Metabotropic Glutamate Receptor Ligands as Potential Therapeutics for Addiction

Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, MSC 861, Charleston, SC 29425, USA.
Current Drug Abuse Reviews 02/2009; 2(1):83-98. DOI: 10.2174/1874473710902010083
Source: PubMed


There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials.

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    • "Here we suggest three incremental requirements, which have to be fulfilled, to demonstrate a therapeutic potential for mGluR5 NAMs in substance-related and addictive disorders, based on animal model-studies: 1. Addiction-like animal behaviour should be reliably suppressed by mGluR5 NAMs 2. Moreover, there should be a clear-cut dose-response relationship allowing a prediction of which dose range and corresponding mGluR5 occupancy range is needed to reduce addiction-like behavior 3. Finally, there should be a " therapeutic window " , within which addiction-like animal behavior is suppressed without affecting responding to natural reinforcers Previous reviews (Markou, 2007;Bird and Lawrence, 2009;Olive, 2009;Holmes et al., 2013;Pomierny-Chamiolo et al., 2014) have demonstrated the high efficacy of mGluR5 NAMs in reducing addiction-like behavior, as required by the first criterion. However, systematic reviews on the second and third requirements are still missing. "
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    ABSTRACT: Background: Abundant evidence at the anatomical, electrophysiological, and molecular level implicates metabotropic glutamate receptors subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential which can be translated to the clinic. Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs MTEP and MPEP on paradigms with cocaine, ethanol, nicotine, and food in rats. Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine, at doses equal to or higher than 1 mg/kg and 2.5 mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine but not food was reduced by MTEP and MPEP in the dose range 1-2 mg/kg and 2.5-3.2mg/kg, respectively. This dose range corresponds to approximately 50%-80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs which can be translated to the treatment of substance-related and addictive disorders.
    Full-text · Article · Jan 2016 · The International Journal of Neuropsychopharmacology
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    • "mGluR5 is abundantly expressed in the nucleus accumbens (Shigemoto et al, 1993). Inhibition of protein synthesis in the nucleus accumbens and other parts of the reward circuitry may account for the effects of mGluR5 antagonists on addictive behavior (Chiamulera et al, 2001; Herzig and Schmidt, 2004; Kenny et al, 2005; Kumaresan et al, 2009; Lee et al, 2005; McGeehan and Olive, 2003; Olive, 2009). "
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    ABSTRACT: Antagonism of group I metabotropic glutamate receptors (mGluR 1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses, and mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome. It remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB(1) receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine.Neuropsychopharmacology accepted article preview online, 24 January 2013; doi:10.1038/npp.2013.29.
    Full-text · Article · Jan 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "The attention is currently focused on metabotropic glutamate receptors (mGluR) as they participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system (Knopfel et al. 1995). In particular, mGlu receptors 5 (mGluR5) seem to have a putative role in several neuropsychiatric disorders (Cleva and Olive 2011; De Leonibus et al. 2009; Spooren et al. 2000a, b), such as in Parkinson's disease (PD) and in drug addiction (Olive 2009; Rylander et al. 2010). Converging evidence in rodents and primates suggested mGluR5 blockade as a novel and effective antiparkinsonian agent. "
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    ABSTRACT: RATIONALE: Metabotropic glutamate mGlu receptors 5 (mGluR5) receptors are abundant in corticolimbic circuitry where they modulate glutamate and dopamine signal transduction. OBJECTIVES: In this study, we explored the hypothesis that mGluR5 antagonist, (2-methyl-6-(phenylethynyl)pyridine hydrochloride) (MPEP), facilitates dopamine-dependent effects on memory and motor functions. METHODS: To this aim, we examined the effects of different doses (from 0 to 24 mg/kg) of the mGluR5 antagonist, MPEP, on the modulation of amphetamine-dependent behaviors, namely passive avoidance, locomotor activity, and rotation behavior in intact and dopamine-depleted CD1 male mice. RESULTS: We demonstrated that a low dose (3 mg/kg) of MPEP, which is void of behavioral effects on its own, facilitates amphetamine-induced effects independently on the behavior measured both in naïve and in dopamine-lesioned mice; this synergistic effect is lost when higher doses of MPEP are used. CONCLUSION: The results are discussed in terms of possible balance between dopamine and glutamate activity in regulating the proper fine tuning of information processing.
    Full-text · Article · Nov 2012 · Psychopharmacology
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