Insular hypocretin transmission regulates nicotine reward
Insular hypocretin transmission regulates nicotine reward
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DOI：
10.1073/pnas.0808023105
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发表时间：
2008-12-09
影响因子：
11.1
通讯作者：
Kenny, Paul J.
中科院分区：
文献类型：
--
作者：
Hollander, Jonathan A.;Lu, Qun;Kenny, Paul J.
岛叶皮质受损会极大地扰乱人类吸烟者的烟草成瘾行为，这体现在吸烟习惯的自发戒除以及吸烟欲望的持续降低上。关于岛叶可能通过何种神经生物学机制控制烟草习惯的维持，人们知之甚少。新出现的证据表明，下丘脑分泌素（食欲素）的传递可能在药物强化过程中起重要作用，但是它在尼古丁（被认为是烟草烟雾中的关键成瘾成分）的奖赏作用中所起的作用在很大程度上仍未被探究。在此我们表明，阻断下丘脑分泌素 -1（Hcrt -1；食欲素 -1）受体的下丘脑分泌素传递会减少大鼠静脉内尼古丁自身给药以及获取该药物的动机。阻断Hcrt -1受体还消除了尼古丁对大脑奖赏回路的刺激作用，这通过尼古丁诱导的颅内自身刺激阈值降低的逆转得以测量。此外，我们表明含下丘脑分泌素的纤维支配岛叶，Hcrt -1受体位于岛叶细胞上，并且阻断岛叶（而非邻近的躯体感觉皮质）中的Hcrt -1受体可减少尼古丁自身给药。这些数据表明，岛叶的下丘脑分泌素传递在尼古丁的激励特性中起一种许可作用，因此可能是维持人类吸烟者烟草成瘾所必需的关键神经生物学基础。
Damage to the insular cortex can profoundly disrupt tobacco addiction in human smokers, reflected in spontaneous cessation of the tobacco habit and persistently decreased urge to smoke. Little is known concerning the neurobiological mechanisms through which the insula may control the maintenance of the tobacco habit. Emerging evidence suggests that hypocretin (orexin) transmission may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoke, remains largely unexplored. Here we show that blockade of hypocretin transmission at hypocretin-1 (Hcrt-1; orexin-1) receptors decreases i.v. nicotine self-administration in rats and the motivation to obtain the drug. Blockade of Hcrt-1 receptors also abolished the stimulatory effects of nicotine on brain reward circuitries, as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds. In addition, we show that hypocretin-containing fibers innervate the insula, Hcrt-1 receptors are located on insular cells, and blockade of Hcrt-1 receptors in the insula but not in the adjacent somatosensory cortex decreases nicotine self-administration. These data demonstrate that insular hypocretin transmission plays a permissive role in the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary for maintaining tobacco addiction in human smokers.