Drug Discrimination in (+)‐Epibatidine‐Trained Monkeys: Agonists and Antagonists Effects of Nicotinic Drugs

Abstract

The behavioral effects of nicotinic agonists and antagonists were studied in squirrel monkeys using a two‐lever drug discrimination procedure. Monkeys (n=4) were trained to discriminate i.m. injections of 0.001 mg/kg (+)‐epibatidine (EPI)–a α4β2 selective nicotinic agonist that is pharmacologically similar and structurally distinct from nicotine (NIC)–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 discriminative‐stimulus (SD) effects [varenicline (VAR), cytisine (CYT)] or did not substitute for (+)‐EPI (lobeline). Minor tobacco alkaloids produced full (nornicotine, anabasine, myosmine, anatabine), intermediate (anabaseine) or no (cotinine) (+)‐EPI‐like effects. Pretreatment studies with nicotinic antagonists show that: a) mecamylamine (non‐selective) unsurmountably antagonized (+)‐EPI's effects; b) dihydro‐β‐erthroidine (α4β2‐selective) surmountably (>3‐fold rightward shift) blocked (+)‐EPI's effects; and c) methyllycaconitine (α7 selective) and hexamethonium (peripherally‐restrictive) failed to modify the SD effects of (+)‐EPI. In further studies, pretreatment with the partial nicotine agonists VAR and CYT did not block the SD effects of (+)‐EPI, and in fact, shifted the (+)‐EPI dose‐effect curve to the left (>3‐10‐fold). These results suggest that the SD effects of (+)‐EPI are mediated through a α4β2 nicotinic receptor subtype at which the partial agonists VAR and CYT do not exert partial antagonist actions (supported by NIH DA031231).