Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate

• Published in: PloS one Vol. 12; no. 2; p. e0172776
• Main Authors: Schrantee, Anouk, Tremoleda, Jordi L, Wylezinska-Arridge, Marzena, Bouet, Valentine, Hesseling, Peter, Meerhoff, Gideon F, de Bruin, Kora M, Koeleman, Jan, Freret, Thomas, Boulouard, Michel, Desfosses, Emilie, Galineau, Laurent, Gozzi, Alessandro, Dauphin, François, Gsell, Willy, Booij, Jan, Lucassen, Paul J, Reneman, Liesbeth
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.02.2017; Public Library of Science (PLoS)
• Subjects: Abnormalities; Amphetamines; Animal biology; Animals; Attention deficit hyperactivity disorder; Autoradiography; Biology and Life Sciences; Brain; Brain - drug effects; Brain - metabolism; Care and treatment; Caudate-putamen; Cellular Biology; Central Nervous System Stimulants; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - pharmacology; Change detection; Chromatography; Chromatography, High Pressure Liquid; Cocaine; Corpus Striatum; Corpus Striatum - metabolism; Damage assessment; Dextroamphetamine; Dextroamphetamine - adverse effects; Dextroamphetamine - pharmacology; Diagnosis; Dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine receptors; Dopamine transporter; Dopamine Uptake Inhibitors; Dopamine Uptake Inhibitors - pharmacology; Dopaminergic mechanisms; Dopaminergic Neurons; Dopaminergic Neurons - drug effects; Drug Administration Schedule; Drug dosages; Drug therapy; Drugs; Experiments; Exposure; Glial Fibrillary Acidic Protein; Glial Fibrillary Acidic Protein - metabolism; Health aspects; Hemodynamics; High performance liquid chromatography; Homovanillic acid; Immunohistochemistry; Life Sciences; Liquid chromatography; Magnetic Resonance Imaging; Male; Medical imaging; Medicine and Health Sciences; Mental disorders; Metabolites; Methylphenidate; Methylphenidate - pharmacology; Nerve endings; Neurons and Cognition; Neurosciences; Neurotoxicity; NMR; Nuclear magnetic resonance; Nuclear medicine; Nucleus accumbens; Pharmaceutical sciences; Pharmacology; Psychopharmacology; Putamen; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D2 - metabolism; Research and Analysis Methods; Rodents; Studies; Transport buildings, stations and terminals; France; United Kingdom > UK; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0172776

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.