Behavioural PharmacologyBrain regions mediating α3β4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration
Introduction
18-Methoxycoronaridine (18-MC), an iboga alkaloid congener that has the potential to be useful in treating multiple forms of drug abuse, has been shown, in rats, to decrease the self-administration of several drugs of abuse, including morphine (Glick et al., 1996), cocaine (Glick et al., 1996), methamphetamine (Glick et al., 2000a), nicotine (Glick et al., 2000a) and alcohol (Rezvani et al., 1997). 18-MC's primary mechanism of action appears to be to selectively block α3β4 nicotinic receptors (Glick et al., 2002, Pace et al., 2004). However, it is not simply an open channel blocker like the nonspecific nicotinic antagonist mecamylamine; rather, 18-MC is a non-competitive negative allosteric modulator that acts by stabilizing the ligand bound, desensitized state of the receptor (Pace et al., 2003). 18-MC, as well as several of its congeners, binds with higher affinity to the desensitized than to the resting state of the nicotinic receptor, and may in fact induce the desensitization process (Yuan et al., 2007). This mechanism potentially confers a unique antagonist profile—18-MC should have little or no effect on fast cholinergic transmission, for example in ganglia, and should not produce the peripheral side effects (constipation, hypotension) associated with mecamylamine. Consequently, 18-MC may have a unique spectrum of in vivo effects in multiple models of addictive disorders.
In one way or another, the mechanisms of action of virtually all drugs of abuse appear to involve the dopaminergic mesolimbic system, and new anti-addictive medications are usually designed to affect this system. Although 18-MC also affects this system, it does so in an indirect way via other pathways (cf. Maisonneuve and Glick, 2003). It was in fact the distribution of α3β4 nicotinic receptors in the brain that suggested a role of these other pathways in mediating 18-MC's behavioral effects. That is, in the brain, α3β4 nicotinic receptors are preferentially localized in the medial habenula and interpeduncular nucleus, while lower densities of these receptors reside in the ventral tegmental area (e.g., Klink et al., 2001, Quick et al., 1999) and other brain regions (e.g., dorsolateral tegmentum and basolateral amygdala; Perry et al., 2002, Zhu et al., 2005).
The interpeduncular nucleus receives its main input from the medial habenula, forming the habenulo-interpeduncular pathway in the fasciculus retroflexus. While there are multiple avenues for interaction between this pathway and the mesolimbic pathway in the medial forebrain bundle, it has been known since the 1980s that the habenulo-interpeduncular pathway can function as a reward system separate from the mesolimbic pathway (e.g., Sutherland and Nakajima, 1981, Rompre and Miliaressis, 1985, Blander and Wise, 1989, Vachon and Miliaressis, 1992). Indeed, it appears that the two pathways probably modulate each other (Sutherland and Nakajima, 1981, Nishikawa et al., 1986). Based on its α3β4 nicotinic antagonist action, we postulated that 18-MC might act in the habenulo-interpeduncular pathway to dampen the activity of the mesolimbic pathway. Accordingly, we recently reported that local administration of 18-MC into either the medial habenula or interpeduncular nucleus decreases morphine self-administration in rats (Glick et al., 2006) and blocks sensitization of morphine-induced dopamine release in the nucleus accumbens (Taraschenko et al., 2007). In the present study, we have sought to determine if locally administered 18-MC also affects the self-administration of methamphetamine. In addition to the medial habenula and interpeduncular nucleus, we have also included the ventral tegmental area, the basolateral amygdala, and the dorsolateral tegmentum as potential sites of action, inasmuch as each of these latter areas is involved in reward mechanisms and has at least low or moderate densities of α3β4 nicotinic receptors. Lastly, we conducted parallel studies with a non-drug reinforcer, sucrose. While previous findings indicated that systemic 18-MC (5–20 mg/kg, i.p.) decreased drug self-administration but had no effects on responding for water or sucrose (e.g., Glick et al., 1996, Glick et al., 2002, Pace et al., 2004), recent work has shown that a higher dose of 18-MC (40 mg/kg) can also decrease sucrose (but not water) self-administration (Taraschenko et al., in press).
Section snippets
Treatment drugs
Treatment drugs included 18-methoxycoronaridine hydrochloride (1–20 µg; Albany Molecular Research, Inc., Albany, NY), mecamylamine hydrochloride (10 µg; Sigma/RBI, St. Louis, MO), and α-conotoxin AuIB (25 pmol; generously provided bv Dr. J. Michael McIntosh, University of Utah). All treatments were injected intracerebrally immediately before behavioral testing.
Animals
Naïve female Long-Evans derived rats (250 g; Charles River, NY), housed individually, were maintained on a normal 12 h light cycle
Results
Fig. 1, Fig. 2 show the effects of local administration of 18-MC into the medial habenula, interpeduncular nucleus, and basolateral amygdala on methamphetamine self-administration. Infusion of 18-MC into either of these three sites decreased methamphetamine self-administration [interpeduncular nucleus: F (4,28) = 3.11, P < 0.05; medial habenula: F (4,28) = 2.81, P < 0.05; basolateral amygdala: F (4,28) = 2.85, P < 0.05]. 18-MC appeared to be more potent in the interpeduncular nucleus than in the medial
Discussion
The results of this study suggest that 18-MC acts in both the medial habenula and interpeduncular nucleus as well as the basolateral amygdala to modulate methamphetamine self-administration. The comparable effects of mecamylamine and α-conotoxin AuIB in all three regions are consistent with the premise that 18-MC's primary mode of action is to block α3β4 nicotinic receptors (Glick et al., 2000a, Pace et al., 2004). While mecamylamine blocks all nicotinic receptor subtypes and has some
Acknowledgements
This study was supported by NIDA grant DA 016283. We wish to thank Dr. J. Michael McIntosh for providing the α-conotoxin AuIB.
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