title: Multiprobe molecular imaging of an NMDA receptor hypofunction rat model for glutamatergic dysfunction.
abstract: There are many indications of a connection between abnormal glutamate transmission through N-methyl-d-aspartate (NMDA) receptor hypofunction and the occurrence of schizophrenia. The importance of metabotropic glutamate receptor subtype 5 (mGluR5) became generally recognized due to its physical link through anchor proteins with NMDAR. Neuroinflammation as well as the kynurenine (tryptophan catabolite; TRYCAT) pathway are equally considered as major contributors to the pathology. We aimed to investigate this interplay between glutamate release, neuronal activation and inflammatory markers, by using small-animal positron emission tomography (PET) in a rat model known to induce schizophrenia-like symptoms. Daily intraperitoneal injection of MK801 or saline were administered to induce the model together with N-Acetyl-cysteine (NAc) or saline as the treatment in 24 male Sprague Dawley rats for one month. Biweekly in vivo [(11)C]-ABP688 microPET was performed together with mGluR5 immunohistochemistry. Simultaneously, weekly in vivo [(18)F]-FDG microPET imaging data for glucose metabolism was acquired and microglial activation was investigated with biweekly in vivo [(18)F]-PBR111 scans versus OX42 immunohistochemistry. Finally, plasma samples were analyzed for TRYCAT metabolites. We show that chronic MK801 administration (and thus elevated endogenous glutamate) causes significant tissue loss in rat brain, enhances neuroinflammatory pathways and may upregulate mGluR5 expression.
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.
authors.forename: Lauren
authors.initials: L
authors.lastname: Kosten
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Verhaeghe
authors.affiliation: Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Verkerk
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium; Department of Nuclear Medicine, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Thomae
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp, Belgium.
authors.forename: Livia
authors.initials: L
authors.lastname: De Picker
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium; Department of Nuclear Medicine, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.affiliation: Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van Eetveldt
authors.affiliation: Translational Neurosciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium; Department of Nuclear Medicine, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium. Electronic address: steven.staelens@uantwerpen.be.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D057054:Molecular Imaging; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D014364:Tryptophan
keywords: Animal model; Glutamate; Molecular imaging; Schizophrenia; TRYCAT