title: The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens.
abstract: The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.
authors.affiliation: Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Shafiqur
authors.initials: S
authors.lastname: Rahman
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Neugebauer
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D045604:Extracellular Fluid / Q000187:drug effects*; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects*; D010847:Picolines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018765:Dopamine Uptake Inhibitors; C513964:N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide; D018733:Nicotinic Antagonists; D010847:Picolines; D009538:Nicotine; D000661:Amphetamine; D004298:Dopamine