Abstract
Changes in gene expression of the brain serotonin (5-HT) 1A receptors may be important for the development and ameliorating depression, however identification of specific stimuli that activate or reduce the receptor transcriptional activity is far from complete. In the present study, the forced swim test (FST) exposure, the first stress session of which is already sufficient to induce behavioral despair in rats, significantly increased 5-HT1A receptor mRNA levels in the brainstem, frontal cortex, and hippocampus at 24 h. In the brainstem and frontal cortex, the elevation in the receptor gene expression after the second forced swim session was not affected following chronic administration of fluoxetine, while in the cortex, both control and FST values were significantly reduced in fluoxetine-treated rats. In contrast to untreated rats, no increase in hippocampal 5-HT1A receptor mRNA was observed in response to FST in rats chronically treated with fluoxetine. Metabolism of 5-HT (5-HIAA/5-HT) in the brainstem was significantly decreased by fluoxetine and further reduced by swim stress, showing a certain degree of independence of these changes on 5-HT1A receptor gene expression that was increased in this brain region only after the FST, but not after fluoxetine. FST exposure also decreased the brainstem dopamine metabolism, which was unexpectedly positively correlated with 5-HT1A receptor mRNA levels in the frontal cortex. Together, these data suggest that the effects of the forced swim stress as well as fluoxetine involve brain region-dependent alterations in 5-HT1A receptor gene transcription, some of which may be interrelated with concomitant changes in catecholamine metabolism.
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References
Adell A, Casanovas JM, Artigas F (1997) Comparative study in the rat of the actions of different types of stress on the release of 5-HT in raphe nuclei and forebrain areas. Neuropharmacology 36:735–741
Albert PR, François BL (2010) Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy. Front Neurosci 4:35
Albert PR, Le François B, Millar AM (2011) Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness. Mol Brain 4:21
Assié MB, Bardin L, Auclair AL, Carilla-Durand E, Depoortère R, Koek W, Kleven MS, Colpaert F, Vacher B, Newman-Tancredi A (2010) F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in vivo profile in behavioural models of antidepressant and serotonergic activity. Int J Neuropsychopharmacol 13:1285–1298
Blier P (2001) Crosstalk between the norepinephrine and serotonin systems and its role in the antidepressant response. J Psychiatry Neurosci 26(Suppl):S3–10
Blier P, de Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220–226
Blier P, Ward NM (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 53:193–203
Brühl AB, Kaffenberger T, Herwig U (2010) Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants. Neuropsychopharmacology 35:521–533
Buda M, Lachuer J, Devauges V, Barbagli B, Blizard D, Sara SJ (1994) Central noradrenergic reactivity to stress in Maudsley rat strains. Neurosci Lett 167:33–36
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389
Commons KG (2008) Evidence for topographically organized endogenous 5-HT-1A receptor-dependent feedback inhibition of the ascending serotonin system. Eur J Neurosci 27:2611–2618
Cryan JF, Leonard BE (2000) 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol 15:113–135
Dabrowska J, Nowak P, Brus R (2008) Reactivity of 5-HT1A receptor in adult rats after neonatal noradrenergic neurons’ lesion—implications for antidepressant-like action. Brain Res 1239:66–76
Dalla C, Pitychoutis PM, Kokras N, Papadopoulou-Daifoti Z (2010) Sex differences in animal models of depression and antidepressant response. Basic Clin Pharmacol Toxicol 106:226–233
Dal-Zotto S, Martí O, Armario A (2000) Influence of single or repeated experience of rats with forced swimming on behavioural and physiological responses to the stressor. Behav Brain Res 114:175–181
Gardier AM, Malagié I, Trillat AC, Jacquot C, Artigas F (1996) Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies. Fundam Clin Pharmacol 10:16–27
Guiard BP, Chenu F, El Mansari M, Blier P (2011) Characterization of the electrophysiological properties of triple reuptake inhibitors on monoaminergic neurons. Int J Neuropsychopharmacol 14:211–223
Günther L, Rothe J, Rex A, Voigt JP, Millan MJ, Fink H, Bert B (2011) 5-HT(1A)-receptor over-expressing mice: genotype and sex dependent responses to antidepressants in the forced swim-test. Neuropharmacology 61:433–441
Haenisch B, Linsel K, Brüss M, Gilsbach R, Propping P, Nöthen MM, Rietschel M, Fimmers R, Maier W, Zobel A, Höfels S, Guttenthaler V, Göthert M, Bönisch H (2009) Association of major depression with rare functional variants in norepinephrine transporter and serotonin1A receptor genes. Am J Med Genet B Neuropsychiatr Genet 150B:1013–1016
Herring NR, Schaefer TL, Tang PH, Skelton MR, Lucot JP, Gudelsky GA, Vorhees CV, Williams MT (2008) Comparison of time-dependent effects of (+)-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats. BMC Neurosci 9:49
Hitoshi S, Maruta N, Higashi M, Kumar A, Kato N, Ikenaka K (2007) Antidepressant drugs reverse the loss of adult neural stem cells following chronic stress. J Neurosci Res 85:3574–3585
Iyo AH, Kieran N, Chandran A, Albert PR, Wicks I, Bissette G, Austin MC (2009) Differential regulation of the serotonin 1A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress. Neuroscience 163:1119–1127
Kendler KS, Karkowski LM, Prescott CA (1999) Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 156:837–841
Kirby LG, Allen AR, Lucki I (1995) Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Brain Res 682:189–196
Krystal JH, Neumeister A (2009) Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Res 1293:13–23
Kvetnansky R, Sabban EL, Palkovits M (2009) Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev 89:535–606
Lanfumey L, Hamon M (2004) 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord 3:1–10
Lin Y, Quartermain D, Dunn AJ, Weinshenker D, Stone EA (2008) Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation. Synapse 62:516–623
Linthorst AC, Peñalva RG, Flachskamm C, Holsboer F, Reul JM (2002) Forced swim stress activates rat hippocampal serotonergic neurotransmission involving a corticotropin-releasing hormone receptor-dependent mechanism. Eur J Neurosci 16:2441–2452
López JF, Liberzon I, Vázquez DM, Young EA, Watson SJ (1999) Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress. Biol Psychiatry 45:934–937
Luo FF, Han F, Shi YX (2011) Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder. Mol Med Report 4:843–847
Mezadri TJ, Batista GM, Portes AC, Marino-Neto J, Lino-de-Oliveira C (2011) Repeated rat-forced swim test: reducing the number of animals to evaluate gradual effects of antidepressants. J Neurosci Methods 195:200–205
Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110:135–370
Morley-Fletcher S, Darnaudéry M, Mocaer E, Froger N, Lanfumey L, Laviola G, Casolini P, Zuena AR, Marzano L, Hamon M, Maccari S (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
Nestler EJ, McMahon A, Sabban EL, Tallman JF, Duman RS (1990) Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus. Proc Natl Acad Sci USA 87:7522–7526
Neumaier JF, Sexton TJ, Hamblin MW, Beck SG (2000) Corticosteroids regulate 5-HT(1A) but not 5-HT(1B) receptor mRNA in rat hippocampus. Brain Res Mol Brain Res 82:65–73
Ou XM, Storring JM, Kushwaha N, Albert PR (2001) Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene. J Biol Chem 276:14299–14307
Ou XM, Lemonde S, Jafar-Nejad H, Bown CD, Goto A, Rogaeva A, Albert PR (2003) Freud-1: A neuronal calcium-regulated repressor of the 5-HT1A receptor gene. J Neurosci 3:7415–7425
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, London
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
Raghupathi RK, McGonigle P (1997) Differential effects of three acute stressors on the serotonin 5-HT1A receptor system in rat brain. Neuroendocrinology 65:246–258
Riad M, Rbah L, Verdurand M, Aznavour N, Zimmer L, Descarries L (2008) Unchanged density of 5-HT(1A) autoreceptors on the plasma membrane of nucleus raphe dorsalis neurons in rats chronically treated with fluoxetine. Neuroscience 151:692–700
Richardson-Jones JW, Craige CP, Guiard BP, Stephen A, Metzger KL, Kung HF, Gardier AM, Dranovsky A, David DJ, Beck SG, Hen R, Leonardo ED (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65:40–52
Savitz J, Lucki I, Drevets WC (2009) 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol 88:17–31
Shishkina GT, Kalinina TS, Dygalo NN (2007) Up-regulation of tryptophan hydroxylase-2 mRNA in the rat brain by chronic fluoxetine treatment correlates with its antidepressant effect. Neuroscience 150:404–412
Shishkina GT, Kalinina TS, Dygalo NN (2008) Serotonergic changes produced by repeated exposure to forced swimming: correlation with behavior. Ann NY Acad Sci 1148:148–153
Shishkina GT, Kalinina TS, Berezova IV, Dygalo NN (2012) Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior. Neuropharmacology 62:177–183
Szabo ST, de Montigny C, Blier P (2000) Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors. Int J Neuropsychopharmacol 3:1–11
Vergé D, Daval G, Marcinkiewicz M, Patey A, el Mestikawy S, Gozlan H, Hamon M (1986) Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 6:3474–3482
Wang SH, Zhang ZJ, Guo YJ, Teng GJ, Chen BA (2009) Decreased expression of serotonin 1A receptor in the dentate gyrus in association with chronic mild stress: a rat model of post-stroke depression. Psychiatry Res 170:245–251
Wong DT, Perry KW, Bymaster FP (2005) Case history: the discovery of fluoxetine hydrochloride (Prozac). Nat Rev Drug Discov 4:764–774
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This study was supported by RFBR grants N 09-04-00284 and N 12-04-01102.
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Shishkina, G.T., Kalinina, T.S. & Dygalo, N.N. Effects of Swim Stress and Fluoxetine on 5-HT1A Receptor Gene Expression and Monoamine Metabolism in the Rat Brain Regions. Cell Mol Neurobiol 32, 787–794 (2012). https://doi.org/10.1007/s10571-012-9828-0
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DOI: https://doi.org/10.1007/s10571-012-9828-0