title: Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.
abstract: Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Biological Imaging Centre, Imperial College London, White City, London, United Kingdom.
authors.forename: Anouk
authors.initials: A
authors.lastname: Schrantee
authors.affiliation: Biological Imaging Centre, Imperial College London, White City, London, United Kingdom.|Centre for Trauma Sciences, The Blizard Institute, London, United Kingdom.
authors.forename: Jordi L
authors.initials: JL
authors.lastname: Tremoleda
authors.affiliation: Biological Imaging Centre, Imperial College London, White City, London, United Kingdom.|Neuroradiological Academic Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Marzena
authors.initials: M
authors.lastname: Wylezinska-Arridge
authors.affiliation: Normandie-Université, GMPc, EA 4259, Université de Caen Basse-Normandie, Caen, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Bouet
authors.affiliation: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Hesseling
authors.affiliation: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gideon F
authors.initials: GF
authors.lastname: Meerhoff
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Kora M
authors.initials: KM
authors.lastname: de Bruin
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koeleman
authors.affiliation: Normandie-Université, GMPc, EA 4259, Université de Caen Basse-Normandie, Caen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Freret
authors.affiliation: Normandie-Université, GMPc, EA 4259, Université de Caen Basse-Normandie, Caen, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Boulouard
authors.affiliation: UMR Inserm U930, Université François-Rabelais de Tours, Tours, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Desfosses
authors.affiliation: UMR Inserm U930, Université François-Rabelais de Tours, Tours, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Galineau
authors.affiliation: Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems @ UNITN, Rovereto, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.affiliation: Normandie-Université, GMPc, EA 4259, Université de Caen Basse-Normandie, Caen, France.
authors.forename: François
authors.initials: F
authors.lastname: Dauphin
authors.affiliation: Biological Imaging Centre, Imperial College London, White City, London, United Kingdom.|Biomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: Gsell
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Booij
authors.affiliation: Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.affiliation: Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Reneman
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D003913:Dextroamphetamine / Q000009:adverse effects / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006439:Hemodynamics; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; C000607792:DRD2 protein, rat; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D017448:Receptors, Dopamine D2; D008774:Methylphenidate; D003913:Dextroamphetamine; D004298:Dopamine