title: Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats.
abstract: BACKGROUND
  Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders.
  
  
  OBJECTIVE
  We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe.
  
  
  METHODS
  Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity.
  
  
  RESULTS
  In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia.
  
  
  CONCLUSIONS
  This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Grimm
authors.affiliation: Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany. natalia.gass@zi-mannheim.de.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gass
authors.affiliation: Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weber-Fahr
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.|Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.affiliation: Neuroscience Drug Discovery Unit, Institut de Recherches Servier, Croissy s/Seine, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Schenker
authors.affiliation: Spedding Research Solutions, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
authors.affiliation: CNS Biomarker, Pharmaceuticals Division, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Celine
authors.initials: C
authors.lastname: Risterucci
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Janina Isabel
authors.initials: JI
authors.lastname: Schweiger
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Böhringer
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Zang
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
authors.affiliation: Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA.|Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.|Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA.
authors.forename: Adam James
authors.initials: AJ
authors.lastname: Schwarz
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D007649:Ketamine
keywords: Cross-species; Ketamine; Prefrontal-hippocampal; Schizophrenia; fMRI