BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nAChRs) containing α6β2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the α6β2* nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) inhibits nicotine-evoked dopamine release from dorsal striatum and decreases nicotine self-administration in rats. However, overt toxicity emerged with repeated bPiDDB treatment. The current study evaluated the preclinical pharmacology of a bPiDDB analogue. EXPERIMENTAL APPROACH: The C₁₀ analogue of bPiDDB, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity. KEY RESULTS: bPiDI inhibits nicotine-evoked [³H]dopamine overflow (IC₅₀= 150 nM, I(max)=58%) from rat striatal slices. Schild analysis revealed a rightward shift in the nicotine concentration-response curve and surmountability with increasing nicotine concentration; however, the Schild regression slope differed significantly from 1.0, indicating surmountable allosteric inhibition. Co-exposure of maximally inhibitory concentrations of bPiDI (1 µM) and the α6β2* nAChR antagonist α-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at α6β2* nAChRs. Nicotine treatment (0.4 mg·kg⁻¹·da⁻¹, 10 days) increased more than 100-fold the potency of bPiDI (IC₅₀=1.45 nM) to inhibit nicotine-evoked dopamine release. Acute treatment with bPiDI (1.94-5.83 µmol·kg⁻¹, s.c.) specifically reduced nicotine self-administration relative to responding for food. Across seven daily treatments, bPiDI decreased nicotine self-administration; however, tolerance developed to the acute decrease in food-maintained responding. No observable body weight loss or lethargy was observed with repeated bPiDI. CONCLUSIONS AND IMPLICATIONS: These results are consistent with the hypothesis that α6β2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.
BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nAChRs) containing α6β2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the α6β2* nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) inhibits nicotine-evoked dopamine release from dorsal striatum and decreases nicotine self-administration in rats. However, overt toxicity emerged with repeated bPiDDB treatment. The current study evaluated the preclinical pharmacology of a bPiDDB analogue. EXPERIMENTAL APPROACH: The C₁₀ analogue of bPiDDB, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity. KEY RESULTS:bPiDI inhibits nicotine-evoked [³H]dopamine overflow (IC₅₀= 150 nM, I(max)=58%) from rat striatal slices. Schild analysis revealed a rightward shift in the nicotine concentration-response curve and surmountability with increasing nicotine concentration; however, the Schild regression slope differed significantly from 1.0, indicating surmountable allosteric inhibition. Co-exposure of maximally inhibitory concentrations of bPiDI (1 µM) and the α6β2* nAChR antagonist α-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at α6β2* nAChRs. Nicotine treatment (0.4 mg·kg⁻¹·da⁻¹, 10 days) increased more than 100-fold the potency of bPiDI (IC₅₀=1.45 nM) to inhibit nicotine-evoked dopamine release. Acute treatment with bPiDI (1.94-5.83 µmol·kg⁻¹, s.c.) specifically reduced nicotine self-administration relative to responding for food. Across seven daily treatments, bPiDI decreased nicotine self-administration; however, tolerance developed to the acute decrease in food-maintained responding. No observable body weight loss or lethargy was observed with repeated bPiDI. CONCLUSIONS AND IMPLICATIONS: These results are consistent with the hypothesis that α6β2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.
Authors: Andrew M Smith; Marharyta Pivavarchyk; Thomas E Wooters; Zhenfa Zhang; Guangrong Zheng; J Michael McIntosh; Peter A Crooks; Michael T Bardo; Linda P Dwoskin Journal: Biochem Pharmacol Date: 2010-03-25 Impact factor: 5.858
Authors: Shafiqur Rahman; Nichole M Neugebauer; Z Zhang; Peter A Crooks; Linda P Dwoskin; Michael T Bardo Journal: Neuropharmacology Date: 2006-11-09 Impact factor: 5.250
Authors: Outi Salminen; Jennifer A Drapeau; J Michael McIntosh; Allan C Collins; Michael J Marks; Sharon R Grady Journal: Mol Pharmacol Date: 2007-03-06 Impact factor: 4.436
Authors: Lawrence Toll; Nurulain T Zaveri; Willma E Polgar; Faming Jiang; Taline V Khroyan; Wei Zhou; Xinmin Simon Xie; Gregory B Stauber; Matthew R Costello; Frances M Leslie Journal: Neuropsychopharmacology Date: 2012-01-25 Impact factor: 7.853
Authors: F Ivy Carroll; Hernán A Navarro; S Wayne Mascarella; Ana H Castro; Charles W Luetje; Charles R Wageman; Michael J Marks; Asti Jackson; M Imad Damaj Journal: ACS Chem Neurosci Date: 2015-04-30 Impact factor: 4.418
Authors: Jirawoot Srisontiyakul; Hanna E Kastman; Elena V Krstew; Piyarat Govitrapong; Andrew J Lawrence Journal: Neurochem Res Date: 2016-08-29 Impact factor: 3.996
Authors: Joshua S Beckmann; Andrew C Meyer; M Pivavarchyk; David B Horton; Guangrong Zheng; Andrew M Smith; Thomas E Wooters; J Michael McIntosh; Peter A Crooks; Michael T Bardo; Linda P Dwoskin Journal: Neurochem Res Date: 2015-07-31 Impact factor: 3.996