, Volume 234, Issue 9–10, pp 1347–1355 | Cite as

From bench to bedside: mGluR2 positive allosteric modulators as medications to treat substance use disorders

  • Jane B. AcriEmail author
  • Alan J. Cross
  • Phil Skolnick



This paper provides an overview of the role of type 2 metabotropic glutamate receptors (mGluR2) in addiction and behaviors reflecting addictive processes.


AZD8529, an mGluR2 positive allosteric modulator (PAM), failed to separate from placebo in a phase II schizophrenia trial. The demonstration by Athina Markou’s laboratory that AZD8529 attenuated both nicotine self-administration and cue-induced reinstatement was a key factor in the decision to move this compound into a smoking cessation study.


Here, we highlight Markou laboratory’s contribution to this project, as well as several innovative features of the phase II clinical trial that has already completed enrollment with top line results expected in early 2017.


Athina Markou mGluR2 Cocaine Nicotine Glutamate Self-administration Cue-induced reinstatement Animal models Smoking cessation 


Compliance with Ethical Standards

Conflicts of interest

JBA and PS are employees of the US Government and have no conflicts of interest. AJC is an employee of AstraZeneca.


  1. Adewale AS, Platt DM, Spealman RD (2006) Pharmacological stimulation of group ii metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther 318:922–931CrossRefPubMedGoogle Scholar
  2. Anwyl R (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev 29:83–120CrossRefPubMedGoogle Scholar
  3. Augier E, Dulman RS, Rauffenbart C, Augier G, Cross AJ, Heilig M (2016) The mGluR2 positive allosteric modulator, AZD8529, and cue-induced relapse to alcohol seeking in rats. Neuropsychopharmacology:1–9. doi: 10.1038/npp.2016.107
  4. Back SE, Hartwell K, Desantis SM, Saladin M, McRae-Clark AL, Price KL, Moran-Santa Maria MM, Baker NL, Spratt E, Kreek MJ, Brady KT (2010) Reactivity to laboratory stress provocation predicts relapse to cocaine. Drug Alcohol Depend 106:21–27CrossRefPubMedGoogle Scholar
  5. Backstrom P, Hyytia P (2006) Ionotropic and metabotropic glutamate receptor antagonism attenuates cueinduced cocaine seeking. Neuropsychopharmacology 31(4):778–786Google Scholar
  6. Baptista MA, Martin-Fardon R, Weiss F (2004) Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer. J Neurosci 24:4723–4727CrossRefPubMedGoogle Scholar
  7. Ben-Shahar O, Moscarello JM, Jacob B, Roarty MP, Ettenberg A (2005) Prolonged daily exposure to i.v. cocaine results in tolerance to its stimulant effects. Pharmacol Biochem Behav 82:411–416CrossRefPubMedGoogle Scholar
  8. Berridge KC (2007) The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology 191:391–431CrossRefPubMedGoogle Scholar
  9. Bossert JM, Busch RF, Gray SM (2005) The novel mGluR2/3 agonist LY379268 attenuates cue-induced reinstatement of heroin seeking. Neuroreport 16:1013–1016CrossRefPubMedGoogle Scholar
  10. Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF (2002a) Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77:683–687CrossRefPubMedGoogle Scholar
  11. Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Hoffman A, Perkins KA, Sved AF (2002b) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology (Berl) 163:230–237CrossRefGoogle Scholar
  12. Cannella N, Halbout B, Uhrig S, Evrard L, Corsi M, Corti C, Deroche-Gamonet V, Hansson AC, Spanagel R (2013) The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology 38:2048–2056CrossRefPubMedPubMedCentralGoogle Scholar
  13. Caprioli D, Venniro M, Zeric T, Li X, Adhikary S, Madangopal R, Marchant NJ, Lucantonio F, Schoenbaum G, Bossert JM, Shaham Y (2015) Effect of the novel positive allosteric modulator of metabotropic glutamate receptor 2 AZD8529 on incubation of methamphetamine craving after prolonged voluntary abstinence in a rat model. Biol Psychiatry 78:463–473CrossRefPubMedPubMedCentralGoogle Scholar
  14. Childress AR, Hole AV, Ehrman RN, Robbins SJ, McLellan AT, O’Brien CP (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73–95PubMedGoogle Scholar
  15. Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18CrossRefPubMedPubMedCentralGoogle Scholar
  16. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713CrossRefPubMedGoogle Scholar
  17. Conn PJ (2003) Physiological roles and therapeutic potential of metabotropic glutamate receptors. Ann N Y Acad Sci 1003:12–21CrossRefPubMedGoogle Scholar
  18. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237CrossRefPubMedGoogle Scholar
  19. Cook D, Brown D, Alexander R, March R, Morgan P, Satterthwaite G, Pangalos MN (2014) Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework. Nat Rev Drug Discov 13:419–431CrossRefPubMedGoogle Scholar
  20. Czobor P, Skolnick P (2011) The secrets of a successful clinical trial: compliance, compliance, and compliance. Mol Interv 11:107–110CrossRefPubMedPubMedCentralGoogle Scholar
  21. D’Souza MS, Liechti ME, Ramirez-Nino AM, Kuczenski R, Markou A (2011) The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine-associated context in rats. Neuropsychopharmacology 36:2111–2124CrossRefPubMedPubMedCentralGoogle Scholar
  22. DiChiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278CrossRefGoogle Scholar
  23. Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, de P T, Conn PJ (2006) Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J Pharmacol Exp Ther 318:173–185CrossRefPubMedGoogle Scholar
  24. Gass JT, Olive MF (2008) Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 75:218–265CrossRefPubMedGoogle Scholar
  25. Gawin F, Kleber H (1986a) Pharmacologic treatments of cocaine abuse. Psychiatr Clin North Am 9:573–583PubMedGoogle Scholar
  26. Gawin FH, Kleber HD (1986b) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch Gen Psychiatry 43:107–113CrossRefPubMedGoogle Scholar
  27. Goldman M, Szucs-Reed RP, Jagannathan K, Ehrman RN, Wang Z, Li Y, Suh JJ, Kampman K, O’Brien CP, Childress AR, Franklin TR (2013) Reward-related brain response and craving correlates of marijuana cue exposure: a preliminary study in treatment-seeking marijuana-dependent subjects. J Addict Med 7:8–16CrossRefPubMedPubMedCentralGoogle Scholar
  28. Hampson AJ, Babalonis S, Lofwall MR, Nuzzo PA, Krieter P, Walsh SL (2016) A pharmacokinetic study examining acetazolamide as a novel adherence marker for clinical trials. J Clin Psychopharmacol 36:324–332CrossRefPubMedGoogle Scholar
  29. Jin X, Semenova S, Yang L, Ardecky R, Sheffler DJ, Dahl R, Conn PJ, Cosford ND, Markou A (2010) The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats. Neuropsychopharmacology 35:2021–2036CrossRefPubMedPubMedCentralGoogle Scholar
  30. Justinova Z, Panlilio LV, Secci ME, Redhi GH, Schindler CW, Cross AJ, Mrzljak L, Medd A, Shaham Y, Goldberg SR (2015) The novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, decreases nicotine self-administration and relapse in squirrel monkeys. Biol Psychiatry 78:452–462CrossRefPubMedPubMedCentralGoogle Scholar
  31. Justinova Z, Le FB, Redhi GH, Markou A, Goldberg SR (2016) Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology 233:1791–1800CrossRefPubMedGoogle Scholar
  32. Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413CrossRefPubMedGoogle Scholar
  33. Karasawa J, Yoshimizu T, Chaki S (2006) A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell. Neurosci Lett 393:127–130CrossRefPubMedGoogle Scholar
  34. Kasanetz F, Lafourcade M, Deroche-Gamonet V, Revest JM, Berson N, Balado E, Fiancette JF, Renault P, Piazza PV, Manzoni OJ (2013) Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol Psychiatry 18:729–737CrossRefPubMedGoogle Scholar
  35. Kashem MA, Ahmed S, Sarker R, Ahmed EU, Hargreaves GA, McGregor IS (2012) Long-term daily access to alcohol alters dopamine-related synthesis and signaling proteins in the rat striatum. Neurochem Int 61:1280–1288CrossRefPubMedGoogle Scholar
  36. Kober H, Mende-Siedlecki P, Kross EF, Weber J, Mischel W, Hart CL, Ochsner KN (2010) Prefrontal-striatal pathway underlies cognitive regulation of craving. Proc Natl Acad Sci U S A 107:14811–14816CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kosten T (1992) Can cocaine craving be a medication development outcome? Drug craving and relapse in opioid and cocaine dependence . pp 230–239Google Scholar
  38. Kosten TR, Scanley BE, Tucker KA, Oliveto A, Prince C, Sinha R, Potenza MN, Skudlarski P, Wexler BE (2006) Cue-induced brain activity changes and relapse in cocaine-dependent patients. Neuropsychopharmacology 31:644–650CrossRefPubMedGoogle Scholar
  39. Li X, D’Souza MS, Nino AM, Doherty J, Cross A, Markou A (2016) Attenuation of nicotine-taking and nicotine-seeking behavior by the mGlu2 receptor positive allosteric modulators AZD8418 and AZD8529 in rats. Psychopharmacology 233:1801–1814CrossRefPubMedGoogle Scholar
  40. Liechti ME, Markou A (2008) Role of the glutamatergic system in nicotine dependence: implications for the discovery and development of new pharmacological smoking cessation therapies. CNS Drugs 22:705–724CrossRefPubMedGoogle Scholar
  41. Litman RE, Smith MA, Doherty JJ, Cross A, Raines S, Gertsik L, Zukin SR (2016) AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: a proof of principle study. Schizophr Res 172:152–157CrossRefPubMedGoogle Scholar
  42. Loweth JA, Tseng KY, Wolf ME (2014) Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving. Neuropharmacology 76 :287–300Pt BCrossRefPubMedGoogle Scholar
  43. Luis C, Cannella N, Spanagel R, Kohr G (2016) Persistent strengthening of the prefrontal cortex-nucleus accumbens pathway during incubation of cocaine-seeking behavior. Neurobiol Learn Mem. doi: 10.1016/j.nlm.2016.10.003 PubMedGoogle Scholar
  44. Lujan R, Nusser Z, Roberts JD, Shigemoto R, Somogyi P (1996) Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur J Neurosci 8:1488–1500CrossRefPubMedGoogle Scholar
  45. Malcolm R, Myrick H, Li X, Henderson S, Brady KT, George MS, See RE (2016) Regional Brain Activity in Abstinent Methamphetamine Dependent Males Following Cue Exposure. J Drug Abuse 2Google Scholar
  46. Mameli M, Luscher C (2011) Synaptic plasticity and addiction: learning mechanisms gone awry. Neuropharmacology 61:1052–1059CrossRefPubMedGoogle Scholar
  47. McCann DJ, Petry NM, Bresell A, Isacsson E, Wilson E, Alexander RC (2015) Medication nonadherence, “professional subjects,” and apparent placebo responders: overlapping challenges for medications development. J Clin Psychopharmacol 35:566–573CrossRefPubMedPubMedCentralGoogle Scholar
  48. Meinhardt MW, Hansson AC, Perreau-Lenz S, Bauder-Wenz C, Stahlin O, Heilig M, Harper C, Drescher KU, Spanagel R, Sommer WH (2013) Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence. J Neurosci 33:2794–2806CrossRefPubMedPubMedCentralGoogle Scholar
  49. Mitchell PB, Morris MJ (2007) Depression and anxiety with rimonabant. Lancet 370:1671–1672CrossRefPubMedGoogle Scholar
  50. Monn JA, Valli MJ, Massey SM, Hansen MM, Kress TJ, Wepsiec JP, Harkness AR, Grutsch JL Jr, Wright RA, Johnson BG, Andis SL, Kingston A, Tomlinson R, Lewis R, Griffey KR, Tizzano JP, Schoepp DD (1999) Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J Med Chem 42:1027–1040CrossRefPubMedGoogle Scholar
  51. Moussawi K, Zhou W, Shen H, Reichel CM, See RE, Carr DB, Kalivas PW (2011) Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci U S A 108:385–390CrossRefPubMedGoogle Scholar
  52. Nakanishi S (1994) Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron 13:1031–1037CrossRefPubMedGoogle Scholar
  53. Olive MF (2009) Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2:83–98CrossRefPubMedPubMedCentralGoogle Scholar
  54. Pecknold JC, McClure D, Appeltauer L (1980) Fenobam in anxious outpatients. Curr Ther Res 27:119–123Google Scholar
  55. Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, Allan T (1982) Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 2:129–133CrossRefPubMedGoogle Scholar
  56. Schoepp DD (2001) Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J Pharmacol Exp Ther 299:12–20PubMedGoogle Scholar
  57. Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith AC, Roberts-Wolfe D, Kalivas PW (2016) The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev 68:816–871CrossRefPubMedGoogle Scholar
  58. Shiovitz TM, Bain EE, McCann DJ, Skolnick P, Laughren T, Hanina A, Burch D (2016) Mitigating the effects of nonadherence in clinical trials. J Clin Pharmacol 56:1151–1164CrossRefPubMedPubMedCentralGoogle Scholar
  59. Sidique S, Dhanya RP, Sheffler DJ, Nickols HH, Yang L, Dahl R, Mangravita-Novo A, Smith LH, D’Souza MS, Semenova S, Conn PJ, Markou A, Cosford ND (2012) Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence. J Med Chem 55:9434–9445CrossRefPubMedPubMedCentralGoogle Scholar
  60. Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology 158:343–359CrossRefPubMedGoogle Scholar
  61. Spooren W, Ballard T, Gasparini F, Amalric M, Mutel V, Schreiber R (2003) Insight into the function of group I and group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders. Behav Pharmacol 14:257–277CrossRefPubMedGoogle Scholar
  62. Wong RK, Bianchi R, Taylor GW, Merlin LR (1999) Role of metabotropic glutamate receptors in epilepsy. Adv Neurol 79:685–698PubMedGoogle Scholar
  63. Wood CM, Nicolas CS, Choi SL, Roman E, Nylander I, Fernandez-Teruel A, Kiianmaa K, Bienkowski P, de Jong TR, Colombo G, Chastagnier D, Wafford KA, Collingridge GL, Wildt SJ, Conway-Campbell BL, Robinson ES, Lodge D (2016) Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour. Neuropharmacology. doi: 10.1016/j.neuropharm.2016.03.020 Google Scholar
  64. Xi ZX, Spiller K, Pak AC, Gilbert J, Dillon C, Li X, Peng XQ, Gardner EL (2008) Cannabinoid CB1 receptor antagonists attenuate cocaine’s rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropsychopharmacology 33:1735–1745CrossRefPubMedGoogle Scholar
  65. Zhao Y, Dayas CV, Aujla H, Baptista MA, Martin-Fardon R, Weiss F (2006) Activation of group II metabotropic glutamate receptors attenuates both stress and cue-induced ethanol-seeking and modulates c-fos expression in the hippocampus and amygdala. J Neurosci 26:9967–9974CrossRefPubMedGoogle Scholar
  66. Zhou Z, Karlsson C, Liang T, Xiong W, Kimura M, Tapocik JD, Yuan Q, Barbier E, Feng A, Flanigan M, Augier E, Enoch MA, Hodgkinson CA, Shen PH, Lovinger DM, Edenberg HJ, Heilig M, Goldman D (2013) Loss of metabotropic glutamate receptor 2 escalates alcohol consumption. Proc Natl Acad Sci U S A 110:16963–16968CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2016

Authors and Affiliations

  1. 1.Division of Therapeutics and Medical ConsequencesNational Institute on Drug AbuseBethesdaUSA
  2. 2.AstraZeneca Neuroscience Innovative Medicines and Early Development Biotech UnitCambridgeUSA

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