Hypocretin/orexin deficiency decreases cocaine abuse liability
Hypocretin/orexin deficiency decreases cocaine abuse liability
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下丘脑分泌素/食欲素缺乏可降低可卡因滥用倾向
DOI：
10.1016/j.neuropharm.2018.02.010
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发表时间：
2018
影响因子：
4.7
通讯作者：
Boutrel Benjamin
中科院分区：
文献类型：
--
作者：
Steiner Nadia;Rossetti Clara;Sakurai Takeshi;Yanagisawa Masashi;de Lecea Luis;Magistretti Pierre J.;Halfon Olivier;Boutrel Benjamin
令人信服的证据表明，下丘脑分泌素/食欲素信号调节唤醒、压力和寻求奖励的行为。然而，到目前为止，大多数关于药物奖励相关过程的研究都描述了药物阻滞剂破坏下丘脑分泌素/食欲素传递的作用。我们在此报道了一项关于下丘脑分泌素/食欲素缺乏小鼠（KO）及其杂合子（HET）和野生型（WT）幼崽可卡因相关行为的广泛研究。我们评估了反复给药后的行为致敏性和对反复注射可卡因的环境的偏好（15 mg/kg）。小鼠也被训练自我给药可卡因（0.5-1.5 mg/kg/输注）。我们的观察表明，尽管所有小鼠对可卡因的急性给药都表现出非常相似的反应，但只有Hcrt KO小鼠在一段时间的戒断或灭绝后表现出减少的可卡因寻求行为，并减少了可卡因潜伏期的渴望。此外，如果目前的研究结果证实Hcrt缺陷小鼠可能表现出低活性表型，可能与警觉性降低以及对环境的探索减少有关，那么下丘脑分泌素/食欲素缺乏不会导致任何注意力缺陷。因此，我们报道先天性下丘脑分泌素/食欲素信号的破坏适度地改变了可卡因奖励，但显着降低了长期的情感依赖，这可能解释了Hcrt KO小鼠中可卡因寻求缺乏复发的原因。总的来说，在最高浓度的可卡因摄入量变钝，长期戒断后对可卡因线索的反应降低，我们的研究结果表明，下丘脑分泌素缺乏的小鼠可能表现出对可卡因成瘾的恢复迹象。
Compelling evidence indicates that hypocretin/orexin signaling regulates arousal, stress and reward-seeking behaviors. However, most studies on drug reward-related processes have so far described the effects of pharmacological blockers disrupting hypocretin/orexin transmission. We report here an extensive study on cocaine-related behaviors in hypocretin/orexin-deficient mice (KO) and their heterozygous (HET) and wildtype (WT) littermates. We evaluated behavioral sensitization following repeated administrations and preference for an environment repeatedly paired with cocaine injections (15 mg/kg). Mice were also trained to self-administer cocaine (0.5–1.5 mg/kg/infusion). Our observations show that whereas all mice exhibited quite similar responses to acute administration of cocaine, only Hcrt KO mice exhibited reduced cocaine-seeking behaviors following a period of abstinence or extinction, and reduced cocaine incubation craving. Further, if the present findings confirm that Hcrt deficient mice may display a hypoactive phenotype, possibly linked to a reduced alertness concomitant to a decreased exploration of their environment, hypocretin/orexin defiency did not cause any attentional deficit. We thus report that innate disruption of hypocretin/orexin signaling moderately alters cocaine reward but significantly reduces long-term affective dependence that may explain the lack of relapse for cocaine seeking seen in Hcrt KO mice. Overall, with blunted cocaine intake at the highest concentration and reduced responsiveness to cocaine cues after prolonged abstinence, our findings suggest that hypocretin deficient mice may display signs of resilience to cocaine addiction.