Chronic Nicotine Exposure Alters Metabotropic Glutamate Receptor 5: Longitudinal PET Study and Behavioural Assessment in Rats
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.
KeywordsNicotine 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.
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.
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.
- 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. https://doi.org/10.1073/pnas.1210984110 CrossRefGoogle Scholar
- 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
- 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
- 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. https://doi.org/10.1111/jnc.13652 CrossRefGoogle Scholar
- 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
- 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
- Collins AC, Pogun S, Nesil T, Kanit L (2012) Oral nicotine self-administration in rodents. J Addict Res Ther 01(S2). https://doi.org/10.4172/2155-6105.S2-004
- 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. https://doi.org/10.1016/j.neuropharm.2011.08.028 CrossRefGoogle Scholar
- 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
- 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. https://doi.org/10.1007/s00259-015-3167-6 CrossRefGoogle Scholar
- Fan X, Konold T (2010) Statistical significance versus effect size. In, pp 444–450. https://doi.org/10.1016/B978-0-08-044894-7.01368-3 Google Scholar
- 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. https://doi.org/10.1038/mp.2013.51 CrossRefGoogle Scholar
- 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. https://doi.org/10.2967/jnumed.116.176032 CrossRefGoogle Scholar
- 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. https://doi.org/10.1007/s12640-017-9727-8 CrossRefGoogle Scholar
- 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. https://doi.org/10.1007/s12640-017-9857-z CrossRefGoogle Scholar
- 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. https://doi.org/10.1007/s00213-006-0441-0 CrossRefGoogle Scholar
- 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. https://doi.org/10.1111/jnc.13001 CrossRefGoogle Scholar
- 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. https://doi.org/10.1016/j.phrs.2015.11.016 CrossRefGoogle Scholar
- 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. https://doi.org/10.1007/s00259-014-2883-7 CrossRefGoogle Scholar