Dopamine D3 receptor antagonists for treating drug addiction: Preclinical models

在2006年10月1日至2007年9月30日期间，该研究项目取得了重大进展。我们发现，在恢复动物模型中，新型多巴胺D3受体拮抗剂NGB2904阻断脑多巴胺D3受体可显著减弱可卡因增强的脑奖励（通过脑电刺激奖励电生理技术评估），减弱渐进比率（PR）强化下静脉内可卡因自我给药（降低PR断点），并减弱可卡因引发的药物寻求行为复发。与我们研究的其他选择性D3受体拮抗剂一样，NGB2904在低努力、高回报的固定比例强化下不会改变可卡因的自我给药。这些发现进一步支持了我们之前的建议，即高度选择性的多巴胺D3受体拮抗剂可能有助于治疗可卡因成瘾。我们进一步发现D3受体拮抗剂SB277011A显著减弱尼古丁增强的脑奖励（通过脑电刺激奖励评估）和尼古丁配对的环境线索功能，使用尼古丁线索配对的运动活动和尼古丁线索配对的条件位置偏好行为范式。这些发现首次证明了多巴胺D3脑受体参与尼古丁依赖和成瘾，也首次证明了高选择性多巴胺D3受体拮抗剂可能在治疗尼古丁依赖和成瘾方面有益。我们进一步发现，SB277011A阻断脑多巴胺D3受体可显著减少实验室小鼠口服酒精自我给药和恢复酒精寻求行为。这些发现进一步支持了我们之前的建议，即高选择性多巴胺D3受体拮抗剂可能有助于治疗酒精依赖和成瘾。我们还发现SB277011A阻断脑多巴胺D3受体可显著减弱实验室啮齿动物的可卡因渴求潜伏期。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有潜在功效，而且对渴望的时间依赖性潜伏期也有潜在功效，这是成瘾性疾病临床管理中的一个问题。我们进一步发现多巴胺D3受体配体SB277011A， NGB2904和BP897显著减弱甲基苯丙胺-增强脑刺激奖励。我们发现SB277011A和NGB2904的抗甲基苯丙胺作用可能与D3受体的选择性拮抗有关，而BP897的抗甲基苯丙胺作用可能与D3和D2受体的联合拮抗有关。这些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多巴胺D3受体拮抗剂可能在治疗甲基苯丙胺成瘾方面有益。我们还研究了新型化合物左-四氢巴马汀（l-THP）对可卡因奖赏效应的影响。我们发现l-THP显著减弱了可卡因在固定比例和递进比例强化条件下静脉注射可卡因的奖励效应，并在实验动物脑电刺激奖励中进行了评估。我们进一步发现，l-THP本身能轻微增强伏隔核细胞外多巴胺（通过体内脑微透析检测），并能强烈增强可卡因增强的伏隔核多巴胺——这表明，突触后而非突触前多巴胺受体机制是l-THP对可卡因奖励作用的基础。然而，l-THP似乎对D3受体没有选择性。相反，它似乎以非选择性的方式作用于多巴胺D1， D2和D3受体。最后，我们发现多巴胺D3受体拮抗剂SB277011A显著抑制基因肥胖啮齿动物的食物摄入，而对基因非肥胖啮齿动物的作用明显较小，这表明选择性多巴胺D3受体拮抗剂在治疗强迫性暴饮暴食和肥胖方面可能具有效用。所有这些发现表明，多巴胺D3受体拮抗剂可能对人类药物成瘾具有抗成瘾、抗渴望和抗复发的功效，并对强迫性暴饮暴食和肥胖具有额外的初步暗示证据。

During the period 01 Oct 06 to 30 Sept 07, major progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the novel dopamine D3 receptor antagonist NGB2904 significantly attenuates cocaine-enhanced brain reward (as assessed by electrical brain-stimulation reward electrophysiological techniques), attenuates intravenous cocaine self-administration under progressive-ratio (PR) reinforcement (lowers the PR break-point), and attenuates cocaine-triggered relapse to drug-seeking behavior in the reinstatement animal model. 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. These findings add further weight to our previous suggestions that highly selective dopamine D3 receptor antagonists may be useful in the treatment of cocaine addiction. We further found that the D3 receptor antagonist SB277011A significantly attenuates nicotine-enhanced brain reward (as assessed by electrical brain-stimulation reward) and nicotine-paired environmental cue functions, using both the nicotine cue-paired locomotor activity and the nicotine cue-paired conditioned place preference behavioral paradigms. These findings constitute the first demonstration that dopamine D3 brain receptors are involved in nicotine dependence and addiction, and the first demonstration that highly selective dopamine D3 receptor antagonists may be therapeutically beneficial in the treatment of nicotine dependence and addiction. We further found that blockade of brain dopamine D3 receptors by SB277011A significantly attenuates oral alcohol self-administration and reinstatement of alcohol-seeking behavior in laboratory mice. These findings add further weight to our previous suggestions that highly selective dopamine D3 receptor antagonists may be useful in the treatment of alcohol dependence and addiction. We also 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. We further found that the dopamine D3 receptor ligands SB277011A, NGB2904, and BP897 significantly attenuate methamphetamine-enhance brain-stimulation reward. We found 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. These findings constitute 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 addiction. We also investigated the effects of the novel compound levo-tetrahydropalmatine (l-THP) on cocaine's rewarding effects. We found that l-THP significantly attenuates cocaine's rewarding effects as assessed by intravenous cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement conditions, and as assessed by electrical brain-stimulation reward in laboratory animals. We further found that l-THP slightly enhances nucleus accumbens extracellular dopamine by itself (assayed by in vivo brain micordialysis), and strongly potentiates cocaine-augmented nucleus accumbens dopamine - suggesting that a postsynaptic, rather than presynaptic, dopamine receptor mechanism underlies l-THP's actions on cocaine reward. However, l-THP does not appear to be selective for the D3 receptor. Rather, it appears to act on dopamine D1, D2, and D3 receptors in a nonselective manner. 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.