18-Methoxycoronaridine (18-MC), a novel iboga
alkaloid congener, is a potential treatment for
drug addiction. 18-MC has been shown to decrease
self-administration of drugs (e.g.,
morphine,
methamphetamine,
nicotine) and attenuate
opioid withdrawal in rats. In previous studies, systemic pretreatment with 18-MC abolished the sensitized increase in accumbens
dopamine levels induced by chronic
morphine administration. In vitro studies have shown that 18-MC is a potent antagonist of alpha3beta4
nicotinic receptors, and alpha3beta4 antagonism is believed to be the primary mechanism responsible for 18-MC's effects on
drug self-administration and possibly on
morphine-induced changes in mesolimbic
dopamine. While there are very low densities of alpha3beta4
nicotinic receptors in the mesolimbic pathway, these receptors are prominently localized in the medial habenula (MHb) and in the interpeduncular nucleus (IPN). These nuclei and the habenulo-interpeduncular pathway connecting them are believed to function as part of an alternate reward pathway modulating the dopaminergic mesolimbic pathway known to be involved in
drug addiction. In the present study, to determine if 18-MC acts in the MHb or in the IPN, the effects of local infusion of 18-MC into these brain areas were assessed on mesolimbic
dopamine responses to acute and repeated
morphine treatment. Administration of 18-MC (10 mug) into either the IPN or MHb blocked the sensitized
dopamine response to repeated
morphine in the nucleus accumbens; 18-MC had no effect on the
dopamine response to acute
morphine. The results suggest that 18-MC acts in the habenulo-interpeduncular pathway to modulate the effects of repeated
morphine in the dopaminergic mesolimbic system.