The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys

Abstract

Background Based on rodent studies, Group II metabotropic glutamate receptors (mGluR2 & 3) were suggested as targets for addiction treatment. However, LY379268 and other Group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator (PAM) of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. Methods We first assessed modulation of mGluR2 function by AZD8529 using functional in-vitro assays in both membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (0.03-10 mg/kg, i.m.) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. Results AZD8529 potentiated agonist-induced activation of mGluR2 in both the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (0.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. Conclusions Our results provide evidence for efficacy of PAMs of mGluR2 in non-human primate models of nicotine reinforcement and relapse. We propose that this drug class should be considered for nicotine addiction treatment.

The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats

“…It was recently shown that AZD8529 decreases nicotine self-administration as well as nicotineprimed and cue-induced reinstatement of nicotine seeking in squirrel monkeys (Justinova et al, 2015). Moreover, AZD8529 reduces cue-induced methamphetamine craving in rats in both models of voluntary and forced abstinence from the drug (Caprioli et al, 2015).…”

“…AZD8529 is a new, highly specific PAM that potentiates the effect of glutamate on the mGluR2 with little effect on other mGluR subtypes (Cross, 2013;Justinova et al, 2015). It has recently been shown that AZD8529 decreases nicotine self-administration, nicotine-primed, and cueinduced reinstatement of nicotine seeking in squirrel monkeys (Justinova et al, 2015), as well as incubation of methamphetamine craving in rats (Caprioli et al, 2015). Its effects on self-administration or relapse to other classes of addictive substances are presently unknown.…”

“…These PAMs exert their effects on mGluR2s through a binding site that is topographically distinct from that bound by the endogenous ligand (Ritzen et al, 2005) and selectively activate the receptor in the presence of glutamate (Schaffhauser et al, 2003). AZD8529 is a new, highly specific PAM that potentiates the effect of glutamate on the mGluR2 with little effect on other mGluR subtypes (Cross, 2013;Justinova et al, 2015). It has recently been shown that AZD8529 decreases nicotine self-administration, nicotine-primed, and cueinduced reinstatement of nicotine seeking in squirrel monkeys (Justinova et al, 2015), as well as incubation of methamphetamine craving in rats (Caprioli et al, 2015).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Systemic administration of this compound decreases cued nicotine intake and cue-and nicotineinduced seeking (Justinova et al, 2015) as well as cueinduced methamphetamine seeking (Caprioli et al, 2015). Interestingly, AZD8529 was effective at inhibiting cued nicotine seeking at doses that did not affect food seeking, indicating that the selective activation of mGluR2 may prove a more effective treatment of relapse given the lack of a negative effect on natural rewards.…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…For these reasons, focus has shifted to selective positive allosteric modulators (PAMs) of mGlu2 receptors. Recent studies show that systemic administration of a PAM of mGlu2 receptors reduces nicotine- and cue-induced reinstatement of nicotine-seeking behavior, and that these effects are associated with reduced dopamine release in the NAc [94, 95]. Based on these studies, a phase II clinical trial examining the efficacy of the mGlu2 receptor PAM AZD8529 in human smokers is currently underway [96], with preliminary results forthcoming.…”