Wooters_2011_Br.J.Pharmacol_163_346

BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nAChRs) containing alpha6beta2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the alpha6beta2* 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 C(1)(0) 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 [(3)H]dopamine overflow (IC(5)(0)= 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 microM) and the alpha6beta2* nAChR antagonist alpha-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at alpha6beta2* nAChRs. Nicotine treatment (0.4 mg.kg(-)(1).da(-)(1), 10 days) increased more than 100-fold the potency of bPiDI (IC(5)(0)=1.45 nM) to inhibit nicotine-evoked dopamine release. Acute treatment with bPiDI (1.94-5.83 micromol.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 alpha6beta2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.