Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction
Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction
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DOI：
10.1038/npp.2010.42
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发表时间：
2010-07-01
影响因子：
7.6
通讯作者：
Le Foll, Bernard
中科院分区：
文献类型：
--
作者：
Forget, Benoit;Wertheim, Carrie;Le Foll, Bernard
尼古丁是烟草中主要的精神活性成分，其奖赏作用被认为是持续吸烟和复吸的主要原因。虽然多巴胺已被广泛地牵连在尼古丁的奖励作用，去甲肾上腺素能系统可能有一个更大的作用比以前怀疑。本研究评价了去甲肾上腺素能α（1）受体在尼古丁和食物自我给药和复发、尼古丁辨别和尼古丁诱导的大鼠延髓核多巴胺释放中的作用。我们发现，去甲肾上腺素能α（1）受体拮抗剂哌唑嗪（0.25-1 mg/kg）剂量依赖性地减少尼古丁（0.03 mg/kg）的自我给药，这种作用在连续的每日给药期间得以维持;但没有减少食物自我给药。哌唑嗪还减少了由尼古丁引发（0.15 mg/kg）或尼古丁相关线索诱导的已熄灭的尼古丁寻求的恢复，但不是食物诱导的食物寻求的恢复，并减少了尼古丁诱导（0.15 mg/kg）的多巴胺在丘脑核壳中的释放。然而，哌唑嗪没有尼古丁样的辨别作用，并没有改变尼古丁辨别的剂量-反应曲线。这些发现表明，去甲肾上腺素能α（1）受体的刺激参与尼古丁自我给药和复发，可能通过促进尼古丁诱导的中脑边缘多巴胺能系统的激活。这些发现指出α 1肾上腺素受体阻滞剂是治疗人类烟草依赖的一种潜在的新方法。Neuropsychopharmacology（2010）35，1751-1760; doi：10.1038/npp.2010.42; 2010年3月31日在线发表
Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic alpha(1) receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic alpha(1) receptor antagonist prazosin (0.25-1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic alpha(1) receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to alpha(1) adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans. Neuropsychopharmacology (2010) 35, 1751-1760; doi:10.1038/npp.2010.42; published online 31 March 2010