Center for Neuropharmacology and Neuroscience, Albany Medical College (MC-136), 47 New Scotland Avenue, Albany, NY 12208, USA.
Eur J Pharmacol. 2011 Nov 1;669(1-3):71-5. doi: 10.1016/j.ejphar.2011.08.001. Epub 2011 Aug 19.
18-Methoxycoronaridine (18-MC), a putative anti-addictive agent, has been shown to decrease the self-administration of several drugs of abuse in rats. 18-MC is a potent antagonist at α3β4 nicotinic receptors. Consistent with high densities of α3β4 nicotinic receptors being located in the medial habenula and the interpeduncular nucleus, 18-MC has been shown to act in these regions to decrease both morphine and methamphetamine self-administration. The present study was conducted to determine if 18-MC's effect on nicotine self-administration is mediated by acting in these same brain regions. Because moderate densities of α3β4 receptors occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, these brain areas were also examined as potential sites of action of 18-MC. Local administration of 18-MC into either the medial habenula, the basolateral amygdala or the dorsolateral tegmentum decreased nicotine self-administration. Surprisingly, local administration of 18-MC into the interpeduncular nucleus increased nicotine self-administration while local administration of 18-MC into the ventral tegmental area had no effect on nicotine self-administration. Similar effects were produced by local administration of either mecamylamine or conotoxin AuIB. These data are consistent with the hypothesis that 18-MC decreases nicotine self-administration by indirectly modulating the dopaminergic mesolimbic pathway via blockade of α3β4 nicotinic receptors in the medial habenula, basolateral amygdala, and dorsolateral tegmentum. The data also suggest that an action of 18-MC in the interpeduncular nucleus may attenuate aversive and/or depressive effects of nicotine.
18-甲氧基考尼丁（18-MC）是一种潜在的抗成瘾药物，已被证明可减少大鼠对几种滥用药物的自我给药。18-MC 是α3β4 烟碱受体的有效拮抗剂。由于α3β4 烟碱受体在中脑被盖和脚间核中的密度较高，因此已证明 18-MC 可在这些区域中发挥作用，以减少吗啡和甲基苯丙胺的自我给药。本研究旨在确定 18-MC 对尼古丁自我给药的影响是否通过在这些相同的脑区起作用来介导。由于α3β4 受体在背外侧脑桥、腹侧被盖区和基底外侧杏仁核中存在中等密度，因此还检查了这些脑区作为 18-MC 潜在作用部位。18-MC 局部给药至中脑被盖、基底外侧杏仁核或背外侧脑桥均可减少尼古丁自我给药。令人惊讶的是，18-MC 局部给药至脚间核增加了尼古丁自我给药，而 18-MC 局部给药至腹侧被盖区对尼古丁自我给药没有影响。局部给予美加明或 Conotoxin AuIB 也产生了类似的效果。这些数据与以下假设一致，即 18-MC 通过阻断中脑被盖、基底外侧杏仁核和背外侧脑桥中的α3β4 烟碱受体，间接调节多巴胺能中脑边缘通路，从而减少尼古丁自我给药。数据还表明，18-MC 在脚间核中的作用可能减轻尼古丁的厌恶和/或抑郁作用。
