Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

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 amoderate intramuscular dose of MA (0.1 mg/kg) from vehicle. These included alpha 4 beta 2-selective ligands that may vary in efficacy from relatively high [nicotine, (+)-and (-)-epibatidine] to relatively low [isoarecolone, varenicline, (-)-cytisine, (-)-lobeline] and the alpha 7-selective ligands anabaseine and anabasine. Results show that nicotine, (1)-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 dose(50) (ED50) values, corresponded more closely with their relative affinities at alpha 4 beta 2 than at alpha 7 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 alpha 4 beta 2-selective antagonist dihydro-beta-erythroidine hydrobromide (DH beta E) (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 aremediated through alpha 4 beta 2 nicotinic acetylcholine receptor actions, and 2) nicotinic alpha 4 beta 2 partial agonists, like the nicotinic antagonist DH beta E, can reduce MA-like behavioral effects of nicotine.