Desai_2014_J.Pharmacol.Exp.Ther_348_478

Nicotine was recently shown to engender d-methamphetamine (MA)-like discriminative-stimulus effects in rats, which may be indicative of shared psychomotor stimulant properties. To further investigate such overlapping discriminative-stimulus effects, nicotinic agonists varying in efficacy and selectivity were studied in squirrel monkeys that discriminated a moderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included alpha4beta2-selective ligands that may vary in efficacy from relatively high [nicotine, (+)- and (-)-epibatidine] to relatively low [isoarecolone, varenicline, (-)-cytisine, (-)-lobeline] and the alpha7-selective ligands anabaseine and anabasine. Results show that nicotine, (+)-epibatidine, and (-)-epibatidine substituted fully for MA, whereas the highest doses of other nicotinic agonists produced intermediate levels of MA-like effects (isoarecolone, anabaseine, anabasine, and varenicline) or did not substitute for MA [(-)-cytisine and (-)-lobeline]. The relative potencies of nicotinic agonists, based on effective dose50 (ED50) values, corresponded more closely with their relative affinities at alpha4beta2 than at alpha7 receptors. Regardless of selectivity or efficacy, nicotinic agonists also were observed to produce untoward effects, including salivation and emesis during or after experimental sessions. In pretreatment studies, the alpha4beta2-selective antagonist dihydro-beta-erythroidine hydrobromide (DHbetaE) (0.032 and 0.1 mg/kg) and the partial agonists varenicline (0.0032-0.1 mg/kg) and (-)-cytisine (0.032 and 0.1 mg/kg) surmountably antagonized (>10-fold rightward shift) nicotine's MA-like effects but were ineffective in blocking nicotine's emetic effects. Overall, our results show that 1) MA-like discriminative-stimulus effects of nicotinic agonists likely are mediated through alpha4beta2 nicotinic acetylcholine receptor actions, and 2) nicotinic alpha4beta2 partial agonists, like the nicotinic antagonist DHbetaE, can reduce MA-like behavioral effects of nicotine.