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Drug Discrimination in (+)‐Epibatidine‐Trained Monkeys: Agonists and Antagonists Effects of Nicotinic Drugs
Author(s) -
Desai Rajeev,
Doyle Michelle,
Bergman Jack
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1019.4
Subject(s) - cytisine , mecamylamine , pharmacology , nicotine , nicotinic agonist , epibatidine , chemistry , nicotinic antagonist , methyllycaconitine , varenicline , nornicotine , partial agonist , hexamethonium , agonist , alkaloid , nicotinic acetylcholine receptor , receptor , medicine , stereochemistry , acetylcholine , biochemistry
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 (S D ) 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 S D effects of (+)‐EPI. In further studies, pretreatment with the partial nicotine agonists VAR and CYT did not block the S D effects of (+)‐EPI, and in fact, shifted the (+)‐EPI dose‐effect curve to the left (>3‐10‐fold). These results suggest that the S D 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).