18-Methoxycoronaridine, morphine and the cholinergic habenulo-interpeduncular pathway.

摘要

Opioid addiction is a significant public health problem in the United States. Currently existing pharmacological treatments for opioid dependence are limited; thus, the need for new efficient therapies is immense. 18-Methoxycoronaridine, (18-MC), an iboga alkaloid congener, is a potential treatment for opioid addiction. Previous studies in this laboratory have shown that 18-MC reduces the self-administration of morphine, cocaine, methamphetamine, nicotine and alcohol, and attenuates several signs of morphine withdrawal in rats. 18-MC has also been shown to alter the effects of morphine on dopamine release in the nucleus accumbens (NAC), such that the sensitized dopamine response to chronic morphine was abolished. Although micromolar affinities of 18-MC at all three opioid receptors and at 5-HT3 receptors are documented, 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors and this now appears to be the primary mechanism of 18-MCs action in the brain. Alpha3beta4 nicotinic receptors are present in high densities in the nuclei of the habenulo-interpeduncular pathway but their densities are very low in the mesolimbic pathway. Since the two pathways are interrelated anatomically and functionally, I hypothesized that 18-MC, by blocking alpha3beta4 nicotinic receptors in the nuclei of the habenulo-interpeduncular pathway, modulates dopamine responses to morphine in the NAC. Furthermore, I hypothesized that the mechanism for such modulation involves acetylcholine release in the IPN. The results of the present studies show that 18-MC locally infused into the medial habenula (MHb) or interpeduncular nucleus (IPN), attenuates sensitized dopamine responses in the NAC to repeated morphine. The present studies also show that morphine, when given acutely, produces biphasic effects on acetylcholine release in the IPN; tolerance develops to the effect of high doses in morphine-dependent rats and this tolerance is not altered by pretreatment with 18-MC. Previous studies assessed the role of the habenulo-interpeduncular pathway in 18-MC's effects on morphine-induced dopamine release in the mesolimbic pathway, known to be involved in positive reinforcement. The present thesis also determined the contribution of the habenulo-interpeduncular pathway, as well as other brain areas (i.e., locus coeruleus), in 18-MC's ability to alter negative reinforcing properties of morphine. In a rat model of opioid dependence, 18-MC was effective in attenuating various signs of withdrawal when locally infused into the locus coeruleus, the MHb or the IPN. Further experiments with other alpha3beta4 nicotinic antagonists suggested that antagonism of alpha3beta4 nicotinic receptors was involved in some of these effects. Taken collectively, these results provide evidence that the nuclei of the habenulo-interpeduncular pathway are responsible for the previously described actions of systemic 18-MC on morphine addiction and dependence. Implications for the therapeutic use of compounds with similar pharmacology are discussed.