RT Journal Article
SR Electronic
T1 Patterns of Nicotinic Receptor Antagonism: Nicotine Discrimination Studies
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.182170
DO 10.1124/jpet.111.182170
A1 Emily M. Jutkiewicz
A1 Emily Brooks
A1 Adam Kynaston
A1 Kenner C Rice
A1 James H. Woods
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/07/05/jpet.111.182170.abstract
AB Evaluation of the discriminative stimulus effects of drugs is a useful procedure for identification of receptor mediation of in vivo drug effects. This assay can be enhanced when the stimulus effects of different doses of agonist are evaluated. In the present study, rats were trained to discriminate small or large doses of nicotine from saline, and interactions of these effects with nicotinic receptor antagonists and partial agonists were determined. The insurmountable nicotine antagonist mecamylamine blocked both the discriminative stimulus and response rate-reducing effects of nicotine, but was less effective against the large dose of nicotine. The α4β2*-selective, competitive antagonist dihydro-beta-erythrodine (DHβE) antagonized the discriminative stimulus effects of both doses, but was less effective against the larger training dose of nicotine. Schild analyses of DHβE suggested that different nicotinic receptor populations may be mediating the stimulus effects of large and small doses of nicotine. This was supported by observations that the discriminative stimulus effects of the partial agonist cytisine were more like those of the large dose than of the small dose of nicotine, and that cytisine antagonized the effects of only the small nicotine dose. Varenicline produced nicotine-like effects in both training dose groups, but reduced the discriminative stimulus effects of intermediate doses of nicotine in the group trained to the small dose of nicotine. Overall, these results suggest that small doses of nicotine produce their stimulus effects via α4β2 nicotine receptors, whereas larger doses of nicotine recruit additional nicotine receptor subtypes, as revealed by drug discrimination assays in rats.