The mGluR5 Antagonist 6-Methyl-2-(phenylethynyl)pyridine Decreases Ethanol Consumption via a Protein Kinase Cϵ-Dependent Mechanism

Ernest Gallo Clinic and Research Center, Department of Neurology, University of California at San Francisco, 5858 Horton St., Suite 200, Emeryville, CA 94608, USA.
Molecular Pharmacology (Impact Factor: 4.13). 03/2005; 67(2):349-55. DOI: 10.1124/mol.104.003319
Source: PubMed


Glutamatergic neurotransmission plays a critical role in addictive behaviors, and recent evidence indicates that genetic or pharmacological inactivation of the type 5 metabotropic glutamate receptor (mGluR5) reduces the self-administration of cocaine, nicotine, and alcohol. Because mGluR5 is coupled to activation of protein kinase C (PKC), and targeted deletion of the epsilon isoform (PKCepsilon) in mice reduces ethanol self-administration, we investigated whether there is a functional link between mGluR5 and PKCepsilon. Here, we show that acute administration of the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine to mice increases phosphorylation of PKCepsilon in its activation loop (T566) as well as in its C-terminal region (S729). Increases in phospho-PKCepsilon are dependent not only on mGluR5 stimulation but also on phosphatidylinositol-3 kinase (PI3K). In addition, the selective mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) reduced basal levels of phosphorylation of PKCepsilon at S729. We also show that MPEP dose dependently reduced ethanol consumption in wild-type but not in PKCepsilon-null mice, suggesting that PKCepsilon is an important signaling target for modulation of ethanol consumption by mGluR5 antagonists. Radioligand binding experiments using [(3)H]MPEP revealed that these genotypic differences in response to MPEP were not a result of altered mGluR5 levels or binding in PKCepsilon-null mice. Our data indicate that mGluR5 is coupled to PKCepsilon via a PI3K-dependent pathway and that PKCepsilon is required for the ability of the mGluR5 antagonist MPEP to reduce ethanol consumption.

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    • "In reinstatement studies, self-administration training was followed by extinction and, subsequently, reinstatement of drug seeking by either a priming administration of the reinforcer (substance-induced reinstatement) or a response-contingent administration of the conditioned cues which had been delivered together with the reinforcer during selfadministration training (cue-induced reinstatement). Thus, the main experimental paradigms were consumption under direct access to the reinforcer, self-administration maintenance under a fixed reinforcement schedule, substance-, or cue-induced reinstatement of drug seeking.A total of 125 reports (Chiamulera et al., 2001;Paterson et al., 2003;Backstrom et al., 2004;Tessari et al., 2004;Bespalov et al., 2005;Bradbury et al., 2005;Cowen et al., 2005;Kenny et al., 2005;Lee et al., 2005;McMillen et al., 2005;Olive et al., 2005;Paterson and Markou, 2005;Schroeder et al., 2005;Varty et al., 2005;Backstrom and Hyytia, 2006;Hodge et al., 2006;Iso et al., 2006;Lominac et al., 2006;Cowen et al., 2007;Liechti and Markou, 2007;Semenova and Markou, 2007;van der Kam et al., 2007;Adams et al., 2008;Besheer et al., 2008;Gupta et al., 2008;Osborne and Olive, 2008;Palmatier et al., 2008;Platt et al., 2008;Schroeder et al., 2008;Gass et al., 2009;Kumaresan et al., 2009;Martin-Fardon et al., 2009;Moussawi et al., 2009;Hao et al., 2010;Ploj et al., 2010;Sidhpura et al., 2010;Tronci et al., 2010;Eiler et al., 2011;Popik et al., 2011;Tronci and Balfour, 2011;Martin-Fardon and Weiss, 2012;Varga et al., 2012;Keck et al., 2013;Watterson et al., 2013;Keck et al., 2014)on the effects of mGluR5 NAMs were extracted and classified with respect to the following parameters: publication (source of the report), mGluR5 NAM (MPEP, MTEP, fenobam, or MFZ 10-7), species (rats, mice, or monkeys), administration route (i.p., s.c., i.m., or i.v.), administered dose (mg/kg), and experimental paradigm (Supplementary Figures S1-4). Furthermore, the alpha error correction-method reported was extracted for each study (Supplementary Table S1). "
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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.
    Full-text · Article · Jan 2016 · The International Journal of Neuropsychopharmacology
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    • "(MTEP), as well as fenobam significantly inhibit behaviors associated with addiction in experimental animals, including cocaine self-administration (Tessari et al. 2004; Kenny et al. 2005; Lee et al. 2005; Paterson & Markou 2005; Martin-Fardon et al. 2009; Keck et al. 2013), cocaine-induced conditioned place preference (McGeehan & Olive 2003; Herzig & Schmidt 2004), cocaine-induced hyperactivity (McGeehan, Janak & Olive 2004), and cocaine-, cue-or stress-induced reinstatement of drug-seeking behavior (Lee et al. 2005; Backström & Hyytiä 2006; Kumaresan et al. 2009; Martin-Fardon & Weiss 2012; Keck et al. 2013; Wang et al. 2013). These data strongly suggest that mGluR5 plays an important role in cocaine abuse and addiction and that mGluR5 NAMs may have potential for the treatment of cocaine addiction in humans (Heidbreder et al. 2003; Olive et al. 2005). However, MPEP and MTEP have not been tested in human trials for multiple reasons (Lindsley & Emmitte 2009). "
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    ABSTRACT: Pre-clinical studies suggest that negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5), including 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and fenobam are highly effective in attenuating drug-taking and drug-seeking behaviors. However, both MPEP and MTEP have no translational potential for use in humans because of their off-target effects and short half-lives. Here, we report that 3-fluoro-5-[(6-methylpyridin-2-yl)ethynyl]benzonitrile (MFZ 10-7), a novel mGluR5 NAM, is more potent and selective than MPEP, MTEP and fenobam in both in vitro binding and functional assays. Similar to MTEP, intraperitoneal administration of MFZ 10-7 inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Although MFZ 10-7 and MTEP lowered the rate of oral sucrose self-administration, they did not alter total sucrose intake. Further, MFZ 10-7 appeared to be more potent than MTEP in inducing downward shifts in the cocaine dose-response curve, but less effective than MTEP in attenuating sucrose-induced reinstatement of sucrose-seeking behavior. MFZ 10-7 and MTEP had no effect on basal locomotor behavior. These findings not only provide additional evidence supporting an important role for mGluR5 in cocaine reward and addiction, but also introduce a new tool for both in vitro and in vivo investigations with which to further characterize this role.
    Full-text · Article · Mar 2014 · Addiction Biology
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    • "One potential pharmacotherapeutic target is the metabotropic glutamate receptor 5 (mGluR5). Inhibition of mGluR5 signaling using the antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reduced the rewarding effects of EtOH in animal models of EtOH drinking as well as during self-administration and reinstatement (B€ ackstr€ om et al., 2004; Besheer et al., 2010; Hodge et al., 2006; Lominac et al., 2006; McMillen et al., 2005; Olive et al., 2005; Schroeder et al., 2005). When locally infused into the nucleus accumbens (NAc), MPEP significantly decreased binge EtOH consumption (Cozzoli et al., 2009, 2012). "
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    ABSTRACT: Background Binge ethanol (EtOH) intake during adolescence leads to an array of behavioral and cognitive consequences including elevated intake of EtOH during adulthood, with female mice showing greater susceptibility than males. Administration of the metabotropic glutamate receptor 5 (mGluR5) antagonist 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) has been shown to reduce EtOH self-administration in adult male mice, but little is known about its effect on female and adolescent mice.MethodsMTEP (0, 10, 20 mg/kg, i.p.) was repeatedly administered to female and male, adult and adolescent C57BL/6J mice during binge sessions using the scheduled high alcohol consumption paradigm. Next, we assessed whether MTEP administration during binge altered the subsequent 24-hour EtOH intake following a period of abstinence. Finally, we investigated whether MTEP administration during binge followed by an abstinence period altered mRNA of glutamatergic genes within the nucleus accumbens of female mice.ResultsMTEP significantly decreased binge EtOH intake in all mice, but only female mice exhibited altered subsequent 24-hour EtOH intake. Interestingly, the alteration in subsequent EtOH intake in female animals was age dependent, with adolescent exposure to MTEP during binge decreasing 24-hour intake and adult exposure to MTEP during binge increasing 24-hour intake. Finally, while there were no effects of MTEP pretreatment on the genes examined, there was a robust age effect found during analysis of mGluR1 (Grm1), mGluR5 (Grm5), the NR2A subunit of the NMDA receptor (Grin2a), phosphatidylinositol 3-kinase (Pik3r1), mammalian target of rapamycin (Mtor), and extracellular signal-regulated kinase (Mapk1) mRNA, with adolescent female animals having lower expression than their adult counterparts.Conclusions Collectively, the present findings add to existing evidence implicating the contribution of long-term effects of adolescent binge drinking to enhance alcohol abuse in adulthood, while suggesting that mGluR5 antagonism may not be the best pharmacotherapy to treat binge alcohol consumption in female and adolescent animals.
    Full-text · Article · Mar 2014 · Alcoholism Clinical and Experimental Research
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