Psychopharmacology

, Volume 234, Issue 9–10, pp 1357–1370 | Cite as

Metabotropic glutamate receptor 5 as a potential target for smoking cessation

  • Cristiano Chiamulera
  • Claudio Marcello Marzo
  • David J. K. Balfour
Review
First Online:
Received:
Accepted:

Abstract

Rationale

Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high, and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments.

Objective

The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence.

Results

Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction.

Conclusions

Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence, they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many “off-target” effects to be used clinically. However, newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence.

Keywords

Tobacco addiction mGluR5 Negative allosteric modulator Nicotine self-administration Cue-evoked relapse Smoking cessation Memory reconsolidation 
This is a preview of subscription content, log in to check access.

Notes

Conflict of interest

Authors declare no conflict of interest.

References

  1. Agren T (2014) Human reconsolidation: a reactivation and update. Brain Res Bull 105:70–82PubMedCrossRefGoogle Scholar
  2. AHRQ (2008) Treating tobacco use and dependence: 2008 update. Agency for Healthcare Research and QualityGoogle Scholar
  3. Akkus F, Ametamey SM, Treyer V, Burger C, Johayem A, Umbricht D, Gomez Mancilla B, Sovago J, Buck A, Hasler G (2013) Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography. Proc Natl Acad Sci U S A 110:737–742PubMedCrossRefGoogle Scholar
  4. Akkus F, Treyer V, Johayem A, Ametamey SM, Mancilla BG, Sovago J, Buck A, Hasler G (2016) Association of long-term nicotine abstinence with normal metabotropic glutamate receptor-5 binding. Biol Psychiatry 79:474–480PubMedCrossRefGoogle Scholar
  5. Ametamey SM, Kessler LJ, Honer M, Wyss MT, Buck A, Hintermann S, Auberson YP, Gasparini F, Schubiger PA (2006) Radiosynthesis and preclinical evaluation of C-11-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med 47:698–705PubMedGoogle Scholar
  6. Ametamey SM, Treyer V, Streffer J, Wyss MT, Schmidt M, Blagoev M, Hintermann S, Auberson Y, Gasparini F, Fischer UC, Buck A (2007) Human PET studies of metabotropic glutamate receptor subtype 5 with C-11-ABP688. J Nucl Med 48:247–252PubMedGoogle Scholar
  7. Anwyl R (2009) Metabotropic glutamate receptor-dependent long-term potentiation. Neuropharmacology 56:735–740PubMedCrossRefGoogle Scholar
  8. Arnold JM, Roberts DCS (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447PubMedCrossRefGoogle Scholar
  9. Ary AW, Szumlinski KK (2007) Regional differences in the effects of withdrawal from repeated cocaine upon Homer and glutamate receptor expression: a two-species comparison. Brain Res 1184:295–305PubMedCrossRefGoogle Scholar
  10. Auber A, Karuppasamy NSM, Pedercini M, Bertoglio D, Tedesco V, Chiamulera C (2014) The effect of postretrieval extinction of nicotine pavlovian memories in rats trained to self-administer nicotine. Nicotine & Tobacco Research 16:1599–1605CrossRefGoogle Scholar
  11. Backstrom P, Bachteler D, Koch S, Hyytia P, Spanagel R (2004) mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 29:921–928CrossRefGoogle Scholar
  12. Balfour DJ (2009) The neuronal pathways mediating the behavioral and addictive properties of nicotine. Handb Exp Pharmacol 192:209–233CrossRefGoogle Scholar
  13. Balfour DJ (2015) The role of mesoaccumbens dopamine in nicotine dependence. Curr Top Behav Neurosci 24:55–98PubMedCrossRefGoogle Scholar
  14. Balfour DJ, Wright AE, Benwell ME, Birrell CE (2000) The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav Brain Res 113:73–83PubMedCrossRefGoogle Scholar
  15. Benwell ME, Balfour DJ (1992) The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br J Pharmacol 105:849–856PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bespalov AY, Dravolina OA, Sukhanov I, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A (2005) Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats. Neuropharmacology 49(Suppl 1):167–178PubMedCrossRefGoogle Scholar
  17. Bozarth MA, Pudiak CM, KuoLee R (1998) Effect of chronic nicotine on brain stimulation reward. I. Effect of daily injections. Behav Brain Res 96:185–188PubMedCrossRefGoogle Scholar
  18. Brakeman PR, Lanahan AA, OBrien R, Roche K, Barnes CA, Huganir RL, Worley PF (1997) Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386:284–288PubMedCrossRefGoogle Scholar
  19. Brauer LH, Behm FM, Lane JD, Westman EC, Perkins C, Rose JE (2001) Individual differences in smoking reward from de-nicotinized cigarettes. Nicotine Tob Res 3:101–109PubMedCrossRefGoogle Scholar
  20. Brown RM, Stagnitti MR, Duncan JR, Lawrence AJ (2012) The mGlu5 receptor antagonist MTEP attenuates opiate self-administration and cue-induced opiate-seeking behaviour in mice. Drug Alcohol Depend 123:264–268PubMedCrossRefGoogle Scholar
  21. Cadoni C, Di Chiara G (2000) Differential changes in accumbens shell and core dopamine in behavioral sensitization to nicotine. Eur J Pharmacol 387:R23–R25PubMedCrossRefGoogle Scholar
  22. Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Hoffman A, Perkins KA, Sved AF (2001) Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav 70:515–530PubMedCrossRefGoogle Scholar
  23. Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF (2002) Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77:683–687PubMedCrossRefGoogle Scholar
  24. Carroll FI (2008) Antagonists at metabotropic glutamate receptor subtype 5: structure activity relationships and therapeutic potential for addiction. Ann N Y Acad Sci 1141:221–232PubMedCrossRefGoogle Scholar
  25. Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF (2006) Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology 184:353–366PubMedCrossRefGoogle Scholar
  26. Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, Palmatier MI, Liu X, Sved AF (2007) Self-administered and noncontingent nicotine enhance reinforced operant responding in rats: impact of nicotine dose and reinforcement schedule. Psychopharmacology 190:353–362PubMedCrossRefGoogle Scholar
  27. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4:873–874PubMedCrossRefGoogle Scholar
  28. Clarke PB (1990) Dopaminergic mechanisms in the locomotor stimulant effects of nicotine. Biochem Pharmacol 40:1427–1432PubMedCrossRefGoogle Scholar
  29. Clarke PBS, Fu DS, Jakubovic A, Fibiger HC (1988) Evidence that mesolimbic dopaminergic activation underlies the locomotor stimulant action of nicotine in rats. J Pharmacol Exp Ther 246:701–708PubMedGoogle Scholar
  30. ClinicalTrials.gov (2007) Effects of AFQ056 and nicotine in reducing cigarette smoking. Available at [online]: https://clinicaltrials.gov/show/NCT00414752. Accessed 3 Oct 2016
  31. Cormier RJ, Mennerick S, Melbostad H, Zorumski CF (2001) Basal levels of adenosine modulate mGluR5 on rat hippocampal astrocytes. Glia 33:24–35PubMedCrossRefGoogle Scholar
  32. Cosford ND, Tehrani L, Roppe J, Schweiger E, Smith ND, Anderson J, Bristow L, Brodkin J, Jiang X, McDonald I, Rao S, Washburn M, Varney MA (2003) 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem 46:204–206PubMedCrossRefGoogle Scholar
  33. Crombag HS, Bossert JM, Koya E, Shaham Y (2008) Review. Context-induced relapse to drug seeking: a review. Philos Trans R Soc Lond Ser B Biol Sci 363:3233–3243CrossRefGoogle Scholar
  34. Cryan JF, Gasparini F, van Heeke G, Markou A (2003) Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond bupropion. Drug Discov Today 8:1025–1034PubMedCrossRefGoogle Scholar
  35. Das RK, Hindocha C, Freeman TP, Lazzarino AI, Curran HV, Kamboj SK (2015) Assessing the translational feasibility of pharmacological drug memory reconsolidation blockade with memantine in quitting smokers. Psychopharmacology 232:3363–3374PubMedPubMedCentralCrossRefGoogle Scholar
  36. D’Souza MS, Markou A (2011) Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments. Addict Sci Clin Pract 6:4–16PubMedPubMedCentralGoogle Scholar
  37. Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79PubMedCrossRefGoogle Scholar
  38. Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326:483–504PubMedCrossRefGoogle Scholar
  39. Floresco SB (2007) Dopaminergic regulation of limbic-striatal interplay. J Psychiatr Neurosci 32:400–411Google Scholar
  40. Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Velicelebi G, Kuhn R (1999) 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503PubMedCrossRefGoogle Scholar
  41. Gass JT, Osborne MPH, Watson NL, Brown JL, Olive MF (2009) mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 34:820–833CrossRefGoogle Scholar
  42. Ghasemzadeh MB, Vasudevan P, Mueller C, Seubert C, Mantsch JR (2009) Neuroadaptations in the cellular and postsynaptic group 1 metabotropic glutamate receptor mGluR5 and Homer proteins following extinction of cocaine self-administration. Neurosci Lett 452:167–171PubMedCrossRefGoogle Scholar
  43. Gould RW, Amato RJ, Bubser M, Joffe ME, Nedelcovych MT, Thompson AD, Nickols HH, Yuh JP, Zhan X, Felts AS, Rodriguez AL, Morrison RD, Byers FW, Rook JM, Daniels JS, Niswender CM, Conn PJ, Emmitte KA, Lindsley CW, Jones CK (2016) Partial mGlu(5) negative allosteric modulators attenuate cocaine-mediated behaviors and lack psychotomimetic-like effects. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 41:1166–1178CrossRefGoogle Scholar
  44. Harrison AA, Gasparini F, Markou A (2002) Nicotine potentiation of brain stimulation reward reversed by DH beta E and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats. Psychopharmacology 160:56–66PubMedCrossRefGoogle Scholar
  45. Heidbreder CA, Bianchi H, Lacroix LP, Faedo S, Perdona E, Remelli R, Cavanni P, Crespi F (2003) Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo. Synapse 50:269–276PubMedCrossRefGoogle Scholar
  46. Hodge CW, Miles MF, Sharko AC, Stevenson RA, Hillmann JR, Lepoutre V, Besheer J, Schroeder JP (2006) The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6 J mice. Psychopharmacology 183:429–438PubMedCrossRefGoogle Scholar
  47. Hou L, Klann E (2004) Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24:6352–6361PubMedCrossRefGoogle Scholar
  48. Hughes JR, Carpenter MJ, Naud S (2010) Do point prevalence and prolonged abstinence measures produce similar results in smoking cessation studies? A systematic review. Nicotine & Tobacco Research 12:756–762CrossRefGoogle Scholar
  49. Hulka LM, Treyer V, Scheidegger M, Preller KH, Vonmoos M, Baumgartner MR, Johayem A, Ametamey SM, Buck A, Seifritz E, Quednow BB (2014) Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans. Mol Psychiatry 19:625–632PubMedCrossRefGoogle Scholar
  50. Hustonlyons D, Kornetsky C (1992) Effects of nicotine on the threshold for rewarding brain-stimulation in rats. Pharmacol Biochem Behav 41:755–759CrossRefGoogle Scholar
  51. Jia ZP, Lu YM, Henderson J, Taverna F, Romano C, Abramow-Newerly W, Wojtowicz JM, Roder J (1998) Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learn Memory 5:331–343Google Scholar
  52. Kalivas PW (2004) Glutamate systems in cocaine addiction. Curr Opin Pharmacol 4:23–29PubMedCrossRefGoogle Scholar
  53. Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16:974–986PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kalivas PW, Lalumiere RT, Knackstedt L, Shen H (2009) Glutamate transmission in addiction. Neuropharmacology 56(Suppl 1):169–173PubMedCrossRefGoogle Scholar
  55. Kawabata S, Tsutsumi R, Kohara A, Yamaguchi T, Nakanishi S, Okada M (1996) Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature 383:89–92PubMedCrossRefGoogle Scholar
  56. Keck TM, Zou MF, Bi GH, Zhang HY, Wang XF, Yang HJ, Srivastava R, Gardner EL, Xi ZX, Newman AH (2014) A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats. Addict Biol 19:195–209PubMedCrossRefGoogle Scholar
  57. Kenny PJ, Paterson NE, Boutrel B, Semenova S, Harrison AA, Gasparini F, Koob GF, Skoubis PD, Markou A (2003) Metabotropic glutamate 5 receptor antagonist MPEP decreased nicotine and cocaine self-administration but not nicotine and cocaine-induced facilitation of brain reward function in rats. Ann N Y Acad Sci 1003:415–418PubMedCrossRefGoogle Scholar
  58. Kenny PJ, Boutrel B, Gasparini F, Koob GF, Markou A (2005) Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology 179:247–254PubMedCrossRefGoogle Scholar
  59. Kim JH, Vezina P (1998) Metabotropic glutamate receptors in the rat nucleus accumbens contribute to amphetamine-induced locomotion. J Pharmacol Exp Ther 284:317–322PubMedGoogle Scholar
  60. Kotecha SA, Jackson MF, Al-Mahrouki A, Roder JC, Orser BA, MacDonald JF (2003) Co-stimulation of mGluR5 and N-methyl-D-aspartate receptors is required for potentiation of excitatory synaptic transmission in hippocampal neurons. J Biol Chem 278:27742–27749PubMedCrossRefGoogle Scholar
  61. Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, Pierce RC (2009) Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res 202:238–244PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lecca D, Cacciapaglia F, Valentini V, Gronli J, Spiga S, Di Chiara G (2006) Preferential increase of extracellular dopamine in the rat nucleus accumbens shell as compared to that in the core during acquisition and maintenance of intravenous nicotine self-administration. Psychopharmacology 184:435–446PubMedCrossRefGoogle Scholar
  63. LeSage MG, Burroughs D, Dufek M, Keyler DE, Pentel PR (2004) Reinstatement of nicotine self-administration in rats by presentation of nicotine-paired stimuli, but not nicotine priming. Pharmacol Biochem Behav 79:507–513PubMedCrossRefGoogle Scholar
  64. Leurquin-Sterk G, Van den Stock J, Crunelle CL, de Laat B, Weerasekera A, Himmelreich U, Bormans G, Van Laere K (2016) Positive association between limbic metabotropic glutamate receptor 5 availability and novelty-seeking temperament in humans: a 18F-FPEB PET study. J Nucl MedGoogle Scholar
  65. Li D, Shan H, Conti P, Li Z (2012) PET imaging of metabotropic glutamate receptor subtype 5 (mGluR5). Am J Nucl Med Mol Imaging 2:29–32PubMedGoogle Scholar
  66. Li X, Semenova S, D’Souza MS, Stoker AK, Markou A (2014) Involvement of glutamatergic and GABAergic systems in nicotine dependence: implications for novel pharmacotherapies for smoking cessation. Neuropharmacology 76(Pt B):554–565PubMedCrossRefGoogle Scholar
  67. Liechti ME, Markou A (2007a) Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats. Eur J Pharmacol 554:164–174PubMedCrossRefGoogle Scholar
  68. Liechti ME, Markou A (2007b) Metabotropic glutamate 2/3 receptor activation induced reward deficits but did not aggravate brain reward deficits associated with spontaneous nicotine withdrawal in rats. Biochem Pharmacol 74:1299–1307PubMedCrossRefGoogle Scholar
  69. 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 22:705–724PubMedCrossRefGoogle Scholar
  70. Lindson N, Aveyard P, Hughes JR (2010) Reduction versus abrupt cessation in smokers who want to quit. Cochrane Db Syst RevGoogle Scholar
  71. Liu X, Caggiula AR, Yee SK, Nobuta H, Sved AF, Pechnick RN, Poland RE (2007) Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 32:710–718CrossRefGoogle Scholar
  72. Louis M, Clarke PB (1998) Effect of ventral tegmental 6-hydroxydopamine lesions on the locomotor stimulant action of nicotine in rats. Neuropharmacology 37:1503–1513PubMedCrossRefGoogle Scholar
  73. Luccini E, Musante V, Neri E, Bas MB, Severi P, Raiteri M, Pittaluga A (2007) Functional interactions between presynaptic NMDA receptors and metabotropic glutamate receptors co-expressed on rat and human noradrenergic terminals. Brit J Pharmacol 151:1087–1094CrossRefGoogle Scholar
  74. Malin DH, Lake JR, Newlin-Maultsby P, Roberts LK, Lanier JG, Carter VA, Cunningham JS, Wilson OB (1992) Rodent model of nicotine abstinence syndrome. Pharmacol Biochem Behav 43:779–784PubMedCrossRefGoogle Scholar
  75. Markou A (2007) Metabotropic glutamate receptor antagonists: novel therapeutics for nicotine dependence and depression? Biol Psychiatry 61:17–22PubMedCrossRefGoogle Scholar
  76. Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology 112:163–182PubMedCrossRefGoogle Scholar
  77. Markou A, Paterson NE, Semenova S (2004) Role of gamma-aminobutyric acid (GABA) and metabotropic glutamate receptors in nicotine reinforcement—potential pharmacotherapies for smoking cessation. Current Status of Drug Dependence/Abuse Studies: Cellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity 1025:491–503Google Scholar
  78. Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T (2009) Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 34:74–89CrossRefGoogle Scholar
  79. Martinez D, Slifstein M, Nabulsi N, Grassetti A, Urban NBL, Perez A, Liu F, Lin SF, Ropchan J, Mao XL, Kegeles LS, Shungu DC, Carson RE, Huang YY (2014) Imaging glutamate homeostasis in cocaine addiction with the metabotropic glutamate receptor 5 positron emission tomography radiotracer [C-11]ABP688 and magnetic resonance spectroscopy. Biol Psychiat 75:165–171PubMedCrossRefGoogle Scholar
  80. Marton TM, Hussain Shuler MG, Worley PF (2015) Homer 1a and mGluR5 phosphorylation in reward-sensitive metaplasticity: a hypothesis of neuronal selection and bidirectional synaptic plasticity. Brain Res 1628:17–28PubMedCrossRefGoogle Scholar
  81. McKee SA, Weinberger AH, Shi J, Tetrault J, Coppola S (2012) Developing and validating a human laboratory model to screen medications for smoking cessation. Nicotine Tob Res 14:1362–1371PubMedPubMedCentralCrossRefGoogle Scholar
  82. Mihov Y, Hasler G (2016) Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window. Int J Neuropsychopharmacol 19Google Scholar
  83. Milella MS, Marengo L, Larcher K, Fotros A, Dagher A, Rosa-Neto P, Benkelfat C, Leyton M (2014) Limbic system mGluR5 availability in cocaine dependent subjects: a high-resolution PET [(11)C]ABP688 study. NeuroImage 98:195–202PubMedCrossRefGoogle Scholar
  84. Milton AL, Everitt BJ (2010) The psychological and neurochemical mechanisms of drug memory reconsolidation: implications for the treatment of addiction. Eur J Neurosci 31:2308–2319PubMedCrossRefGoogle Scholar
  85. Milton AL, Merlo E, Ratano P, Gregory BL, Dumbreck JK, Everitt BJ (2013) Double dissociation of the requirement for GluN2B- and GluN2A- containing NMDA receptors in the destabilization and Restabilization of a reconsolidating memory. J Neurosci 33:1109–1115PubMedPubMedCentralCrossRefGoogle Scholar
  86. Mu L, Schubiger PA, Ametamey SM (2010) Radioligands for the PET imaging of metabotropic glutamate receptor subtype 5 (mGluR5). Curr Top Med Chem 10:1558–1568PubMedCrossRefGoogle Scholar
  87. Nickols HH, Yuh JP, Gregory KJ, Morrison RD, Bates BS, Stauffer SR, Emmitte KA, Bubser M, Peng W, Nedelcovych MT, Thompson A, Lv X, Xiang Z, Daniels JS, Niswender CM, Lindsley CW, Jones CK, Conn PJ (2016) VU0477573: partial negative allosteric modulator of the subtype 5 metabotropic glutamate receptor with in vivo efficacy. J Pharmacol Exp Ther 356:123–136PubMedPubMedCentralCrossRefGoogle Scholar
  88. Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041PubMedCrossRefGoogle Scholar
  89. Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol 50:295–322CrossRefGoogle Scholar
  90. Nordquist RE, Steckler T, Wettstein JG, Mackie C, Spooren W (2008) Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety. Psychopharmacology 199:389–402PubMedCrossRefGoogle Scholar
  91. O’Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, Sur C, Duggan ME, Pettibone DJ, Conn PJ, Williams DL Jr (2004) A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther 309:568–577PubMedCrossRefGoogle Scholar
  92. Olive M (2009) Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2:83–98PubMedPubMedCentralCrossRefGoogle Scholar
  93. Osborne MPH, Olive MF (2008) A role for mGluR5 receptors in intravenous methamphetamine self-administration. Drug Addiction: Research Frontiers and Treatment Advances 1139:206–211Google Scholar
  94. Owesson-White CA, Roitman MF, Sombers LA, Belle AM, Keithley RB, Peele JL, Carelli RM, Wightman RM (2012) Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens. J Neurochem 121:252–262PubMedPubMedCentralCrossRefGoogle Scholar
  95. Pachas GN, Gilman J, Orr SP, Hoeppner B, Carlini SV, Loebl T, Nino J, Pitman RK, Evins AE (2015) Single dose propranolol does not affect physiologic or emotional reactivity to smoking cues. Psychopharmacology 232:1619–1628PubMedCrossRefGoogle Scholar
  96. Palmatier MI, Matteson GL, Black JJ, Liu X, Caggiula AR, Craven L, Donny EC, Sved AF (2007) The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections. Drug Alcohol Depend 89:52–59PubMedPubMedCentralCrossRefGoogle Scholar
  97. Palmatier MI, Liu X, Donny EC, Caggiula AR, Sved AF (2008) Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 33:2139–2147CrossRefGoogle Scholar
  98. Parodi M, Patti L, Grilli M, Raiteri M, Marchi M (2006) Nicotine has a permissive role on the activation of metabotropic glutamate 5 receptors coexisting with nicotinic receptors on rat hippocampal noradrenergic nerve terminals. Neurochem Int 48:138–143PubMedCrossRefGoogle Scholar
  99. Paterson NE, Markou A (2005) The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology 179:255–261PubMedCrossRefGoogle Scholar
  100. Paterson NE, Semenova S, Gasparini F, Markou A (2003) The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology 167:257–264PubMedCrossRefGoogle Scholar
  101. Peavy RD, Conn PJ (1998) Phosphorylation of mitogen-activated protein kinase in cultured rat cortical glia by stimulation of metabotropic glutamate receptors. J Neurochem 71:603–612PubMedCrossRefGoogle Scholar
  102. Pillai RL, Tipre DN (2016) Metabotropic glutamate receptor 5—a promising target in drug development and neuroimaging. Eur J Nucl Med Mol Imaging 43:1151–1170PubMedCrossRefGoogle Scholar
  103. Romano C, Sesma MA, Mcdonald CT, Omalley K, Vandenpol AN, Olney JW (1995) Distribution of metabotropic glutamate-receptor Mglur5 immunoreactivity in rat-brain. J Comp Neurol 355:455–469PubMedCrossRefGoogle Scholar
  104. Rong R, Ahn JY, Huang H, Nagata E, Kalman D, Kapp JA, Tu J, Worley PF, Snyder SH, Ye K (2003) PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nat Neurosci 6:1153–1161PubMedCrossRefGoogle Scholar
  105. Rose JE (2006) Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology 184:274–285PubMedCrossRefGoogle Scholar
  106. Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003) Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76:243–250PubMedCrossRefGoogle Scholar
  107. Schroeder JP, Overstreet DH, Hodge CW (2005) The mGluR5 antagonist MPEP decreases operant ethanol self-administration during maintenance and after repeated alcohol deprivations in alcohol-preferring (P) rats. Psychopharmacology 179:262–270PubMedCrossRefGoogle Scholar
  108. Severance AJ, Parsey RV, Kumar JS, Underwood MD, Arango V, Majo VJ, Prabhakaran J, Simpson NR, Van Heertum RL, Mann JJ (2006) In vitro and in vivo evaluation of [11C]MPEPy as a potential PET ligand for mGlu5 receptors. Nucl Med Biol 33:1021–1027PubMedCrossRefGoogle Scholar
  109. Shigemoto R, Nomura S, Ohishi H, Sugihara H, Nakanishi S, Mizuno N (1993) Immunohistochemical localization of a metabotropic glutamate-receptor, Mglur5, in the rat-brain. Neurosci Lett 163:53–57PubMedCrossRefGoogle Scholar
  110. Stoker AK, Olivier B, Markou A (2012) Involvement of metabotropic glutamate receptor 5 in brain reward deficits associated with cocaine and nicotine withdrawal and somatic signs of nicotine withdrawal. Psychopharmacology 221:317–327PubMedCrossRefGoogle Scholar
  111. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4:131–U34PubMedCrossRefGoogle Scholar
  112. Szumlinski KK, Kalivas PW, Worley PF (2006) Homer proteins: implications for neuropsychiatric disorders. Curr Opin Neurobiol 16:251–257PubMedCrossRefGoogle Scholar
  113. Taber MT, Fibiger HC (1995) Electrical-stimulation of the prefrontal cortex increases dopamine release in the nucleus-accumbens of the rat—modulation by metabotropic glutamate receptors. J Neurosci 15:3896–3904PubMedGoogle Scholar
  114. Tallaksen-Greene SJ, Kaatz KW, Romano C, Albin RL (1998) Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons. Brain Res 780:210–217PubMedCrossRefGoogle Scholar
  115. Tedesco V, Mutti A, Auber A, Chiamulera C (2014) Nicotine-seeking reinstatement is reduced by inhibition of instrumental memory reconsolidation. Behav Pharmacol 25:725–731PubMedCrossRefGoogle Scholar
  116. Tessari M, Pilla M, Andreoli M, Hutcheson DM, Heidbreder CA (2004) Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. Eur J Pharmacol 499:121–133PubMedCrossRefGoogle Scholar
  117. Tronci V, Balfour DJ (2011) The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on the stimulation of dopamine release evoked by nicotine in the rat brain. Behav Brain Res 219:354–357PubMedCrossRefGoogle Scholar
  118. Tronci V, Vronskaya S, Montgomery N, Mura D, Balfour DJ (2010) The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on behavioural responses to nicotine. Psychopharmacology 211:33–42PubMedPubMedCentralCrossRefGoogle Scholar
  119. van der Kam EL, de Vry J, Tzschentke TM (2007) Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat. Behav Pharmacol 18:717–724PubMedCrossRefGoogle Scholar
  120. Welsby P, Rowan M, Anwyl R (2006) Nicotinic receptor-mediated enhancement of long-term potentiation involves activation of metabotropic glutamate receptors and ryanodine-sensitive calcium stores in the dentate gyrus. Eur J Neurosci 24:3109–3118PubMedCrossRefGoogle Scholar
  121. WHO (2015) Report on the global tobacco epidemic, 2015. World Health OrganizationGoogle Scholar
  122. Wing VC, Shoaib M (2008) Contextual stimuli modulate extinction and reinstatement in rodents self-administering intravenous nicotine. Psychopharmacology 200:357–365PubMedCrossRefGoogle Scholar
  123. Xiao B, Tu JC, Worley PF (2000) Homer: a link between neural activity and glutamate receptor function. Curr Opin Neurobiol 10:370–374PubMedCrossRefGoogle Scholar
  124. Zhang T, Zhang L, Liang Y, Siapas AG, Zhou FM, Dani JA (2009) Dopamine signaling differences in the nucleus accumbens and dorsal striatum exploited by nicotine. J Neurosci 29:4035–4043PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Cristiano Chiamulera
    • 1
  • Claudio Marcello Marzo
    • 1
  • David J. K. Balfour
    • 2
  1. 1.Neuropsychopharmacology Lab., Section Pharmacology, Department Diagnostic and Public HealthUniversity of VeronaVeronaItaly
  2. 2.Division of NeuroscienceUniversity of Dundee Medical SchoolDundeeUK

Personalised recommendations