title: r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement.
abstract: α6β2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6β2* antagonists inhibit these effects of nicotine, such that α6β2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on α4β2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6β2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small molecule that acts as a potent and selective antagonist at α6β2* nAChRs to specifically decrease nicotine self-administration in rats, thus, establishing r-bPiDI as a lead compound for development as a treatment for nicotine addiction.
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Meyer
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536-0596, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pivavarchyk
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536-0596, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Horton
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536-0596, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wooters
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536-0596, USA. ldwoskin@email.uky.edu.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020916:Conotoxins / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D010847:Picolines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020916:Conotoxins; C562065:N,N-decane-1,10-diyl-bis-3-picolinium; D018733:Nicotinic Antagonists; D010847:Picolines; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C054634:methyllycaconitine; D009538:Nicotine; D004298:Dopamine; D000157:Aconitine
keywords: Abuse; Dopamine; Nicotine; Reinforcement