Effects of Chronic Exposure to the CB1 Agonist AM 411 in Squirrel Monkeys

Abstract

Cannabinoid CB1 agonists produce tolerance that may be associated with dependence and increased sensitivity to the behavioral effects of the CB1 antagonist SR141716A, perhaps indicative of antagonist‐precipitated withdrawal. In the present studies, the effects of the long‐acting CB1 agonist AM 411 and the CB1 antagonist SR141716A on operant responding were examined in squirrel monkeys before and during chronic AM 411 treatment (1.0 mg/kg/day, im). Prechronically, AM 411 (0.01‐1 mg/kg) produced dose‐related decreases in responding; the highest dose decreased behavior to approximately 20% of control values. In contrast, SR 141716A (1‐10 mg/kg) had little effect on behavior; the highest dose decreased responding only to >80% of control values. Re‐determination of drug effects during the chronic regimen revealed a >10‐fold rightward shift in the dose‐response function for AM 411, indicative of tolerance. On the other hand, SR 141716A (0.32‐3.2 mg/kg) produced dose‐related decreases in behavior; the highest dose decreased responding to <50% of control values. These data are consistent with the view that chronic CB1 receptor activation produces tolerance to the effects of CB1 agonists and enhances sensitivity to the behaviorally disruptive effects of CB1 antagonists. The increased sensitivity to the effects of SR 141716A may be indicative of antagonist‐precipitated withdrawal (supported by DA19205).