BPiDI: a novel selective ?6?2* nicotinic receptor antagonist and preclinical candidate treatment for nicotine abuse.

ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) containing ?6?2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the ?6?2* 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.The C?? analogue of bPiDDB, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity.bPiDI inhibits nicotine-evoked [³H]dopamine overflow (IC??= 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 ?6?2* nAChR antagonist ?-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at ?6?2* nAChRs. Nicotine treatment (0.4 mg·kg?¹·da?¹, 10 days) increased more than 100-fold the potency of bPiDI (IC??=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.These results are consistent with the hypothesis that ?6?2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.

SUBMITTER: Wooters TE 

PROVIDER: S-EPMC3087136 | biostudies-other | 2011 May

REPOSITORIES: biostudies-other