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首页> 外文期刊>The European Journal of Neuroscience >The dopamine D3 receptor, a quarter century later
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The dopamine D3 receptor, a quarter century later

机译：多巴胺D3受体，四分之一世纪之后

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This review updates the existing knowledge suggesting a role for the D3 receptor in schizophrenia and drug addiction. The D3 receptor is expressed in brain regions controlling reward, emotions, and motivation. Antipsychotics bind invitro to the D3 receptor with similar affinity as to the D2 receptor, and occupancy of D3 receptors invivo by these compounds given acutely at clinical dosage have been demonstrated in Positron Emission Tomography (PET) studies. The D3 receptor modulates glutamatergic pathways from the prefrontal cortex to subcortical areas, either directly by interacting with N-methyl-D-aspartate (NMDA) receptors in the nucleus accumbens, or indirectly by controlling dopamine release from ventral tegmental area neurons. In animals, D3 receptor antagonists reverse behavioral manifestations of NMDA receptor blockade and improve cognitive performances in various paradigms. Two D3 receptor-selective compounds have reached clinical trials in schizophrenia, with negative results seemingly due to insufficient target engagement; the results with a third compound, F17464, have not been disclosed yet. There is converging evidence that D3 receptors do not control the reinforcing effects of drugs of abuse (with the exception of alcohol under low requirement), but rather affects the motivation to take the drugs under high requirement, reactivity to drug-associated cues, and drug-seeking behaviors triggered by stimuli associated with relapse in humans. D3 receptor expression measured by PET is upregulated in humans with various drug addictions. A single administration of the D3 receptor-selective antagonist, GSK598809, in humans transiently alleviated craving in smokers after overnight abstinence. The clinical development of D3-selective compounds will benefit from initial assessment of target engagement through the use of PET.
机译：这篇综述更新了现有的知识，提示D3受体在精神分裂症和药物成瘾中的作用。D3受体在控制奖赏、情绪和动机的大脑区域表达。抗精神病药物以与D2受体相似的亲和力将体外受体与D3受体结合，正电子发射断层扫描（PET）研究表明，这些化合物在临床剂量下急性给予D3受体后，体内受体的占有率已得到证实。D3受体通过直接与伏隔核内的N-甲基-D-天冬氨酸（NMDA）受体相互作用，或通过控制腹侧被盖区神经元释放多巴胺，调节从前额叶皮质到皮质下区的谷氨酸能通路。在动物身上，D3受体拮抗剂可以逆转NMDA受体阻断的行为表现，并改善各种模式下的认知能力。两种D3受体选择性化合物已在精神分裂症中进行临床试验，其负面结果似乎是由于靶点参与不足；第三种化合物F17464的结果尚未公布。越来越多的证据表明，D3受体并不控制滥用药物的强化效应（低需求下的酒精除外），而是影响高需求下服用药物的动机、对药物相关线索的反应性，以及由与人类复发相关的刺激触发的寻药行为。PET测量的D3受体表达在各种药物成瘾的人类中上调。在人身上单次服用D3受体选择性拮抗剂GSK598809，可暂时缓解夜间禁欲后吸烟者的渴求。D3选择性化合物的临床开发将受益于通过使用PET对靶参与的初步评估。

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