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Region-Specific Transcriptional Changes Following the Three Molecular Psychiatry (2007) 12, 167–189 & 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00 www.nature.com/mp ORIGINAL ARTICLE Region-specific transcriptional changes following the three antidepressant treatments electro convulsive therapy, sleep deprivation and fluoxetine B Conti1, R Maier2, AM Barr1,3, MC Morale1,4,XLu1, PP Sanna1, G Bilbe2, D Hoyer2 and T Bartfai1 1Molecular and Integrative Neuroscience Department, The Harold L Dorris Neurological Research Institute, The Scripps Research Institute, La Jolla, CA, USA and 2Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland 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. The transcriptional changes induced by SD, ECT and SSRI display a regionally specific distribution distinct to each treatment. 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. 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. 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. 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. Molecular Psychiatry (2007) 12, 167–189. doi:10.1038/sj.mp.4001897; published online 10 October 2006 Keywords: electroconvulsive; sleep; fluoxetine; depression; antidepressant; microarray Correspondence: Dr T Bartfai, Molecular and Integrative Neuroscience Department, The Harold L Dorris Neurological Research Institute, The Scripps Research Institute, 10550 N Torrey Pines Rd, SR-307, La Jolla, CA 92037, USA. E-mail: [email protected] 3Current address: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. 4Current address: Dipartimento di Neurofarmacologia, OASI (IRCCS), Troina, Italy. Received 14 April 2006; revised 13 July 2006; accepted 5 August 2006; published online 10 October 2006 Region-specific transcriptional changes B Conti et al 168 Introduction transcriptional changes associated with antidepres- sant treatment in multiple brain regions. Several The most commonly employed pharmacological treat- studies have been recently reported including those ments of Major Depression (MD) aim at the manipula- investigating transcriptional changes following treat- tion of the monoaminergic systems.1,2 For the past 30 ment with an SSRI24,25 and lithium25,26 with respect to years, the prominent theories of mood disorders major depression and bipolar disorders,27 respec- pointed to the pathological evidence of decreased tively. monoamine levels, including the low 5-HIAA found In order to develop a strategy that would enable in suicide victims.3,4 Indeed, the monoamine oxidase identification of molecular mechanisms suitable for inhibitors since iproniazide, the tricyclic antidepres- pharmacotherapy for major depression, we compared sants (TCAs), the selective serotonin reuptake inhibi- the transcriptional changes occurring in seven rat tors (SSRIs) and the serotonin/noradrenaline reuptake brain regions implicated in control of mood and inhibitors (SNRIs) are all causing elevation of synaptic anxiety upon treatment with the two fast-onset/short- monoamine levels.5,6 Such pharmacological treat- lived antidepressant paradigms, ECT and SD and the ments are widely and successfully used in alleviating late-onset/prolonged-lasting SSRI fluoxetine (FLX). the symptoms in ca 70% of patients with MD, but The major weaknesses of today’s gene chipping remain ineffective in ca 30% of them. In addition, studies, the overwhelming amount of information that treating MD with these drugs can require several needs to be verified and organized, the experimental months of therapy but, most importantly, commonly problems of control tissues and of dissection artefacts used antidepressants have a slow onset of action.7 For were uppermost in the design and execution of the instance, the SSRIs and SNRIs require treatment for study. Further separate control groups were used for 14–21 days (or longer) before the Hamilton score each treatment. Inclusion of three different treatment returns towards normal values. Clinically, this slow paradigms permits analysis of common transcrip- onset of action can be problematic, especially as MD is tional changes and indeed resulted in a remarkable a severely debilitating disorder whose symptoms focusing/narrowing of the number of transcripts should be treated promptly once diagnosis is made requiring verification, and subsequent follow up in to reduce the high suicide risk, common in depressed behavioral models to validate the functional signifi- patients. In terms of mechanistic understanding of the cance of the transcriptional change in mood regula- current drugs’ antidepressant action, this delay in the tion. onset of clinical improvements is in strong contrast to The results show that ECT and SD cause larger-scale the rapid change in synaptic monoamine levels transcriptional changes and affect similar brain achieved upon the first or second dose of SSRIs/ regions, different from those found for SSRI treat- SNRIs. This has been interpreted as an indication of ment. Transcripts commonly regulated by two or all the need for large, multiple changes in several three treatments were identified and relevance as signaling systems in order to achieve therapeutic possible pharmacological targets for MD is discussed. effect,6,8,9 although neuroprotection and neurogenesis mechanisms may be targeted by antidepressants Materials and methods contributing to the slow onset of action.10–14 Thus, the existence of a large group of depressed Animals and treatment patients resistant to monoaminergic therapy and the All procedures were approved by the Institutional slow onset of therapeutic effects of the SSRIs/SNRIs Animal Care and Use Committee of the Scripps are two major reasons for the sustained search for new Research Institute and were carried out on adult male antidepressant mechanisms. In contrast to drugs Sprague–Dawley rats (250–300 g). Animals were affecting the monoaminergic system, sleep depriva- housed two per cage, food and water were ad libitum tion (SD) and electro convulsive therapy (ECT) are and the light/dark cycle was of 12/12 h with light on two clinically well-documented, robust, fast-acting at 0700 hours. The experimental design is summar- methods for treatment of severely depressed pa- ized in Figure 1. tients.15–20 Both treatments require hospitalization For electroconvulsive shock (ECT) animals received and have been extensively used over the past century. four shock applications daily (70 pulses/s; pulse However, the molecular and cellular mechanisms width of 0.5 ms; current of 90 mA; shock duration underlying their antidepressant effects are poorly up to 8 s delivered with a 1 h time interval between understood. Many studies have examined the effects applications) for 2 days and were killed 1 h after final of ECT on the CSF or serum level of selected markers treatment. Only animals exhibiting full tonic/clonic including neurotransmitters, neuropeptide and hor-
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