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Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats

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Abstract

Rationale

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.

Objectives

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.

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Acknowledgments

The authors thank Felix Hörner and Claudia Falfan-Melgoza for their excellent technical assistance.

Conflict of interest

NEWMEDS—the research leading to these results, has received support from the Innovative Medicine Initiative Joint Undertaking under Grant Agreement No. 115008 of which resources are composed of the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union’s Seventh Framework Program (FP7/2007–2013). Also the work was supported by the BMBF (01EW1110) in the frame of ERA-Net NEURON. AJS is an employee and shareholder of Eli Lilly and Company; ES is an employee of Instituts de Recherches Servier; MS is an employee of Spedding Research Solutions; and CR is an employee of F. Hoffman-La Roche.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany

    Oliver Grimm, Alexander Sartorius, Janina Isabel Schweiger, Andreas Böhringer, Zhenxiang Zang, Heike Tost & Andreas Meyer-Lindenberg

  2. Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany

    Natalia Gass, Wolfgang Weber-Fahr & Alexander Sartorius

  3. Neuroscience Drug Discovery Unit, Institut de Recherches Servier, Croissy s/Seine, France

    Esther Schenker

  4. Spedding Research Solutions, Paris, France

    Michael Spedding

  5. CNS Biomarker, Pharmaceuticals Division, F. Hoffmann-La Roche, Basel, Switzerland

    Celine Risterucci

  6. Tailored Therapeutics, Eli Lilly and Company, Indianapolis, IN, USA

    Adam James Schwarz

  7. Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA

    Adam James Schwarz

  8. Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA

    Adam James Schwarz

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  2. Natalia Gass
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  3. Wolfgang Weber-Fahr
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Corresponding author

Correspondence to Natalia Gass.

Additional information

Oliver Grimm and Natalia Gass shared first authorship.

Adam J. Schwarz and Andreas Meyer-Lindenberg shared last authorship.

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Grimm, O., Gass, N., Weber-Fahr, W. et al. Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats. Psychopharmacology 232, 4231–4241 (2015). https://doi.org/10.1007/s00213-015-4022-y

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