Premium
Antagonism of CB1‐mediated discriminative‐stimulus effects by CB1 neutral and inverse‐agonist antagonists
Author(s) -
Kangas Brian D.,
Vemuri Kiran,
Thakur Ganesh,
Makriyannis Alex,
Bergman Jack
Publication year - 2012
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.26.1_supplement.660.7
Subject(s) - rimonabant , inverse agonist , agonist , antagonist , cannabinoid , antagonism , stimulus control , cannabinoid receptor , pharmacology , chemistry , potency , neuroscience , medicine , psychology , receptor , biochemistry , in vitro , nicotine
CB1 inverse‐agonist antagonists (e.g., rimonabant) have behavioral effects that limit their clinical utility. Recent data suggest that CB1 neutral antagonists may not have rimonabant‐like effects, raising the possibility of improved clinical utility. The present studies were conducted to compare how inverse‐agonist antagonists (SR141716A, AM 6538) and neutral antagonists (AM 4113, AM 6545, AM 6527) modify the discriminative‐stimulus effects of the CB1 full agonist AM 4054 (0.01 mg/kg, i.m.) in nonhuman primates (n=4). Results show that each antagonist except AM 6545 produced dose‐related rightward shifts in the AM 4054 dose‐effect curve. Also, antagonist effects of AM 6538 were evident up to 4 days following administration. Pretreatment with AM 6545 (10 mg/kg acutely or daily for 5 days) did not greatly alter AM 4054 discrimination. These results show that: 1) both CB1 neutral and inverse‐agonist antagonists, while differing in potency, can surmountably antagonize CB1 discrimination and 2) AM 6538 has long‐lasting CB1 antagonist actions. The ineffectiveness of AM 6545 agrees with previous reports of its limited brain penetration. The present data indicate that CB1 neutral antagonism is an effective strategy for blocking addiction‐related effects of CB1 agonists, and support the idea that it may be useful in managing cannabis‐related disorders. (Supported by DA023142 and DA007252)