title: In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry.
abstract: Abuse of methamphetamine (METH) is a major and significant societal problem in the US, as a number of studies have suggested that METH is associated with increased cerebrovascular events, hemorrhage or vasospasm. Although cellular and molecular mechanisms involved in METH-induced toxicity are not completely understood, changes in brain O₂ may play an important role and contribute to METH-induced neurotoxicity including dopaminergic receptor degradation. Given that O₂ is the terminal electron acceptor for many enzymes that are important in brain function, the impact of METH on brain tissue pO₂ in vivo remains largely uncharacterized. This study investigated striatal tissue pO₂ changes in male C57BL/6 mice (16-20 g) following METH administration using EPR oximetry, a highly sensitive modality to measure pO₂ in vivo, in situ and in real time. We demonstrate that 20 min after a single injection of METH (8 mg/kg i.v.), the striatal pO₂ was reduced to 81% of the pretreatment level and exposure to METH for 3 consecutive days further attenuated striatal pO₂ to 64%. More importantly, pO₂ did not recover fully to control levels even 24 h after administration of a single dose of METH and continual exposure to METH exacerbates the condition. We also show a reduction in cerebral blood flow associated with a decreased brain pO₂ indicating an ischemic condition. Our findings suggests that administration of METH can attenuate brain tissue pO₂, which may lead to hypoxic insult, thus a risk factor for METH-induced brain injury and the development of stroke in young adults.
authors.affiliation: Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. Electronic address: jmweaver@salud.unm.edu.
authors.forename: John
authors.initials: J
authors.lastname: Weaver
authors.affiliation: Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Yirong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Purvis
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Weatherwax
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD 21201, USA; Center for EPR Imaging In Vivo Physiology, University of Maryland, Baltimore, MD 21201, USA; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Rosen
authors.affiliation: Center of Biomedical Research Excellence, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D002560:Cerebrovascular Circulation; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D002534:Hypoxia, Brain / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects* / Q000473:pathology; D010092:Oximetry / Q000379:methods*; D010100:Oxygen / Q000378:metabolism*
chemical_list: D008694:Methamphetamine; D010100:Oxygen
keywords: Brain oxygen; Cerebral blood flow; EPR oximetry; Hypoxia; Methamphetamine; Neurotoxicity