Brain regions mediating [alpha]3[beta]4 nicotinic antagonist effects of 18-MC on nicotine self-administration

• Published in: European journal of pharmacology 2011-11, Vol.669 (1-3), p.71-75
• Main Authors: Glick, Stanley D, Sell, Elizabeth M, McCallum, Sarah E, Maisonneuve, Isabelle M
• Format: Article
• Language: English
• ISSN: 0014-2999
• DOI: 10.1016/j.ejphar.2011.08.001

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 [alpha]3[beta]4 nicotinic receptors. Consistent with high densities of [alpha]3[beta]4 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 [alpha]3[beta]4 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 [alpha]3[beta]4 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.