In 2014, we proposed that orexin signaling transformed motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as motivational activation. Advancements in animal models since then have permitted higher-resolution measurements of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This motivational plasticity is paralleled by persistently increased orexin expression in a topographically specific manner—a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for the orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation and that this is achieved via a pool of reserve orexin neurons. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug, driven by aberrantly and persistently high expression in the orexin reserve pool. This mechanistic framework has implications for the understanding and treatment of several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction.

2014 年，我们提出食欲素信号传导将动机相关状态转化为旨在利用机会或管理威胁的适应性行为，我们将这一过程称为动机激活。从那时起，动物模型的进步使得能够对动机状态进行更高分辨率的测量。特别是，用于研究毒品需求的行为经济学方法描述了导致成瘾动机增强的条件。这种动机可塑性与以地形特定方式持续增加的食欲素表达相平行——这一发现在包括人类在内的物种中得到了证实。食欲素水平的正常化也会降低成瘾模型中的药物动机。这些新进展促使我们更新了我们提出的食欲素功能框架。我们现在提出，食欲素神经元在肽产生中表现出动态变化的能力有助于其在适应性动机调节中的作用，并且这是通过储备食欲素神经元库来实现的。这种储备通常是双向的，以实现动机的可塑性，从而促进灵活、适应性的行为。然而，在成瘾等病理状态下，我们提出，食欲素系统丧失了适应性调节肽产生的能力，导致食欲素储备池中异常且持续的高表达所驱动，导致对药物的集中过度兴奋。这种机制框架对于理解和治疗成瘾以外的几种精神疾病具有重要意义，特别是那些以动机功能障碍为特征的疾病。