证明选择性多巴胺D3受体拮抗剂不仅对渴望本身，而且对渴望的时间依赖性孵化的潜在功效，这是成瘾性疾病临床管理中的一个问题。 最后，我们发现多巴胺D3受体拮抗剂SB 277011 A显著抑制遗传性肥胖啮齿动物的食物摄入，对遗传性非肥胖啮齿动物的影响显著较小-这表明选择性多巴胺D3受体拮抗剂在治疗强迫性暴食和肥胖中的可能效用。 所有这些研究结果表明，多巴胺D3受体拮抗剂可能具有抗成瘾，抗渴望和抗复发的功效，在人类药物成瘾，与其他初步的暗示性证据，在强迫性暴饮暴食和肥胖症的疗效。

During the period 01 Oct 07 to 30 Sept 08, significant progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel dopamine D3 receptor antagonist NGB2904 emulates to a very high degree the putative anti-addiction, anti-craving, and anti-relapse efects that we have previously seen with our lead proof-of-concept dopamine D3 receptor antagonist SB277011A. Specifically, we found that NGB2904 attenuates intravenous cocaine self-administration under progressive-ratio (PR) reinforcement (lowers the PR break-point), attenuates relapse to cocaine-seeking behavior (using the reinstatement animal model) triggered by both cocaine itself and by environmental cues (sights, sounds) that were previously associated with cocaine-taking behavior, and significantly attenuates drug-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques) produced by cocaine, nicotine, and heroin. Like the other selective D3 receptor antagonists that we have studied, NGB2904 does not alter cocaine self-administration under low-effort high-payoff fixed-ratio reinforcement. Like SB277011A, NGB2904 has no effect by itself on electrical brain-stimulation reward - a highly promising finding with respect to possible eventual human use of these candidate anti-addiction medications. These findings add further weight to our previous suggestions that highly selective dopamine D3 receptor antagonists may be useful in the treatment of a wide range of drug addictions. We further found that both of our highly-selective D3 receptor antagonists - SB277011A and NGB2904 - significantly attenuate methamphetamine-enhanced brain reward (as assessed by electrical brain-stimulation reward). This finding constitutes the first demonstration that dopamine D3 brain receptors are involved in methamphetamine dependence and addiction, and the first demonstration that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of methamphetamine dependence and addiction. We further compared the effects of SB277011A and NGB2904 with those of BP897 against methamphetamine-enhanced brain reward, and concluded that the anti-methamphetamine effects of SB277011A and NGB2904 are likely attributable to selective D3 receptor antagonism, while the observed effects of BP897 are likely attributable to a combination of D3 and D2 receptor antagonism. We continued our investigation of the anti-addiction effects of SB277011A in an oral ethanol self-administration model, and confirmed our previous findings that SB277011A significantly attenuates ethanol self-administration and reinstatement of ethanol-seeking behavior in laboratory mice. We continued our investigation of the novel anti-addiction compound levo-tetrahydropalmatine (l-THP) on cocaine's rewarding effects, and confirmed that l-THP significantly attenuates cocaine self-administration and cocaine-enhanced brain-stimulation reward. In a series of neurochemical experiments, we found that l-THP likely works via a postsynaptic mechanism, and appears to antagonize dopamine D1, D2, and D3 receptors nonselectively. Additionally, we found that blockade of brain dopamine D3 receptors by SB277011A significantly attenuates incubation of cocaine craving in laboratory rodents. This is the first demonstration of the potential efficacy of selective dopamine D3 receptor antagonists against not only craving itself, but the time-dependent incubation of craving that is such a problem in the clinical management of addictive diseases. Finally, we found that the dopamine D3 receptor antagonist SB277011A significantly inhibits food intake in genetically obese rodents, with significantly lesser effect on genetically non-obese rodents - suggesting a possible utility for selective dopamine D3 receptor antagonists in the treatment of compulsive over-eating and obesity. All of these findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, with additional preliminary suggestive evidence for efficacy in compulsive over-eating and obesity.