Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats.
Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats.
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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。
DOI：
10.1038/s41386-018-0054-4
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Contet,Candice
中科院分区：
文献类型：
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作者：
Schmeichel,BrookeE;Matzeu,Alessandra;Koebel,Pascale;Vendruscolo,LeandroF;Sidhu,Harpreet;Shahryari,Roxana;Kieffer,BrigitteL;Koob,GeorgeF;Martin-Fardon,Rémi;Contet,Candice
下丘脑分泌素/食欲素（HCRT）神经肽系统调节摄食、觉醒状态、应激反应和奖励，特别是在动机相关性增强的条件下。特别是，HCRT神经传递促进了在需要更多努力和/或动机服用药物的情况下寻求药物的行为。本研究使用shrna编码腺相关病毒载体敲除成年大鼠整个下丘脑背侧的HCRT表达，并确定HCRT在可卡因自我给药中的作用。在短时间获取条件下，慢性基因沉默不影响可卡因的自我给药，但在长时间获取条件下，它显著减少了可卡因的摄入，这一模式模仿了强迫性可卡因摄入的关键特征。此外，Hcrtsilencing降低动机可卡因和高度可口的食物奖励（即甜炼乳；SCM）在一个渐进的比例强化计划，但没有改变对SCM的反应在一个固定的比例计划。重要的是，沉默不影响食物或水的消耗，对唤醒和应激反应的一般测量没有影响。在分子水平上，chronicHcrtknockdown减少了下丘脑背侧表达dynorphin （DYN）的神经元数量，并在较小程度上减少了表达melanin- concentration hormone （MCH）的神经元数量。这些最初的发现支持了HCRT神经传递促进药物和非药物奖励的操作性反应的假设，特别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系统参与可卡因自我给药，在低努力条件下，允许大鼠扩展接触，可能通过与DYN和MCH信号的功能相互作用。
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 knockdownHcrtexpression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. ChronicHcrtsilencing 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,Hcrtsilencing 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,Hcrtsilencing did not affect food or water consumption, and had no consequence for general measures of arousal and stress reactivity. At the molecular level, chronicHcrtknockdown 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.