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Psychopharmacology

, Volume 236, Issue 12, pp 3451–3463 | Cite as

NMDA receptor antagonists traxoprodil and lanicemine improve hippocampal-prefrontal coupling and reward-related networks in rats

  • Robert BeckerEmail author
  • Natalia Gass
  • Lothar Kußmaul
  • Bernhard Schmid
  • Stefan Scheuerer
  • David Schnell
  • Cornelia Dorner-Ciossek
  • Wolfgang Weber-Fahr
  • Alexander Sartorius
Original Investigation

Abstract

Rationale

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine is known to have not only a rapid antidepressant effect but also dissociative side effects. Traxoprodil and lanicemine, also NMDA antagonists, are candidate antidepressant drugs with fewer side effects.

Objectives

In order to understand their mechanism of action, we investigated the acute effects of traxoprodil and lanicemine on brain connectivity using resting-state functional magnetic resonance imaging (rs-fMRI).

Methods

Functional connectivity (FC) alterations were examined using interregional correlation networks. Graph theoretical methods were used for whole brain network analysis. As interest in NMDAR antagonists as potential antidepressants was triggered by the antidepressant effect of ketamine, results were compared to previous findings from our ketamine studies.

Results

Similar to ketamine but to a smaller extent, traxoprodil increased hippocampal-prefrontal (Hc-PFC) coupling. Unlike ketamine, traxoprodil decreased connectivity within the PFC. Lanicemine had no effect on these properties. The improvement of Hc-PFC coupling corresponds well to clinical result, showing ketamine to have a greater antidepressant effect than traxoprodil, while lanicemine has a weak and transient effect. Connectivity changes overlapping between the drugs as well as alterations of local network properties occurred mostly in reward-related regions.

Conclusion

The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs.

Keywords

NMDA antagonists fMRI Networks Hippocampal-prefrontal coupling 

Notes

Acknowledgments

We thank Claudia Falfan-Melgoza and Felix Hörner for excellent technical assistance.

Funding information

This study was supported by an unrestricted grant of Boehringer Ingelheim Pharma, Ingelheim, Germany.

It was partially supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft): DFG GA 2109/2-1 to N.G. and DFG SA 1869/11-2 and SA 1869/14–1 to A.S.

Compliance with ethical standards

Conflict of interest

LK, BS, SS, DS, and CDC are employees of Boehringer Ingelheim Pharma, Ingelheim, Germany. All other authors state no conflict of interest.

Supplementary material

213_2019_5310_MOESM1_ESM.pdf (351 kb)
ESM 1 (PDF 350 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Robert Becker
    • 1
    Email author
  • Natalia Gass
    • 1
  • Lothar Kußmaul
    • 2
  • Bernhard Schmid
    • 2
  • Stefan Scheuerer
    • 2
  • David Schnell
    • 2
  • Cornelia Dorner-Ciossek
    • 2
  • Wolfgang Weber-Fahr
    • 1
  • Alexander Sartorius
    • 1
    • 3
  1. 1.Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  2. 2.Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany
  3. 3.Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany

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