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Molecular Pathways Associated with Stress Resilience and Drug Resistance in the Chronic Mild Stress Rat Model of Depression—a Gene Expression Study

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Abstract

The current antidepressant drugs are ineffective in 30 to 40% of the treated patients; hence, the pathophysiology of the disease needs to be further elucidated. We used the chronic mild stress (CMS) paradigm to induce anhedonia, a core symptom of major depression, in rats. A fraction of the animals exposed to CMS is resistant to the development of anhedonia; they are CMS resilient. In the CMS-sensitive animals, the induced anhedonic state is reversed in 50% of the animals when treating with escitalopram, whereas the remaining animals are treatment resistant. We used the microarray and the real-time quantitative reverse transcription polymerase chain reaction technique, as well as the ingenuity pathway analysis software to identify the differential gene expression pathways, which are associated with the occurrence of the treatment resistance and the stress-resilient rats. In the hippocampus, we found a significant upregulation of apoptotic pathways in the treatment-resistant animals and significantly increased expression levels of genes involved in hippocampal signaling in the CMS-resilient rats. We hypothesize that sensitivity to the stress-induced anhedonia in rats is correlated with the impairment of hippocampal neurogenesis.

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Abbreviations

APP:

amyloid beta precursor protein

CMS:

chronic mild stress

CMS-Es-R:

chronic mild stress sensitive escitalopram responders

CMS-Es-NR:

chronic mild stress sensitive escitalopram non-responders

CMS-RS:

chronic mild stress resilient

CMS-V:

chronic mild stress sensitive vehicle

IPA:

ingenuity pathway analysis

qRT-PCR:

(real-time) quantitative reverse transcription-polymerase chain reaction

RT-PCR:

reverse transcription-polymerase chain reaction

TNF:

tumor necrosis factor

U-Es:

unchallenged escitalopram

U-V:

unchallenged vehicle

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Acknowledgments

The authors would like to thank Ph.D. Arne Mørk at H. Lundbeck, Copenhagen for excellent advice on neuropsychopharmacology in general. We also thank Jan Torleif Pedersen and Karina Fog at H. Lundbeck, Copenhagen, for instructions on the use of the Ingenuity Pathway Analysis software. Specifically, we are grateful for the use of the Lundbeck license of IPA. Finally, we are grateful to Lundbeckfonden and the Danish Medical Research Council for supporting the project.

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Authors and Affiliations

  1. Centre for Basic Psychiatric Research, Aarhus Psychiatric Hospital, Aarhus, Denmark

    A. Bergström, M. N. Jayatissa & O. Wiborg

  2. Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital/Skejby Sygehus, Aarhus, Denmark

    T. Thykjær

  3. OWn Research Aps, Science Park Skejby, Brendstrupgaardsvej 102, Aarhus, Denmark

    O. Wiborg

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  1. A. Bergström
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Correspondence to O. Wiborg.

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Bergström, A., Jayatissa, M.N., Thykjær, T. et al. Molecular Pathways Associated with Stress Resilience and Drug Resistance in the Chronic Mild Stress Rat Model of Depression—a Gene Expression Study. J Mol Neurosci 33, 201–215 (2007). https://doi.org/10.1007/s12031-007-0065-9

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