title: Ketamine-induced brain activation in awake female nonhuman primates: a translational functional imaging model.
abstract: BACKGROUND
  There is significant interest in the NMDA receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis.
  
  
  OBJECTIVE
  The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine.
  
  
  METHODS
  Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic intravenous (i.v.) infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/h constant infusion) with and without risperidone pretreatment (0.06 mg/kg). Statistical parametric maps of ketamine-induced blood oxygenation level-dependent (BOLD) activation were obtained with appropriate general linear regression models (GLMs) incorporating motion and hemodynamics of ketamine infusion.
  
  
  RESULTS
  Ketamine infusion induced and sustained robust BOLD activation in a number of cortical and subcortical regions, including the thalamus, cingulate gyrus, and supplementary motor area. Pretreatment with the antipsychotic drug risperidone markedly blunted ketamine-induced activation in many brain areas.
  
  
  CONCLUSIONS
  The results are remarkably similar to human imaging studies showing ketamine-induced BOLD activation in many of the same brain areas, and pretreatment with risperidone or another antipsychotic blunting the ketamine response to a similar extent. The strong concordance of the functional imaging data in humans with these results from nonhuman primates highlights the translational value of the model and provides an excellent avenue for future research examining the CNS effects of ketamine. This model may also be a useful tool for evaluating the efficacy of novel antipsychotic drugs.
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Maltbie
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Kaundinya
authors.initials: K
authors.lastname: Gopinath
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA.|Dainippon Sumitomo Pharma, Co. Ltd., Osaka, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Urushino
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA.
authors.forename: Doty
authors.initials: D
authors.lastname: Kempf
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA. lhowell@emory.edu.|Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. lhowell@emory.edu.
authors.forename: Leonard
authors.initials: L
authors.lastname: Howell
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007649:Ketamine / Q000494:pharmacology*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018967:Risperidone / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D018967:Risperidone
keywords: Antipsychotic drugs; Ketamine; Nonhuman primates; Pharmacological MRI; Schizophrenia; Translational models