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，这一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NGB2904对脑多巴胺D3受体的阻断在很大程度上模拟了我们之前在先导概念验证多巴胺D3受体拮抗剂SB277011A中看到的抗成瘾、抗渴求和抗复发的假定效果。具体地说，我们发现NGB2904在累进比率(PR)强化下减弱了静脉注射可卡因的自我给药(降低PR断点)，减少了由可卡因本身和先前与可卡因吸食行为相关的环境线索(视觉、声音)触发的可卡因寻求行为的复发，并显著减弱了由可卡因、尼古丁和海洛因产生的药物增强的大脑奖赏(通过脑电刺激奖赏电生理技术评估)。像我们研究的其他选择性D3受体拮抗剂一样，NGB2904不会改变低努力高回报固定比率强化下的可卡因自我给药。与SB277011A一样，NGB2904本身对电刺激大脑奖励没有影响--对于人类最终可能使用这些候选的抗成瘾药物来说，这是一个非常有希望的发现。这些发现进一步加强了我们之前的建议，即高选择性的多巴胺D3受体拮抗剂可能在治疗广泛的药物成瘾中有用。我们进一步发现，我们的两种高选择性D3受体拮抗剂-SB277011A和NGB2904-显著减弱甲基苯丙胺增强的大脑奖励(通过电刺激大脑奖励来评估)。这一发现首次证明了多巴胺D3脑受体与甲基苯丙胺依赖和成瘾有关，也首次证明了高选择性的多巴胺D3受体拮抗剂在治疗甲基苯丙胺依赖和成瘾方面可能是有益的。我们进一步比较了SB277011A和NGB2904与BP897对甲基苯丙胺增强的脑奖赏的作用，得出结论：SB277011A和NGB2904的抗甲基苯丙胺作用可能是由于选择性的D3受体拮抗作用，而BP897的作用可能是D3和D2受体拮抗作用的结合。我们继续我们在口服乙醇自我给药模型中对SB277011A的抗成瘾作用的研究，并证实了我们之前的发现，SB277011A显著减弱了乙醇自我给药和恢复小鼠的酒精寻求行为。我们继续我们对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研究，证实L-THP显著减弱可卡因的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发挥作用，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，SB277011A阻断脑多巴胺D3受体显著减弱了实验室啮齿动物对可卡因的渴望。这是首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潜伏期的潜在疗效，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SB277011A显著抑制遗传性肥胖啮齿动物的食物摄入，而对遗传非肥胖啮齿动物的影响明显较小-这表明选择性多巴胺D3受体拮抗剂可能用于治疗强迫性暴食和肥胖。所有这些发现表明，多巴胺D3受体拮抗剂可能在人类药物成瘾中具有抗成瘾、抗渴求和抗复发的功效，并有更多的初步证据表明对强迫性暴食和肥胖症有效。

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.