Pharmacological Characterization of the Discriminative‐Stimulus Effects of the Nicotinic Agonist (+)‐Epibatidine in Squirrel Monkeys

Abstract

The present studies were undertaken to characterize the discriminative‐stimulus (SD) effects of (+)‐epibatidine (EPI)–an α4β2 selective nicotinic agonist that is pharmacologically similar and structurally distinct from nicotine (NIC). Using a standard two‐lever drug discrimination procedure, squirrel monkeys (n=4) were trained to discriminate i.m. injections of 0.001 mg/kg (+)‐epibatidine (EPI) from saline on a 10‐response fixed‐ratio schedule of stimulus‐termination. Results show that high efficacy nicotinic agonists [(+)‐EPI, (−)‐EPI, NIC] substituted fully for (+)‐EPI, whereas the highest doses of other nicotinic agonists produced intermediate levels of (+)‐EPI‐like SD effects [varenicline (VAR), cytisine (CYT), isoarecolone (ISO)] or did not substitute for (+)‐EPI (lobeline). Drugs from other pharmacological classes (methamphetamine, atropine, citalopram, arecoline) did not generalize for (+)‐EPI's stimulus effects. Pretreatment studies with nicotinic antagonists show that: a) mecamylamine (non‐selective) insurmountably antagonized (+)‐EPI's effects; b) dihydro‐β‐erthroidine (α4β2‐selective) surmountably (>3‐fold rightward shift) blocked (+)‐EPI's effects; and c) methyllycaconitine (α7 selective) failed to modify the SD effects of (+)‐EPI. Interestingly, the peripherally‐restricted nicotinic antagonist hexamethonium also appeared to block (+)‐EPI's SD effects (approximately 3‐fold rightward shift) suggesting that a peripheral component may also play a role in 0.001 mg/kg (+)‐EPI's discriminable effects. In further studies, pretreatment with the partial nicotinic agonists VAR and CYT did not block the SD effects of (+)‐EPI, and in fact, CYT pretreatment shifted the (+)‐EPI dose‐effect curve to the left (>3‐10‐fold). These results suggest that the discriminative‐stimulus effects of (+)‐EPI are mediated through α4β2 nicotinic receptor subtypes at which the partial agonists VAR and CYT do not exert partial antagonist actions.Support or Funding InformationSupported by NIH/NIDA DA031231