Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration

Kufahl, Peter R.; Watterson, Lucas R.; Nemirovsky, Natali E.; Hood, Lauren E.; Villa, Angel; Halstengard, Casey; Zautra, Nicholas; Olive, M. Foster

doi:10.1016/j.neuropharm.2012.05.037

Cited by 46 publications

(39 citation statements)

References 63 publications

(104 reference statements)

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“…In fact, beside cocaine, LY379268 was efficacious in blocking cue-and contextinduced reinstatement of alcohol, heroin, methamphetamine, nicotine, and natural reward-seeking (Bossert et al, 2004(Bossert et al, , 2005(Bossert et al, , 2006aKufahl et al, 2011Kufahl et al, , 2013Liechti et al, 2007;Zhao et al, 2006). This wide spectrum ranging from addictive to non-addictive rewards may suggest a more general role for mGluR2/3 in the conditioned effect of drugs.…”

Section: Discussionmentioning

confidence: 99%

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

Cannella

Halbout

Uhrig

et al. 2013

Neuropsychopharmacol

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Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior.

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Section: Discussionmentioning

confidence: 99%

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

Cannella

Halbout

Uhrig

et al. 2013

Neuropsychopharmacol

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“…Several reports have indicated that group II (mGluR2 and mGluR3) agonists can affect addiction-related behaviors in animal models. For example, the orthosteric mGluR2/3 agonist LY379268 has been shown to attenuate contextual as well as cue-induced heroin seeking (Bossert et al, 2005;Bossert et al, 2004), cue-induced methamphetamine seeking (Kufahl et al, 2013), incubation of cocaine-craving (Lu et al, 2007), and cue-induced nicotine seeking (Liechti et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

Augier

Dulman

Rauffenbart

et al. 2016

Neuropsychopharmacol

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Group II metabotropic glutamate receptors (mGluR2 and mGluR3) may control relapse of alcohol seeking, but previously available Group II agonists were unable to discriminate between mGluR2 and mGluR3. Here we use AZD8529, a novel positive allosteric mGluR2 modulator, to determine the role of this receptor for alcohol-related behaviors in rats. We assessed the effects of AZD8529 (20 and 40 mg/kg s.c.) on male Wistar rats trained to self-administer 20% alcohol and determined the effects of AZD8529 on self-administration, as well as stress-induced and cue-induced reinstatement of alcohol seeking. The on-target nature of findings was evaluated in Indiana P-rats, a line recently shown to carry a mutation that disrupts the gene encoding mGluR2. The behavioral specificity of AZD8529 was assessed using self-administration of 0.2% saccharin and locomotor activity tests. AZD8529 marginally decreased alcohol self-administration at doses that neither affected 0.2% saccharin self-administration nor locomotor activity. More importantly, cue-but not stress-induced alcohol seeking was blocked by the mGluR2 positive allosteric modulator. This effect of AZD8529 was completely absent in P rats lacking functional mGluR2s, demonstrating the receptor specificity of this effect. Our findings provide evidence for a causal role of mGluR2 in cueinduced relapse to alcohol seeking. They contribute support for the notion that positive allosteric modulators of mGluR2 block relapse-like behavior across different drug categories.

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“…In rats, systemic injections of LY379268 or related mGluR2/3 agonists decrease discriminative-cue-induced reinstatement of cocaine seeking and context-induced reinstatement of heroin seeking (12, 13), decrease discrete cue-induced reinstatement of heroin seeking (14), cocaine priming-induced reinstatement (15), spontaneous recovery of alcohol seeking (16), cue-induced cocaine seeking (17), and discrete cue- and drug priming-induced reinstatement of methamphetamine seeking (18). LY379268 injections also decrease cocaine priming-induced reinstatement in squirrel monkeys (19).…”

Section: Introductionmentioning

confidence: 99%

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

Justinová

Panlilio

Secci

et al. 2015

Biological Psychiatry

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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.

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Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration

Cited by 46 publications

References 63 publications

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

The mGluR2/3 Agonist LY379268 Induced Anti-Reinstatement Effects in Rats Exhibiting Addiction-like Behavior

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

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

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