The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Chronic Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake under extended access conditions, a model that mimics key features of compulsive cocaine taking. In addition, Hcrt silencing decreased motivation for both cocaine and a highly palatable food reward (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence for general measures of arousal and stress reactivity. At the molecular level, chronic Hcrt knockdown reduced the number of neurons expressing dynorphin (DYN), and to a smaller extent melanin-concentrating hormone (MCH), in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.

中文翻译：

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下丘脑分泌素的敲低会减弱大鼠体内可卡因自我给药的延长。


下丘脑分泌素/食欲素 (HCRT) 神经肽系统调节进食、唤醒状态、应激反应和奖励，尤其是在动机相关性增强的情况下。特别是，在需要增加努力和/或动机来服用药物的情况下，HCRT 神经传递会促进寻求药物的行为。本研究使用 shRNA 编码腺相关病毒载体来敲低成年大鼠背侧下丘脑的 Hcrt 表达，并确定 HCRT 在可卡因自我给药中的作用。慢性 Hcrt 沉默不会影响短期接触条件下的可卡因自我给药，但会在长期接触条件下大幅减弱可卡因的摄入量，这是一种模仿强迫性可卡因吸食的关键特征的模型。此外，在渐进比例强化方案下，Hcrt 沉默降低了对可卡因和高度可口的食物奖励（即甜炼乳；SCM）的动机，但在固定比例方案下没有改变对 SCM 的反应。重要的是，Hcrt 沉默不会影响食物或水的消耗，并且对唤醒和应激反应性的一般测量没有影响。在分子水平上，慢性 Hcrt 敲低减少了背侧下丘脑中表达强啡肽 (DYN) 的神经元数量，并在较小程度上减少了黑色素浓缩激素 (MCH)。这些原始发现支持这样的假设：HCRT 神经传递促进药物和非药物奖励的操作反应，尤其是在需要高度动机的条件下。 此外，目前的研究提供了令人信服的证据，证明 HCRT 系统在大鼠的低努力条件下也参与可卡因自我给药，允许延长可卡因的使用范围，可能是通过与 DYN 和 MCH 信号传导的功能相互作用。