Cannabinoid Discrimination and Antagonism by CB₁Neutral and Inverse Agonist Antagonists

Abstract

Cannabinoid receptor 1 (CB 1 ) 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 CB 1 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 CB 1 inverse agonist SR141716A (rimonabant) and the CB 1 neutral antagonist AM4113 were compared for their ability to modify CB 1 receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB 1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB 1 discriminative stimulus, with an onset and time course of action comparable with that of the CB 1 agonist D 9 -tetrahydrocannabinol, and that 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 show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA 2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB 1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB 1 receptors.

JWH-018 in rhesus monkeys: Differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects

“…When Δ 9 -THC is the training drug, various cannabinoid CB 1 receptor agonists produce high levels of drug-appropriate responding, i.e., substitute for the Δ 9 -THC discriminative stimulus (Balster and Prescott, 1992). Cannabinoid CB 1 receptor agonists aside from Δ 9 -THC have been used less frequently as training drugs; however, the results are similar to those obtained when Δ 9 -THC is trained, i.e., cannabinoid CB 1 receptor agonists share effects with each other regardless of the training drug (De Vry and Jentzsch, 2004; Järbe et al, 2010; Kangas et al, 2013), with a few exceptions noted for endogenous cannabinoid-based drugs that are rapidly metabolized (McMahon et al, 2008; Wiley et al, 2011). The cannabinoid CB 1 receptor-selective antagonist rimonabant has been shown to antagonize the discriminative stimulus effects of Δ 9 -THC and other cannabinoid agonists.…”

Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

“…The apparatus and methodology were comparable to those employed previously (Tidey and Bergman, 1998;Kangas et al, 2013). During experimental sessions, monkeys sat in customized Plexiglas chairs (Kelleher and Morse, 1968) that were enclosed in ventilated, sound-attenuating chambers provided with white noise at all times to mask extraneous sounds.…”

Endocannabinoid and nitric oxide interaction mediates food intake in neonatal chicken

“…Animal tissues express at least two cannabinoidergic (CBergic) receptors: CB 1 and CB 2 which belong to the Gprotein coupled receptors (GPCRs) (Kangas et al, 2013). CB 1 receptors are mainly expressed in presynaptic nerve terminals of inhibitory and excitatory nerves in the CNS in both mammals and birds (Novoseletsky et al, 2011;Sharkey et al, 2014) where they mediate inhibition of transmitter release (Pertwee, 2005).…”