18‐MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens

Abstract

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.

Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement

“…In addition, ␣3␤2* nAChRs of the habenulo-interpeduncular system may in part contribute to inhibition of nicotine self-administration, as suggested by the implication of this pathway in reward processes (Glick et al, 2006;Taraschenko et al, 2007;Morissette and Boye, 2008). Note, however, that available evidence points to a relevant role of ␣3␤4* rather than ␣3␤2* nAChRs.…”

The ibogaine medical subculture

“…Eleven of the 13 published preclinical studies of iboga alkaloids in opioid withdrawal indicate a significant attenuation of opioid withdrawal signs in the rat (Dzoljic et al, 1988;Sharpe and Jaffe, 1990;Maisonneuve et al, 1991;Glick et al, 1992;Cappendijk et al, 1994;Rho and Glick, 1998;Parker et al, 2002;Panchal et al, 2005), mouse (Frances et al, 1992;Popik et al, 1995;Layer et al, 1996;Leal et al, 2003), and primate (Aceto et al, 1992). Iboga alkaloids are also reported to reduce the self-administration of morphine Glick et al, 1994;Glick et al, 1996;Maisonneuve and Glick, 1999;Pace et al, 2004), cocaine (Cappendijk and Dzoljic, 1993;Glick et al, 1994), amphetamine , methamphetamine (Glick et al, 2000;Pace et al, 2004), alcohol (Rezvani et al, 1995;Rezvani et al, 1997;He et al, 2005) and nicotine Glick et al, 2000), and to diminish dopamine efflux in the nucleus accumbens (NAc), which is regarded as a correlate of drug salience (Berridge, 2007), in response to opioids Glick et al, 1994;Glick et al, 2000;Taraschenko et al, 2007b) or nicotine (Benwell et al, 1996;Glick et al, 1998).…”

Structural and functional diversity of native brain neuronal nicotinic receptors

“…The Hb is a diencephalic structure that receives substantial input from multiple parts of the limbic system, and communicates with the IPnby means of the fasciculus retroflexus. Components of the Hb-IPn system are involvedin the physiology and pathophysiology of reward phenomena [78,79], and subserve a variety of behaviours such as learning and memory, nociception, stress, sleeping and eating.…”