Abstract
Rationale and objectives
The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT2c serotonin receptor antagonist.
Results
Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40–50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a “disease-dependent” drug.
Conclusions
These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.
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References
Abdel-Razaq W, Bates TE, Kendall DA (2007) The effects of antidepressants on cyclic AMP-response element-driven gene transcription in a model cell system. Biochem Pharmacol 73:1995–2003
Aimone JB, Deng W, Gage FH (2010) Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci 14:325–337
AlAhmed S, Herbert J (2010) Effect of agomelatine and its interaction with the daily corticosterone rhythm on progenitor cell proliferation in the dentate gyrus of the adult rat. Neuropharmacology 59:375–379
Banasr M, Soumier A, Hery M, Mocaer E, Daszuta A (2006) Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psych 59:1087–1096
Barden N, Shink E, Labbé M, Vacher R, Rochford J, Mocaër E (2005) Antidepressant action of agomelatine (S 20098) in a transgenic mouse model. Prog Neuropsychopharmacol Biol Psychiatry 29:908–916
Bertaina-Anglade V, la Rochelle CD, Boyer PA, Mocaër E (2006) Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model. Behav Pharmacol 17:703–713
Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, Almeida OF, Sousa N (2009) The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 14:764–773
Bisgaard CF, Jayatissa MN, Enghild JJ, Sanchéz C et al (2007) Proteomic investigation of the ventral rat hippocampus links DRP-2 to escitalopram treatment resistance and SNAP to stress resilience in the chronic mild stress model of depression. J Mol Neurosci 32:132–144
Bourin M, Mocaër E, Porsolt R (2004) Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J Psychiatry Neurosci 29:126–133
Brummelte S, Galea LA (2010) Chronic corticosterone during pregnancy and postpartum affects maternal care, cell proliferation and depressive-like behavior in the dam. Horm Behav 58:769–779
Calabrese F, Molteni R, Gabriel C, Mocaer E, Racagni G, Riva MA (2010) Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine. Psychopharmacology. doi:10.1007/s00213-010-2129-8
Czéh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA 98:12796–12801
Dagyte G, Trentani A, Postema F, Luiten PG, Den Boer JA, Gabriel C, Mocaër E, Meerlo P, Van der Zee EA (2010) The novel antidepressant agomelatine normalizes hippocampal neuronal activity and promotes neurogenesis in chronically stressed rats. CNS Neurosci Ther 16:195–207
Dagyte G, Crescente I, Postema F, Seguin L, Gabriel C, Mocaër E, Boer JA, Koolhaas JM (2011) Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav Brain Res 218(1):121–128
Darnaudéry M, Maccari S (2008) Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res Rev 57:571–585
Darnaudery M, Perez-Martin M, Belizaire G, Maccari S et al (2006) Insulin-like growth factor 1 reduces age-related disorders induced by prenatal stress in female rats. Neurobiol Aging 27:119–127
David DJ, Samuels BA, Rainer Q, Wang JW et al (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493
De Bodinat C, Guardiola-Lemaitre B, Mocaër E, Renard P et al (2010) Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov 9:628–642
Di Giorgi-Gerevini V, Melchiorri D, Battaglia G, Ricci-Vitiani L, Ciceroni C, Busceti CL, Biagioni F, Iacovelli L, Canudas AM, Parati E, De Maria R, Nicoletti F (2005) Endogenous activation of metabotropic glutamate receptors supports the proliferation and survival of neural progenitor cells. Cell Death Differ 12:1124–1133
Dugovic C, Maccari S, Weibel L, Turek FW et al (1999) High corticosterone levels in prenatally stressed rats predict persistent paradoxical sleep alterations. J Neurosci 19:8656–8664
Dworkin S, Mantamadiotis T (2010) Targeting CREB signalling in neurogenesis. Exper Opin Ther Targets 14:869–879
Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19
Filippov V, Kronenberg G, Pivneva T, Reuter K et al (2003) Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol Cell Neurosci 23:373–382
Fuchs E, Czéh B, Kole MH, Michaelis T, Lucassen PJ et al (2004) Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol 14(Suppl 5):S481–S490
Gass P, Riva MA (2007) CREB, neurogenesis and depression. Bioessays 29:957–961
Heim C, Bradley B, Mletzko TC, Deveau TC et al (2009) Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Front Behav Neurosci 3:41
Henke PG (1990) Granule cell potentials in the dentate gyrus of the hippocampus: coping behavior and stress ulcers in rats. Behav Brain Res 36:97–103
Jayatissa MN, Bisgaard C, Tingström A, Papp M, Wiborg O (2006) Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology 31:2395–2404
Jayatissa MN, Henningsen K, West MJ, Wiborg O (2009) Decreased cell proliferation in the dentate gyrus does not associate with development of anhedonic-like symptoms in rats. Brain Res 1290:133–141
Jayatissa MN, Henningsen K, Nikolajsen G, West MJ et al (2010) A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression. Stress 13:95–105
Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27:447–452
Kjelstrup KG, Tuvnes FA, Steffenach HA, Murison R et al (2002) Reduced fear expression after lesions of the ventral hippocampus. Proc Natl Acad Sci USA 99:10825–10830
Koch JM, Kell S, Hinze-Selch D, Aldenhoff JB (2002) Changes in CREB-phosphorylation during recovery from major depression. J Psychiatr Res 36:369–375
Koehl M, Lemaire V, Le Moal M, Abrous DN (2009) Age-dependent effect of prenatal stress on hippocampal cell proliferation in female rats. Eur J Neurosci 29:635–640
Koo JW, Russo SJ, Ferguson D, Nestler EJ et al (2010) Nuclear factor-kappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci USA 107:2669–2674
Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902
Lemaire V, Koehl M, Le Moal M, Abrous DN (2000) Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA 97:11032–11037
Lemaire V, Lamarque S, Le Moal M, Piazza PV et al (2006) Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis. Biol Psychiatry 59:786–792
López JF, Akil H, Watson SJ (1999) Neural circuits mediating stress. Biol Psychiatry 46:1461–1471
Lucassen PJ, Bosch OJ, Jousma E, Krömer SA, Andrew R, Seckl JR, Neumann ID (2009) Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11beta-hydroxysteroid dehydrogenase type 2. Eur J Neurosci 29:97–103
Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, Oomen CA, Czéh B (2010a) Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur Neuropsychopharmacol 20:1–17
Lucassen PJ, Stumpel MW, Wang Q, Aronica E (2010b) Decreased numbers of progenitor cells but no response to antidepressant drugs in the hippocampus of elderly depressed patients. Neuropharmacology 58:940–949
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445
Maccari S, Morley-Fletcher S (2007) Effects of prenatal restraint stress on the hypothalamus–pituitary–adrenal axis and related behavioural and neurobiological alterations. Psychoneuroendocrinology 32:S10–S15
Maccari S, Piazza PV, Kabbaj M, Barbazanges A et al (1995) Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. J Neurosci 15:110–116
Maccari S, Darnaudery M, Morley-Fletcher S, Zuena AR et al (2003) Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neurosci Biobehav Rev 27:119–127
Malberg JE, Schechter LE (2005) Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs. Curr Pharm Des 11:145–155
Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110
Marais L, Hattingh SM, Stein DJ, Daniels WM (2009) A proteomic analysis of the ventral hippocampus of rats subjected to maternal separation and escitalopram treatment. Metab Brain Dis 24:569–586
Marlatt MW, Lucassen PJ, van Praag H (2010) Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice. Brain Res 1341:93–99
Matrisciano F, Storto M, Ngomba RT, Cappuccio I, Caricasole A, Scaccianoce S, Riozzi B, Melchiorri D, Nicoletti F (2002) Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus. Neuropharmacology 42:1008–1015
Matrisciano F, Panaccione I, Zusso M, Giusti P, Tatarelli R, Iacovelli L, Mathé AA, Gruber SH, Nicoletti F, Girardi P (2007) Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication? Mol Psychiatry 12:704–706
Matrisciano F, Caruso A, Orlando R, Marchiafava M, Bruno V, Battaglia G, Gruber SH, Melchiorri D, Tatarelli R, Girardi P, Mathè AA, Nicoletti F (2008) Defective group-II metabotropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology 55:525–531
McEwen BS, Olié JP (2005) Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine. Mol Psychiatry 10:525–537
Melchiorri D, Cappuccio I, Ciceroni C, Spinsanti P, Mosillo P, Sarichelou I, Sale P, Nicoletti F (2007) Metabotropic glutamate receptors in stem/progenitor cells. Neuropharmacology 53:473–480
Morley-Fletcher S, Rea M, Maccari S, Laviola G (2003a) Environmental enrichment during adolescence reverses the effects of prenatal stress on play behaviour and HPA axis reactivity in rats. Eur J Neurosci 18:3367–3374
Morley-Fletcher S, Darnaudery M, Koehl M, Casolini P et al (2003b) Prenatal stress in rats predicts immobility behaviour in the forced swim test. Effects of a chronic treatment with tianeptine. Brain Res 989:246–251
Morley-Fletcher S, Darnaudery M, Mocaer E, Froger N et al (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats. Neuropharmacology 47:841–847
Moser MB, Moser EI, Forrest E, Andersen P, Morris RG (1995) Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci USA 92:9697–9701
Navailles S, Hof PR, Schmauss C (2008) Antidepressant drug-induced stimulation of mouse hippocampal neurogenesis is age-dependent and altered by early life stress. J Comp Neurol 509:372–381
Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169
Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2010) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology. doi:10.1016/j.neuropharm.2010.10.022
Oitzl MS, Workel JO, Fluttert M, Frösch F, De Kloet ER (2000) Maternal deprivation affects behaviour from youth to senescence: amplification of individual differences in spatial learning and memory in senescent Brown Norway rats. Eur J Neurosci 12:3771–3780
Oomen CA, Girardi CE, Cahyadi R, Verbeek EC, Krugers H, Joëls M, Lucassen PJ (2009) Opposite effects of early maternal deprivation on neurogenesis in male versus female rats. PLoS ONE 4:e3675
Oomen CA, Soeters H, Audureau N, Vermunt L, van Hasselt FN, Manders EM, Joëls M, Lucassen PJ, Krugers H (2010) Severe early life stress hampers spatial learning and neurogenesis, but improves hippocampal synaptic plasticity and emotional learning under high-stress conditions in adulthood. J Neurosci 30:6635–6645
Overstreet DH, Friedman E, Mathé AA, Yadid G (2005) The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 29:739–759
Païzanis E, Renoir T, Lelievre V, Saurini F, Melfort M, Gabriel C, Barden N, Mocaër E, Hamon M, Lanfumey L (2010) Behavioural and neuroplastic effects of the new-generation antidepressant. Int J Neuropsychopharmacol 13:759–774
Papp M, Gruca P, Boyer PA, Mocaer E (2003) Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 28:694–703
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391
Santarelli L, Saxe M, Gross C, Surget A et al (2003) Requirement of hippocampal neurogenesis for the behavioural effects of antidepressants. Science 301:805–809
Sapolsky RM (2004) Is impaired neurogenesis relevant to the affective symptoms of depression? Biol Psychiatry 56:137–139
Schmitz C, Rhodes ME, Bludau M, Kaplan S et al (2002) Depression: reduced number of granule cells in the hippocampus of female, but not male, rats due to prenatal restraint stress. Mol Psychiatry 7:810–813
Seki T, Arai Y (1999) Temporal and spatial relationships between PSA-NCAM-expressing, newly generated granule cells, and radial glia-like cells in the adult dentate gyrus. J Comp Neurol 410:503–513
Shonkoff JP, Boyce WT, McEwen BS (2009) Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA 301:2252–2259
Soumier A, Banasr M, Lortet S, Masmejean F, Bernard N, Kerkerian-Le-Goff L, Gabriel C, Millan MJ, Mocaer E, Daszuta A (2009) Mechanisms contributing to the phase-dependent regulation of neurogenesis by the novel antidepressant, agomelatine, in the adult rat hippocampus. Neuropsychopharmacology 34:2390–2403
Surget A, Saxe M, Leman S, Ibarguen-Vargas Y et al (2008) Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry 64:293–301
Szymańska M, Budziszewska B, Jaworska-Feil L, Basta-Kaim A et al (2009) The effect of antidepressant drugs on the HPA axis activity, glucocorticoid receptor level and FKBP51 concentration in prenatally stressed rats. Psychoneuroendocrinology 34:822–832
Tanti A, Belzung C (2010) Open questions in current models of antidepressant action. Br J Pharmacol 159:1187–1200
Tardito D, Milanese M, Bonifacino T, Musazzi L, Grilli M, Mallei A, Mocaer E, Gabriel-Gracia C, Racagni G, Popoli M, Bonanno G (2010) Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways. BMC Neurosci 11:68
Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M (2004) Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831–1840
Vallee M, Mayo W, Dellu F, Le Moal M et al (1997) Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J Neurosci 17:2626–2636
Van Reeth O, Olivares E, Zhang Y, Zee PC et al (1997) Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters. Brain Res 762:185–194
Van Reeth O, Mairesse J, Giovine A, Mennunni G et al (2007) Prenatal stress induces abnormal stress response and alters circadian rhythms of corticosterone and locomotor activity in adult rats. Program No. 501.29/KK2. Neuroscience Meeting Planner, Society for Neuroscience, San Diego, CA
Van Reeth O, Weibel L, Spiegel K, Leproult R, Dugovic C, Maccari S (2000) Interactions between stress and sleep: from basic research to clinical situations. Sleep Med Rev 4:201–219
Vollmayr B, Simonis C, Weber S, Gass P et al (2003) Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 54:1035–1040
Warner-Schmidt JL, Duman RS (2006) Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus 16:239–249
Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086
Zhang JM, Tonelli L, Regenold WT et al (2010) Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats. Neuroscience 169:544–554
Zuena AR, Mairesse J, Casolini P, Cinque C et al (2008) Prenatal restraint stress generates two distinct behavioural and neurochemical profiles in male and female rats. PLoS ONE 3(5):e2170
Acknowledgements
This study was supported by the University of Lille North 1 and the Sapienza University of Rome (Frame Agreement signed between the two universities on 15/02/2007) and by CNRS in the framework of the European Research Team (GDRE 691) “Early Programming of Modern Diseases”.
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S. Morley-Fletcher and J. Mairesse contributed equally to this work.
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Morley-Fletcher, S., Mairesse, J., Soumier, A. et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology 217, 301–313 (2011). https://doi.org/10.1007/s00213-011-2280-x
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DOI: https://doi.org/10.1007/s00213-011-2280-x