title: 18-Methoxycoronaridine acts in the medial habenula to attenuate behavioral and neurochemical sensitization to nicotine.
abstract: Systemic 18-methoxycoronaridine, an alpha3beta4 nicotinic antagonist, slows the rate of induction of behavioral sensitization to nicotine (Glick et al., 1996; 2011). The primary mechanism of action of 18-MC is believed to be the inhibition of α3β4 nicotinic acetylcholine receptors which are densely expressed in the medial habenula and interpeduncular nucleus (Pace et al., 2004; Glick et al., 2012). Recently, these habenular nicotinic receptors and their multiple roles in nicotine aversion and withdrawal have been increasingly emphasized (Antolin-Fontes et al., 2015). Here, we investigated the effects of 18-MC on both behavioral and neurochemical sensitization to nicotine. Daily systemic administration of 18-MC slowed the rate of induction of behavioral sensitization to nicotine but failed to block the expression of a sensitized locomotor response when absent. In contrast, in nicotine sensitized animals, systemic 18-MC significantly reduced the expression of behavioral sensitization. Results from intra-habenular administration of 18-MC paralleled these findings in that the expression of behavioral sensitization was also reduced in sensitized animals. Consistent with its effects on behavioral sensitization, intra-MHb treatment with 18-MC completely abolished sensitized dopamine responses in the nucleus accumbens in nicotine sensitized animals. These results show that α3β4 nicotinic receptors in the MHb contribute to nicotine sensitization, a phenomenon associated with drug craving and relapse.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, United States. Electronic address: Egganb@mail.amc.edu.
authors.forename: Branden L
authors.initials: BL
authors.lastname: Eggan
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, United States. Electronic address: Mccalls@mail.amc.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: McCallum
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D019262:Habenula / Q000187:drug effects*; D006719:Homovanillic Acid / Q000378:metabolism; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D017551:Microdialysis; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D015102:3,4-Dihydroxyphenylacetic Acid; D007050:Ibogaine; D009538:Nicotine; C103345:18-methoxycoronaridine; D006719:Homovanillic Acid
keywords: 18-Methoxycoronaridine; Locomotor activity; Medial habenula; Microdialysis; Nicotine; Rat; Sensitization; α3β4 nicotinic acetylcholine receptors