Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Switzerland.
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Japan.
Neuropharmacology. 2018 May 1;133:395-403. doi: 10.1016/j.neuropharm.2018.02.010. Epub 2018 Feb 15.
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.
有力的证据表明，食欲肽/下丘脑分泌素信号调节觉醒、应激和寻求奖励的行为。然而，大多数关于药物奖励相关过程的研究迄今为止都描述了药理学阻断剂干扰食欲肽/下丘脑分泌素传递的作用。我们在这里报告了关于食欲肽/下丘脑分泌素缺乏小鼠（KO）及其杂合子（HET）和野生型（WT）同窝仔鼠的可卡因相关行为的广泛研究。我们评估了重复给药后的行为敏化作用和对与可卡因注射反复配对的环境的偏好（15mg/kg）。还对小鼠进行了可卡因（0.5-1.5mg/kg/次）的自我给药训练。我们的观察结果表明，虽然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 小鼠在禁欲或消退后表现出可卡因寻求行为减少，以及可卡因潜伏期渴望减少。此外，如果目前的发现证实缺乏食欲肽/下丘脑分泌素的小鼠可能表现出低活性表型，可能与警觉性降低同时伴随着环境探索减少有关，那么食欲肽/下丘脑分泌素缺乏不会导致任何注意力缺陷。因此，我们报告说，内源性破坏食欲肽/下丘脑分泌素信号适度改变可卡因奖励，但显著减少长期情感依赖，这可能解释了在 Hcrt KO 小鼠中观察到的可卡因寻求缺乏复发的原因。总的来说，由于最高浓度的可卡因摄入量减少，以及长时间禁欲后对可卡因线索的反应性降低，我们的研究结果表明，缺乏食欲肽的小鼠可能表现出对可卡因成瘾的弹性迹象。
