Brain regions mediating α3β4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration

The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of several drugs of abuse. Previous work has established that 18-MC is a potent antagonist at alpha 3 beta 4 nicotinic receptors. Because high densities of alpha 3 beta 4 nicotinic receptors occur in the medial habenula and the interpeduncular nucleus and moderate densities occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, the present study was conducted to determine if 18-MC could act in these brain areas to modulate methamphetamine self-administration in rats. Local administration of 18-MC into either the medial habenula, the interpeduncular area or the basolateral amygdala decreased methamphetamine self-administration. Similar results were produced by local administration into the same brain areas of two other alpha 3 beta 4 nicotinic antagonists, mecamylamine and alpha-conotoxin AuIB. Local administration of 18-MC, or the other antagonists, into the dorsolateral tegmentum or the ventral tegmental area had no effect on methamphetamine self-administration. In contrast, local administration of 18-MC and the other antagonists decreased sucrose self-administration when administered into the dorsolateral tegmentum or basolateral amygdala but had no effect when infused into the medial habenula, interpeduncular nucleus, or ventral tegmental area. These data are consistent with the hypothesis that 18-MC decreases methamphetamine self-administration by indirectly modulating the dopaminergic mesolimbic pathway via blockade of alpha 3 beta 4 nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala. The data also suggest that the basolateral amygdala along with a different pathway involving alpha 3 beta 4 receptors in the dorsolateral tegmentum mediate the effect of 18-MC on sucrose self-administration. (C) 2008 Elsevier B.V. All rights reserved.