title: Awake rat pharmacological magnetic resonance imaging as a translational pharmacodynamic biomarker: metabotropic glutamate 2/3 agonist modulation of ketamine-induced blood oxygenation level dependence signals.
abstract: Neuroimaging techniques have been exploited to characterize the effect of N-methyl-d-aspartate (NMDA) receptor antagonists on brain activation in humans and animals. However, most preclinical imaging studies were conducted in anesthetized animals and could be confounded by potential drug-anesthetic interactions as well as anesthetic agents' effect on brain activation, which may affect the translation of these basic research findings to the clinical setting. The main aim of the current study was to examine the brain activation elicited by the infusion of a subanesthetic dose of ketamine using blood oxygenation level dependence (BOLD) pharmacological magnetic resonance imaging (phMRI) in awake rats. However, a secondary aim was to determine whether a behaviorally active metabotropic glutamate 2/3 receptor agonist, (1S,2R,5R,6R)-2-amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268), could modulate the effects of ketamine-induced brain activation. Our data indicate that ketamine produces positive BOLD signals in several cortical and hippocampal regions, whereas negative BOLD signals were observed in regions, such as periaqueductal gray (PAG) (p < 0.05). Furthermore, pretreatment of LY379268 significantly attenuated ketamine-induced brain activation in a region-specific manner (posterior cingulate, entorhinal, and retrosplenial cortices, hippocampus CA1, and PAG). The [corrected] region-specific brain activations observed in this ketamine phMRI study may afford a method of confirming central activity and dose selection in early clinical trials for novel experimental therapeutics. [corrected]
authors.affiliation: Translational Imaging, Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Chin
authors.forename: Jaymin
authors.initials: J
authors.lastname: Upadhyay
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Marek
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Mario
authors.initials: M
authors.lastname: Mezler
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Mark
authors.initials: M
authors.lastname: Day
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001784:Blood Gas Analysis / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D010865:Pilot Projects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects* / Q000502:physiology
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D007649:Ketamine