title: 1H NMR-based metabolomics reveals neurochemical alterations in the brain of adolescent rats following acute methylphenidate administration.
abstract: The psychostimulant methylphenidate (MPH) is increasingly used in the treatment of attention deficit hyperactivity disorder (ADHD). While there is little evidence for common brain pathology in ADHD, some studies suggest a right hemisphere dysfunction among people diagnosed with the condition. However, in spite of the high usage of MPH in children and adolescents, its mechanism of action is poorly understood. Given that MPH blocks the neuronal transporters for dopamine and noradrenaline, most research into the effects of MPH on the brain has largely focused on these two monoamine neurotransmitter systems. Interestingly, recent studies have demonstrated metabolic changes in the brain of ADHD patients, but the impact of MPH on endogenous brain metabolites remains unclear. In this study, a proton nuclear magnetic resonance (1H NMR)-based metabolomics approach was employed to investigate the effects of MPH on brain biomolecules. Adolescent male Sprague Dawley rats were injected intraperitoneally with MPH (5.0 mg/kg) or saline (1.0 ml/kg), and cerebral extracts from the left and right hemispheres were analysed. A total of 22 variables (representing 13 distinct metabolites) were significantly increased in the MPH-treated samples relative to the saline-treated controls. The upregulated metabolites included: amino acid neurotransmitters such as GABA, glutamate and aspartate; large neutral amino acids (LNAA), including the aromatic amino acids (AAA) tyrosine and phenylalanine, both of which are involved in the metabolism of dopamine and noradrenaline; and metabolites associated with energy and cell membrane dynamics, such as creatine and myo-inositol. No significant differences in metabolite concentrations were found between the left and right cerebral hemispheres. These findings provide new insights into the mechanisms of action of the anti-ADHD drug MPH.
authors.affiliation: Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Quansah
authors.affiliation: Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz-Rodado
authors.affiliation: Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Grootveld
authors.affiliation: Department of Pharmacology, Oxford University, Mansfield Road, Oxford OX1 3QT, UK.
authors.forename: Fay
authors.initials: F
authors.lastname: Probert
authors.affiliation: Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK. Electronic address: tscz@dmu.ac.uk.
authors.forename: Tyra S C
authors.initials: TSC
authors.lastname: Zetterström
mesh_terms: D000367:Age Factors; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008774:Methylphenidate / Q000008:administration & dosage* / Q000633:toxicity; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D011522:Protons; D008774:Methylphenidate
keywords: (1)H NMR; ADHD; Cerebral hemispheres; GABA; Methylphenidate; Tyrosine