Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior
Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior
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DOI：
10.1073/pnas.0507480102
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发表时间：
2005-12-27
影响因子：
11.1
通讯作者：
de Lecea, L
中科院分区：
文献类型：
--
作者：
Boutrel, B;Kenny, PJ;de Lecea, L
下丘脑分泌素-1和-2 (Hcrt-1和Hcrt-2)，也被称为食欲素- a和-B，是由下丘脑外侧几千个神经元合成的神经肽。含有下丘脑泌素的神经元遍布整个大脑，主要输入与动机、奖励和压力有关的基底前脑结构。然而，下丘脑泌素在成瘾相关行为中的作用在很大程度上仍未被探索。本研究表明，在不改变大鼠可卡因摄入量的情况下，脑室内注入Hcrt-1可导致剂量相关的可卡因寻求恢复。Hcrt-1还显著提高了颅内自我刺激阈值，这表明，与可卡因等具有强化特性的治疗不同，Hcrt-1负向调节大脑奖励回路的活动。下丘脑泌素诱导的可卡因寻求恢复可以通过阻断去甲肾上腺素能和促肾上腺皮质激素释放因子系统来阻止，这表明Hcrt-1通过诱导应激样状态来恢复药物寻求。与这一解释一致，选择性Hcrt-1受体拮抗剂SB334867阻断了足震诱导的先前消失的可卡因寻求行为的恢复。这些发现揭示了下丘脑分泌素在通过激活大脑中的应激途径来驱动药物寻找中的作用。
Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are neuropeptides synthesized by a few thousand neurons in the lateral hypothalamus. Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. However, the role of hypocretins in addiction-related behaviors remains largely unexplored. Here we show that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats. Hcrt-1 also dramatically elevates intracranial self-stimulation thresholds, indicating that, unlike treatments with reinforcing properties such as cocaine, Hcrt-1 negatively regulates the activity of brain reward circuitries. Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist SB334867 blocked footshock-induced reinstatement of previously extinguished cocaine-seeking behavior. These findings reveal a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain.