JPET #201962 1 Title Page Cannabinoid Discrimination and Antagonism by CB1 Neutral and Inverse Agonist Antagonists

CB1 inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB1 inverse agonist SR141716A (rimonabant) and the CB1 neutral antagonist AM4113 were compared for their ability to modify CB1 receptormediated discriminative-stimulus effects in nonhuman primates trained to discriminate the novel CB1 full agonist AM4054. Results indicate that: 1) AM4054 serves as an effective CB1 discriminative stimulus, with an onset and time course of action comparable to that of the CB1 agonist ∆ -THC; and 2) the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative-stimulus effects of AM4054. Schild analyses further shows that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB1 receptors. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on January 3, 2013 as DOI: 10.1124/jpet.112.201962 at A PE T Jornals on A ril 9, 2017 jpet.asjournals.org D ow nladed from