Chronic Nicotine Exposure Alters Metabotropic Glutamate Receptor 5: Longitudinal PET Study and Behavioural Assessment in Rats

  • Adrienne Müller Herde
  • Yoan Mihov
  • Stefanie D. Krämer
  • Linjing Mu
  • Antoine Adamantidis
  • Simon M. Ametamey
  • Gregor HaslerEmail author
Original Article


Using positron emission tomography (PET), a profound alteration of the metabotropic glutamate receptor 5 (mGluR5) was found in human smoking addiction and abstinence. As human PET data either reflect the impact of chronic nicotine exposure or a pre-existing vulnerability to nicotine addiction, we designed a preclinical, longitudinal study to investigate the effect of chronic nicotine exposure on mGluR5 with the novel radiotracer [18F]PSS232 using PET. Twelve male dark Agouti rats at the age of 6 weeks were assigned randomly to three groups. From day 0 to day 250 the groups received 0 mg/L, 4 mg/L, or 8 mg/L nicotine solution in the drinking water. From day 250 to 320 all groups received nicotine-free drinking water. PET scans with [18F]PSS232 were performed in all animals on days 0, 250, and 320. To assess locomotion, seven tests in square open field arenas were carried out 72 days after the last PET scan. During the first four tests, rats received 0 mg/L nicotine and for the last three tests 4 mg/L nicotine in the drinking water. After 250 days of nicotine consumption [18F]PSS232 binding was reduced in the striatum, hippocampus, thalamus, and midbrain. At day 320, after nicotine withdrawal, [18F]PSS232 binding increased. These effects were more pronounced in the 4 mg/L nicotine group. Chronic administration of nicotine through the drinking water reduced exploratory behaviour. This preliminary longitudinal PET study demonstrates that chronic nicotine administration alters behaviour and mGluR5 availability. Chronic nicotine administration leads to decreased [18F]PSS232 binding which normalizes after prolonged nicotine withdrawal.


Nicotine mGluR5 PET [18F]PSS232 Addiction 



We thank Bruno Mancosu, Gloria Pla-Gonzales, and Annette Krämer for radiotracer production. Claudia Keller is acknowledged for animal care and performing PET/CT scans. Interim analyses of parts of the data from this study were presented at the conference “Biological Psychiatry” (“Biologische Psychiatrie”) in Oberlech, Austria, on March, 15–18, 2015, and published as a part of the proceedings of the ECNP congress in the journal “European Neuropsychopharmacology”, 2016, vol. 26, Supplement 2, Page S126.

Funding Information

This work was supported by the University of Bern and the OPO Foundation, Zurich, Switzerland.

Compliance with Ethical Standards

Conflict of Interest

G. Hasler received consulting fees and/or honoraria within the last three years from Eli Lilly, Janssen, Lundbeck, Otsuka, Schwabe, Servier and Takeda. Adrienne Herde, Yoan Mihov, Stefanie Krämer, Linjing Mu, Antoine Adamantidis, and Simon Ametamey have no conflicts of interest to report.

Ethical Approval

Animal husbandry and experiments were carried out in accordance with the Swiss legislation on animal welfare and were approved by the Veterinary Offices of the Canton Zurich and Bern, Switzerland.

Supplementary material

12640_2019_55_MOESM1_ESM.doc (5.5 mb)
ESM 1 (DOC 5681 kb)


  1. 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 110:737–742. CrossRefGoogle Scholar
  2. Akkus F, Mihov Y, Treyer V, Ametamey SM, Johayem A, Senn S, Rösner S, Buck A, Hasler G (2018) Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorder. Transl Psychiatry 8:17. CrossRefGoogle Scholar
  3. Akkus F, Treyer V, Ametamey SM, Johayem A, Buck A, Hasler G (2017) Metabotropic glutamate receptor 5 neuroimaging in schizophrenia. Schizophr Res 183:95–101. CrossRefGoogle 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 79:474–480. CrossRefGoogle 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 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med 47:698–705Google 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 11C-ABP688. J Nucl Med 48:247–252Google Scholar
  7. Barr DJ, Levy R, Scheepers C, Tily HJ (2013) Random effects structure for confirmatory hypothesis testing: keep it maximal. J Mem Lang 68:255–278. CrossRefGoogle Scholar
  8. Bates D, Mächler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models using lme4 2015 67:48 doi: Google Scholar
  9. Beggiato S, Tomasini MC, Borelli AC, Borroto-Escuela DO, Fuxe K, Antonelli T, Tanganelli S, Ferraro L (2016) Functional role of striatal A2A, D2, and mGlu5 receptor interactions in regulating striatopallidal GABA neuronal transmission. J Neurochem 138:254–264. CrossRefGoogle Scholar
  10. Brunner E, Domhof S, Langer F (2002) Nonparametric analysis of longitudinal data in factorial experiments. Wiley series in probability and statistics. J. Wiley, New YorkGoogle Scholar
  11. Caldarone BJ, King SL, Picciotto MR (2008) Sex differences in anxiety-like behavior and locomotor activity following chronic nicotine exposure in mice. Neurosci Lett 439:187–191. CrossRefGoogle Scholar
  12. Catania MV, D'Antoni S, Bonaccorso CM, Aronica E, Bear MF et al (2007) Group I metabotropic glutamate receptors: a role in neurodevelopmental disorders? Mol Neurobiol 35:298–307CrossRefGoogle Scholar
  13. Centers for Disease Control and Prevention (2005) Annual smoking-attributable mortality, years of potential life lost, and productivity losses–United States, 1997-2001. MMWR Morb Mortal Wkly Rep 54:625–628Google Scholar
  14. Chiamulera C, Marzo CM, Balfour DJK (2017) Metabotropic glutamate receptor 5 as a potential target for smoking cessation. Psychopharmacology 234:1357–1370. CrossRefGoogle Scholar
  15. Collins AC, Pogun S, Nesil T, Kanit L (2012) Oral nicotine self-administration in rodents. J Addict Res Ther 01(S2).
  16. Conn PJ, Battaglia G, Marino MJ, Nicoletti F (2005) Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat Rev Neurosci 6:787–798. CrossRefGoogle Scholar
  17. D'Souza MS, Markou A (2011) Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) microinfusions into the nucleus accumbens shell or ventral tegmental area attenuate the reinforcing effects of nicotine in rats. Neuropharmacology 61:1399–1405. CrossRefGoogle Scholar
  18. Domenici MR, Pintor A, Potenza RL, Gaudi S, Gro MC et al (2003) Metabotropic glutamate receptor 5 (mGluR5)-mediated phosphoinositide hydrolysis and NMDA-potentiating effects are blunted in the striatum of aged rats: a possible additional mechanism in striatal senescence. Eur J Neurosci 17:2047–2055CrossRefGoogle Scholar
  19. DuBois JM, Rousset OG, Rowley J, Porras-Betancourt M, Reader AJ et al (2016) Characterization of age/sex and the regional distribution of mGluR5 availability in the healthy human brain measured by high-resolution [(11)C]ABP688 PET. Eur J Nucl Med Mol Imaging 43:152–162. CrossRefGoogle Scholar
  20. Emmitte KA (2017) mGlu5 negative allosteric modulators: a patent review (2013 - 2016). Expert Opin Ther Pat 27:691–706. CrossRefGoogle Scholar
  21. Fan X, Konold T (2010) Statistical significance versus effect size. In, pp 444–450. Google Scholar
  22. Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326:483–504. CrossRefGoogle Scholar
  23. Gaddnas H, Pietila K, Ahtee L (2000) Effects of chronic oral nicotine treatment and its withdrawal on locomotor activity and brain monoamines in mice. Behav Brain Res 113:65–72CrossRefGoogle Scholar
  24. Galli G, Wolffgramm J (2011) Long-term development of excessive and inflexible nicotine taking by rats, effects of a novel treatment approach. Behav Brain Res 217:261–270. CrossRefGoogle Scholar
  25. Hamilton KR, Starosciak AK, Chwa A, Grunberg NE (2012) Nicotine behavioral sensitization in Lewis and Fischer male rats. Exp Clin Psychopharmacol 20:345–351. CrossRefGoogle Scholar
  26. Higa KK, Grim A, Kamenski ME, van Enkhuizen J, Zhou X et al (2017) Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice. Psychopharmacology 234:1573–1586. CrossRefGoogle Scholar
  27. 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 19:625–632. CrossRefGoogle Scholar
  28. Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572. CrossRefGoogle Scholar
  29. Kane JK, Hwang Y, Konu O, Loughlin SE, Leslie FM, Li MD (2005) Regulation of Homer and group I metabotropic glutamate receptors by nicotine. Eur J Neurosci 21:1145–1154. CrossRefGoogle Scholar
  30. Kita T, Nakashima T, Kurogochi Y (1985) Effects of oral administration of nicotine on circadian rhythms of ambulatory activity and drinking in rats. Jpn J Pharmacol 39:554–557CrossRefGoogle Scholar
  31. Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3:760–773. CrossRefGoogle Scholar
  32. Leurquin-Sterk G, Van den Stock J, Crunelle CL, de Laat B, Weerasekera A et al (2016) Positive association between limbic metabotropic glutamate receptor 5 availability and novelty-seeking temperament in humans: an 18F-FPEB PET study. J Nucl Med 57:1746–1752. CrossRefGoogle Scholar
  33. Ludwig V, Mihov Y, Schwarting RK (2008) Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior. Behav Brain Res 189:52–64. CrossRefGoogle Scholar
  34. Manavalan S, Getachew B, Manaye KF, Khundmiri SJ, Csoka AB, McKinley R, Tamas A, Reglodi D, Tizabi Y (2017) PACAP protects against ethanol and nicotine toxicity in SH-SY5Y cells: implications for drinking-smoking co-morbidity. Neurotox Res 32:8–13. CrossRefGoogle Scholar
  35. Marszalek-Grabska M, Gibula-Bruzda E, Bodzon-Kulakowska A, Suder P, Gawel K, Filarowska J, Listos J, Danysz W, Kotlinska JH (2018) Effects of the positive allosteric modulator of metabotropic glutamate receptor 5, VU-29, on impairment of novel object recognition induced by acute ethanol and ethanol withdrawal in rats. Neurotox Res 33:607–620. CrossRefGoogle Scholar
  36. Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR, Craig CR, Collins AC, Damaj MI, Donny EC, Gardiner PS, Grady SR, Heberlein U, Leonard SS, Levin ED, Lukas RJ, Markou A, Marks MJ, McCallum SE, Parameswaran N, Perkins KA, Picciotto MR, Quik M, Rose JE, Rothenfluh A, Schafer WR, Stolerman IP, Tyndale RF, Wehner JM, Zirger JM (2007) Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 190:269–319. CrossRefGoogle Scholar
  37. Menard C, Quirion R (2012) Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways. PLoS One 7:e28666. CrossRefGoogle Scholar
  38. Mihov Y, Hasler G (2016) Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window. Int J Neuropsychopharmacol 19:pyw002. CrossRefGoogle Scholar
  39. Müller Herde A, Keller C, Milicevic Sephton S, Mu L, Schibli R, Ametamey SM, Krämer SD (2015) Quantitative positron emission tomography of mGluR5 in rat brain with [18F]PSS232 at minimal invasiveness and reduced model complexity. J Neurochem 133:330–342. CrossRefGoogle Scholar
  40. Nesil T, Kanit L, Collins AC, Pogun S (2011) Individual differences in oral nicotine intake in rats. Neuropharmacology 61:189–201. CrossRefGoogle Scholar
  41. Olive MF (2009) Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2:83–98CrossRefGoogle Scholar
  42. Pietila K, Lahde T, Attila M, Ahtee L, Nordberg A (1998) Regulation of nicotinic receptors in the brain of mice withdrawn from chronic oral nicotine treatment. Naunyn Schmiedeberg’s Arch Pharmacol 357:176–182CrossRefGoogle Scholar
  43. Pistillo F, Fasoli F, Moretti M, McClure-Begley T, Zoli M, Marks MJ, Gotti C (2016) Chronic nicotine and withdrawal affect glutamatergic but not nicotinic receptor expression in the mesocorticolimbic pathway in a region-specific manner. Pharmacol Res 103:167–176. CrossRefGoogle Scholar
  44. Pomierny-Chamiolo L, Rup K, Pomierny B, Niedzielska E, Kalivas PW et al (2014) Metabotropic glutamatergic receptors and their ligands in drug addiction. Pharmacol Ther 142:281–305. CrossRefGoogle Scholar
  45. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291CrossRefGoogle Scholar
  46. Romano C, Sesma MA, McDonald CT, O'Malley K, Van den Pol AN et al (1995) Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 355:455–469. CrossRefGoogle Scholar
  47. Romano C, Smout S, Miller JK, O’Malley KL (2002) Developmental regulation of metabotropic glutamate receptor 5b protein in rodent brain. Neuroscience 111:693–698CrossRefGoogle Scholar
  48. Sephton SM, Herde AM, Mu L, Keller C, Rudisuhli S et al (2015) Preclinical evaluation and test-retest studies of [(18)F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5). Eur J Nucl Med Mol Imaging 42:128–137. CrossRefGoogle Scholar
  49. 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 219:354–357. CrossRefGoogle Scholar
  50. Tsamis KI, Mytilinaios DG, Njau SN, Baloyannis SJ (2013) Glutamate receptors in human caudate nucleus in normal aging and Alzheimer’s disease. Curr Alzheimer Res 10:469–475CrossRefGoogle Scholar
  51. Welzl H, Alessandri B, Oettinger R, Batig K (1988) The effects of long-term nicotine treatment on locomotion, exploration and memory in young and old rats. Psychopharmacology 96:317–323CrossRefGoogle Scholar
  52. Wijetunge LS, Till SM, Gillingwater TH, Ingham CA, Kind PC (2008) mGluR5 regulates glutamate-dependent development of the mouse somatosensory cortex. J Neurosci 28:13028–13037. CrossRefGoogle Scholar
  53. Yu MF, Fu WM, Yin HS (2000) Effect of amphetamine on the expression of the metabotropic glutamate receptor 5 mRNA in developing rat brain. J Mol Neurosci 15:177–188. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Adrienne Müller Herde
    • 1
  • Yoan Mihov
    • 2
  • Stefanie D. Krämer
    • 1
  • Linjing Mu
    • 3
  • Antoine Adamantidis
    • 4
    • 5
  • Simon M. Ametamey
    • 1
  • Gregor Hasler
    • 6
    Email author
  1. 1.Center for Radiopharmaceutical Sciences of ETH, PSI, and USZDepartment of Chemistry and Applied Biosciences of ETHZurichSwitzerland
  2. 2.Translational Research Center, University Hospital of PsychiatryUniversity of BernBern 60Switzerland
  3. 3.Department of Nuclear Medicine, University Hospital ZurichCenter for Radiopharmaceutical Sciences of ETH, PSI, and USZZurichSwitzerland
  4. 4.Department of Biomedical Research, Inselspital University HospitalUniversity of BernBernSwitzerland
  5. 5.Centre for Experimental Neurology, Department of Neurology, Inselspital University HospitalUniversity of BernBernSwitzerland
  6. 6.Psychiatry Research UnitUniversity of FribourgFribourgSwitzerland

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