Dopamine D3 receptor antagonists-treating drug addiction

在2004年10月1日至2005年9月30日期间，该研究项目取得了重大进展。我们发现，D3受体拮抗剂SB277011A阻断脑多巴胺D3受体可显著减少应激触发的可卡因寻求行为复发，这些小鼠已从先前的静脉注射可卡因习惯中药理学解毒和行为消失。通过将D3受体拮抗剂直接微注射到大脑中，我们发现伏隔核是一个具有抗复发作用的大脑部位。我们进一步发现，D3受体拮抗剂SB277011A、NGB2904或BP897对脑多巴胺D3受体的阻断可显著减轻实验室大鼠因暴露于先前与静脉注射可卡因习惯相关的环境线索而引发的可卡因寻求行为的复发。我们进一步确定SB277011A和NGB2904的抗复发作用可能是由于它们的D3受体拮抗剂特性，而BP897的抗复发作用可能是由于D2受体拮抗剂特性。我们进一步确定D3受体拮抗剂SB277011A在遗传上偏爱酒精和不喜欢酒精的实验室大鼠中都能阻断酒精消耗。我们进一步确定D3受体拮抗剂SB277011A通过两种不同的临床前程序（渐进比率强化和可变成本/可变回报强化）显著减弱实验室大鼠的可卡因诱导奖励。我们进一步确定D3受体拮抗剂SB277011A、NGB2904或BP897显著减弱尼古丁诱导的脑奖励增强。这些结果提示多巴胺D3受体拮抗剂可能对人类药物成瘾具有抗成瘾、抗渴求和抗复吸的作用。

During the period 01 Oct 04 to 30 Sept 05, major progress was made on this research project. We found that blockade of brain dopamine D3 receptors by the D3 receptor antagonist SB277011A significantly attenuates stress-triggered relapse to cocaine-seeking behavior in laboratory rats who had been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. By microinjecting the D3 receptor antagonist directly into the brain, we found that one brain site of anti-relapse action is the nucleus accumbens. We further found that blockade of brain dopamine D3 receptors by the D3 receptor antagonists SB277011A, NGB2904, or BP897 significantly attenuates relapse to cocaine-seeking behavior in laboratory rats triggered by exposure to environmental cues previously associated with the intravenous cocaine-taking habit. We further determined that the anti-relapse actions of SB277011A and NGB2904 were likely due to their D3 receptor antagonist properties, but that the anti-relapse action of BP897 was likely due to D2 receptor antagonist properties. We further determined that the D3 receptor antagonist SB277011A blocks alcohol consumption in both genetically alcohol-preferring and alcohol-nonpreferring laboratory rats. We further determined that the D3 receptor antagonist SB277011A significantly attenuates cocaine-induced reward in laboratory rats by two different preclinical procedures--progressive-ratio reinforcement and variable-cost/variable-payoff reinforcement. We further determined that the D3 receptor antagonists SB277011A, NGB2904, or BP897 significantly attenuate nicotine-induced enhancement of brain reward. All of these findings suggest that dopamine D3 receptor antagonists may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction.