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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

Abstract

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.

Keywords

Nicotine mGluR5 PET [18F]PSS232 Addiction 

Notes

Acknowledgements

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)

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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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