A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?
A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?
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DOI：
10.1007/7854_2016_57
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发表时间：
2017
影响因子：
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通讯作者：
Aston-Jones G
中科院分区：
文献类型：
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作者：
James MH;Mahler SV;Moorman DE;Aston-Jones G
十年前，我们的实验室通过显示这些神经元的激活促进条件吗啡寻求行为，提供了将食欲素/下丘脑分泌素信号与药物寻求联系起来的第一个直接证据。从那以后的几年里，许多研究者的贡献揭示了食欲素在所有被测试的滥用药物成瘾中的作用，但只是在特定的情况下。我们最近提出，在许多行为条件下，食欲素在协调“动机激活”方面起着基本统一的作用，在这里，我们将这一假设解释为适用于药物成瘾。我们描述了过去10年收集的证据，这些证据详细阐述了食欲素在寻求药物时的作用，在这种情况下，需要付出很高的努力才能获得药物，或者当药物奖励动机被药物相关线索/环境或压力源等外部刺激增强时。使用传统自我给药和恢复模型的研究证据，以及药物需求弹性的行为经济学分析，清楚地描绘了食欲素在调节动机方面的作用，而不是药物奖励的主要强化方面。我们还讨论了食欲素系统与更广泛的动机和奖励回路的解剖互连性，特别关注食欲素如何调节前额叶和其他谷氨酸输入到腹侧被盖区多巴胺神经元。最后，我们展望了该领域未来十年的研究，重点强调了最近FDA批准的双食欲素受体拮抗剂suvorexant （Belsomra®）用于治疗失眠，这是一个基于食欲素治疗成瘾的潜在临床应用的有希望的迹象。
One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating “motivational activation” under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra®) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.