ArticlePharmacology, biochemistry, and behavior2026
Discriminative stimulus and locomotor activity profiles of nicotine and varenicline.
Article in Pharmacology, biochemistry, and behavior, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
rationaleThese studies characterized the locomotor and discriminative stimulus effect of nicotine, mecamylamine, and varenicline in efforts to optimize detection of substitutes and antagonists of nicotine.
objectivesWe compared nicotine- and varenicline-induced locomotor activity (LMA) to confirm the assay's utility as a predictor of therapeutic potential, and determined how training dose and pretreatment interval affect the nicotine discriminative stimulus, and influence varenicline's ability to substitute.
methodsMice were assessed for LMA following injection of nicotine tartrate (NicT), varenicline, mecamylamine, or saline. A time-course study in rats was conducted to identify the minimum effective dose and shortest pretreatment time at which NicT exerts discriminative stimulus control. Cohorts were trained using (i) a standard 0.4 mg/kg, 15-min, (ii) a 0.1 mg/kg, 5-min, or (iii) a dose-fading (0.4 → 0.1 mg/kg), 5-min protocols. Substitution and antagonism tests were conducted with varenicline and mecamylamine.
resultsNicotine and varenicline produced early depressant and delayed stimulant effects; mecamylamine was inactive. Nicotine's depressant effect had four-fold greater potency than varenicline. In discrimination, 0.1 mg/kg NicT fully substituted at a 5-min pretreatment interval. The low-dose and faded groups showed enhanced sensitivity. Varenicline fully substituted in the standard and faded groups but only partially in the low-dose group.
conclusionsThe matching biphasic profiles of nicotine and varenicline suggest that LMA studies may be useful in identifying compounds with therapeutic potential targeting the nicotinic acetylcholine receptor. Low-dose, short pre-treatment time discrimination procedures reveal varenicline's predicted α4β2 partial agonist profile, whereas high dose, long pre-treatment times may broaden the nicotine cue and mask partial substitution.
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