Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats

Abstract

Cannabinoid CB receptors (CBRs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CBR antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CBR antagonist AM4113 may retain the therapeutic anti-addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self-administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CBR antagonists such as AM4113 deserve further research as a new class of CBR-based medications for the treatment of opioid addiction without SR141716A-like aversive effects.

Δ8‐Tetrahydrocannabivarin has potent anti‐nicotine effects in several rodent models of nicotine dependence

“…The assumption has been that these effects result from CB 1 receptor inverse agonism, but this has not been proven. In animal models, SR141716 by itself produces an anhedonic‐like effect—as assessed by electrical brain‐stimulation reward (He et al, ; Xi et al, ), in vivo brain microdialysis (Gardner, Gamaleddin, Manzanares Robles, & Rodrígues de Fonseca, ), and conditioned place aversion (Gardner et al, ). It also produces anxiety‐like effects and depressive‐like effects as shown in the elevated plus maze and forced swim test (Gueye et al, ).…”

The Opioid-Addicted Tetrapartite Synapse

“…Akin to mGluR2/3, presynaptic cannabinoid CB 1 receptors regulate glutamate release probability, and intra-accumbens administration of AM251, a CB 1 receptor antagonist, diminishes the duration required to extinguish morphine conditioned place preference (CPP) as well as the duration of morphine-induced reinstatement of CPP (59). In addition, the CB 1 receptor antagonist AM4113 dose-dependently suppresses heroin selfadministration (60). Taken together, these data demonstrate that regulating glutamate presynaptic release probability in the NA core inhibits opioid seeking.…”

Cannabis, cannabinoid receptors, and endocannabinoid system: yesterday, today, and tomorrow

“…However, SR141716A also exhibited aversive effect while AM4113 did not. These findings suggest that AM4113 or other neutral CB 1 R antagonists may serve as a new class of CB 1 R-based medications for the treatment of opioid addiction without SR141716A-like side-effects [5]. In the review article entitled "Translational potential of allosteric modulators targeting the cannabinoid CB 1 receptor", the authors discuss recent advances in structural and mechanistic studies on CB 1 R allosteric modulators.…”