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  • Original Article
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Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine

Molecular Psychiatry volume 12, pages 167–189 (2007)Cite this article

Abstract

The significant proportion of depressed patients that are resistant to monoaminergic drug therapy and the slow onset of therapeutic effects of the selective serotonin reuptake inhibitors (SSRIs)/serotonin/noradrenaline reuptake inhibitors (SNRIs) are two major reasons for the sustained search for new antidepressants. In an attempt to identify common underlying mechanisms for fast- and slow-acting antidepressant modalities, we have examined the transcriptional changes in seven different brain regions of the rat brain induced by three clinically effective antidepressant treatments: electro convulsive therapy (ECT), sleep deprivation (SD), and fluoxetine (FLX), the most commonly used slow-onset antidepressant. Each of these antidepressant treatments was applied with the same regimen known to have clinical efficacy: 2 days of ECT (four sessions per day), 24 h of SD, and 14 days of daily treatment of FLX, respectively. Transcriptional changes were evaluated on RNA extracted from seven different brain regions using the Affymetrix rat genome microarray 230 2.0. The gene chip data were validated using in situ hybridization or autoradiography for selected genes. The major findings of the study are:

  1. 1

    The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment.

  2. 2

    The fast-onset, short-lived antidepressant treatments ECT and SD evoked transcriptional changes primarily in the catecholaminergic system, whereas the slow-onset antidepressant FLX treatment evoked transcriptional changes in the serotonergic system.

  3. 3

    ECT and SD affect in a similar manner the same brain regions, primarily the locus coeruleus, whereas the effects of FLX were primarily in the dorsal raphe and hypothalamus, suggesting that both different regions and pathways account for fast onset but short lasting effects as compared to slow-onset but long-lasting effects. However, the similarity between effects of ECT and SD is somewhat confounded by the fact that the two treatments appear to regulate a number of transcripts in an opposite manner.

  4. 4

    Multiple transcripts (e.g. brain-derived neurotrophic factor (BDNF), serum/glucocorticoid-regulated kinase (Sgk1)), whose level was reported to be affected by antidepressants or behavioral manipulations, were also found to be regulated by the treatments used in the present study. Several novel findings of transcriptional regulation upon one, two or all three treatments were made, for the latter we highlight homer, erg2, HSP27, the proto oncogene ret, sulfotransferase family 1A (Sult1a1), glycerol 3-phosphate dehydrogenase (GPD3), the orphan receptor G protein-coupled receptor 88 (GPR88) and a large number of expressed sequence tags (ESTs).

  5. 5

    Transcripts encoding proteins involved in synaptic plasticity in the hippocampus were strongly affected by ECT and SD, but not by FLX.

The novel transcripts, concomitantly regulated by several antidepressant treatments, may represent novel targets for fast onset, long-duration antidepressants.

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Acknowledgements

We acknowledge all our collagues for their help: colleagues in the Bartfai lab: Hedie Badieh, Marga Behrens, Svetlana Gaidarova, Jeffrey Kinney, Janell Laca, Jacinta Lucero, Shuei Sugama, Iustin Tabarean and Sebastian Wirz all spent countless hours in assisting us with the treatments described. Colleagues in the Hoyer lab: Dominique Fehlmann, Edi Schuepbach, Sabine Leonhard and Deepak Thakker have performed ISH, autoradiography and data analysis thereof. Colleagues in the Maier lab: Jose Luis Crespo and Doris Rueegg have performed the RNA isolations and cloning of the in situ probes. We also thank Nicole Hartmann and her team from the Genomics Factory at NIBR Basel for the microarray work.

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Author notes

  1. A M Barr

    Present address: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

  2. M C Morale

    Present address: Dipartimento di Neurofarmacologia, OASI (IRCCS), Troina, Italy

Authors and Affiliations

  1. Molecular and Integrative Neuroscience Department, The Harold L Dorris Neurological Research Institute, The Scripps Research Institute, La Jolla, CA, USA

    B Conti, A M Barr, M C Morale, X Lu, P P Sanna & T Bartfai

  2. Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland

    R Maier, G Bilbe & D Hoyer

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  1. B Conti
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  2. R Maier
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Correspondence to T Bartfai.

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Conti, B., Maier, R., Barr, A. et al. Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine. Mol Psychiatry 12, 167–189 (2007). https://doi.org/10.1038/sj.mp.4001897

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  • DOI: https://doi.org/10.1038/sj.mp.4001897

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