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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    • ") LSP1-3081 (3S)-3-[(3-amino-3-carboxypropyl(hydroxy)phosphinyl)- hydroxymethyl]-5-nitrothiophene EC 50 = 417 μM ( Olive, 2009) LSP1-2111 (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro- phenyl)methyl]phosphoryl]-butanoic acid EC 50 = 52.8 μM ( Olive, 2009) L-SOP L-Serine-O-phosphate EC 50 N 160 μM ( Conn & Pin, 1997) RS-PPG (RS)-4-phosphono-2-aminobutyric acid EC 50 = 185 μM ( Gasparini et al., 1999) L-CCG-I (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine EC 50 = 230 μM ( Brabet et al., 1998) L-AP4 L-(+)-2-amino-4-phosphonobutyric acid EC 50 = 100–500 μM (Gasparini et al., 1999; Beurrier et al., 2009; Flor & Acher, 2012) AMN082 N,N′-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride EC 50 = 64–290 nM (Beurrier et al., 2009; Urwyler, 2011) CPPG (RS)-α-cyclopropyl-4-phosphonophenylglycine – (Toms et al., 1996) Moreover, activation of these receptors can reduce locomotor hyperactivity and dopamine release induced by psychostimulants (Mao et al., 2000; Xi et al., 2003 "
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    ABSTRACT: Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction.
    Pharmacology [?] Therapeutics 12/2013; 142(3). DOI:10.1016/j.pharmthera.2013.12.012 · 9.72 Impact Factor
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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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(7). DOI:10.1038/npp.2013.29 · 7.05 Impact Factor
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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.
    Psychopharmacology 11/2012; 226(3). DOI:10.1007/s00213-012-2925-4 · 3.88 Impact Factor
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