Summary
The effects of the cytokines interferon (IFN)-γ, interleukin (IL)-1, and tumor necrosis factor (TNF)-α on the serotoninergic transmission in the nucleus raphe dorsalis (NRD) were studied after peripheral and central application. The studies were performed in the freely moving rat using differential pulse voltammetry with multicarbon fibre electrodes to study the extracellular levels of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA). The extracellular 5-HIAA levels were not changed in the NRD after peripheral application of rat recombinant IFN-γ, but elevated by the cytokines IL-1β and TNF-α. After intracerebroventricular (i.c.v.) application the cytokines IFN-γ, IL-1β and TNF-α stimulated the serotoninergic transmission in the NRD. Our data suggest that the effect of peripherally elevated cytokine concentrations on the serotonin metabolism in the NRD of the rat is cytokine-dependent. In this respect the T-cell and NK-cell cytokine IFN-γ acts clearly different when compared to the mainly macrophage-derived cytokines IL-1β and TNF-α, and plays a different role in the communication between immune and central nervous system.
Similar content being viewed by others
References
Banks WA, Kastin AJ (1992) The interleukins-1alpha, 1β and -2 do not acutely disrupt the murine blood brain barrier. Int J Immunopharmacol 14: 629–636
Berkenbosch F, De Rijk R, Schotanus K, Wolvers D, Van Dam AM (1992) The immune-hypothalamo-pituitary adrenal axis: its role in immunoregulation and tolerance to self-antigens. In: Rothwell NJ, Dantzer RD (eds) Interleukin-1 in the brain. Pergamon Press, Oxford, pp 75–91
Bluthé RM, Walter V, Parnet P, Laye S, Lestage J, Verrier D, Pooloe S, Stenning BE, Kelley KW, Dantzer R (1994) Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C R Acad Sci 317 Ser III: 499–503
Borgerding RA, Murphy S (1995) Expression of inducible nictric oxide synthase in cerebral endothelial cells is regulated by cytokine-activated atrocytes. J Neurochem 65: 1342–1347
Carey F, Forder R, Edge MD, Greene AR, Horan MA, Strijbos PJLM, Rothwell NJ (1990) Lipocortin 1 fragment modifies pyrogenic actions of cytokines in rats. Am J Physiol 259: R266-R269
Cespuglio R, Houdouin F, Oulerich M, El Mansari M (1992) Axonal and somatodendritic modalities of serotonin release: their involvement in sleep preparation, triggering and maintenance. J Sleep Res 1: 150–156
Chang JY, Martin DP, Johnson Jr EM (1990) Interferon suppresses sympathetic neuronal cell death caused by nerve growth factor deprivation. J Neurochem 55: 436–445
Clement HW, Schäfer F, Ruwe C, Gemsa D, Wesemann W (1993) Stress-induced serotonin release in the N. raphe dorsalis and the frontal cortex of the rat followed by in vivo voltammetry after different stressors. Brain Res 614: 117–124
Crnic LS, Segall MA (1992) Behavioral effects of mouse interferons-α and γ and human interferon-α in mice. Brain Res 590: 277–284
Cunningham ET Jr, De Souza EB (1993) Interleukin 1 receptors in the brain and endocrine tissues. Immunol Today 14: 171–176
Dantzer RD, Bluthe RM, Kent S, Kelley KW (1992) Behavioural effects of cytokines. In: Rothwell NJ, Dantzer RD (eds) Interleukin-1 in the brain. Pergamon Press, Oxford, pp 135–150
Dunn AJ (1992) The role of interleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin. Brain Res Bull 29: 807–812
Dunn AJ (1993) Role of cytokines in infection-induced stress. Ann NY Acad Sci 697: 189–202
Dunn AJ, Welch J (1991) Stress- and endotoxin-induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity. J Neurochem 57: 1615–1622
El-Kafi B, Cespuglio R, Leger L, Marinesco S, Jouvet M (1994) Is the nucleus raphe dorsalis a target for the peptides possessing hypnogenic properties? Brain Res 637: 211–221
Feist W, Ulmer AJ, Wang M, Musehold J, Schlüter C, Gerdes J, Herzbeck H, Brade H, Kusumoto S, Diamantstein T, Rietschel ET, Flad HD (1992) Modulation of lipopolysaccharide-induced production of tumor necrosis factor, interleukin-1, and interleukin-6 by synthetic precursor Ia of lipid A. FEMS Microbiol Immunol 89: 73–90
Fleshner M, Goehler LE, Hermann J, Relton JK, Maier SF, Watkins LR (1995) Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated. Brain Res Bull 37: 605–610
Gemma C, Ghezzi P, De Simoni MG (1991) Activation of the hypothalamic serotoninergic system by central interluekin 1. Eur J Pharmacol 209: 139–140
Gemma C, De Luigi A, De Simoni MG (1994) Permissive role of glucocorticoids on interleukin-1 activation of the hypothalamic serotonergic system. Brain Res 651: 169–173
Goehler LE, Busch CR, Tartaglia N, Relton J, Sisk D, Maier SF, Watkins LR (1995) Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal mediation of immune-brain communication. Neurosci Lett 185: 163–166
Gottschall PE, Komaki G, Arimura A (1992) Interleukin-1β activation of the central nervous system. In: Rothwell NJ, Dantzer RD (eds) Interleukin-1 in the brain. Pergamon Press, Oxford, pp 27–50
Jansky L, Vybiral S, Pospisilova D, Roth J, Dornand J, Zeisberger E, Kaminkova J (1995) Production of systemic and hypothalamic cytokines during the early phase of endotoxin fever. Neuroendocrinol 62: 55–61
Kabiersch A, Del Rey A, Honegger CG, Besedoysky HO (1988) Interleukin-1 induces changes in norepinephrine metabolism in the rat brain. Brain Behav Immun 2: 267–274
Kiefer R, Haas CA, Kreutzberg GW (1991) Gamma interferon-like immunoreactive materail in rat neurons: evidence against a close relationship to gamma interferon. Neurosci 45: 551–560
Krueger JM, Majde JA (1994) Microbial products and cytokines in sleep and fever regulation. Crit Rev Immunol 14: 355–379
Laye S, Parnet P, Goujon E, Dantzer R (1994) Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Res Mol Brain Res 27: 157–162
Linthorst AC, Flachskamm C, Müller-Preuss P, Holsboer F, Reul JMHM (1995) Effect of bacterial endotoxin and interleukin-1β on hippocampal serotonergic neurotransmission, behavioural activity, and free corticosterone concentrations: an in vivo microdialysis study. J Neurosci 15: 2920–2934
Loughlin AJ, Woodroofe MN, Cuzner ML (1993) Modulation of interferon-γ-induced major histocompatibility complex class II and Fc receptor expression on isolated microglia by transforming growth factor-β1, interleukin-4, noradrenaline and glucocorticoids. Immunology 79: 125–130
Moldawer LL, Anderson C, Gelin J, Lundholm KG (1988) Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 254: 6450–6456
Monhankumar PS, Thyagarajan S, Quadri SK (1993) Interleukin-1 beta increases 5-hydroxyindoleacetic acid release in the hypothalamus in vivo. Brain Res Bull 31: 745–748
Myers RD (1981) Serotonin and thermoregulation: old and new views. J Physiol 77: 505–513
Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, Sydney
Peng ZC, Mohammed AH, Olsson T, Edlund C, Kristensson K (1994) Interferon-γ and a factor derived from trypanosomes cause behavioral changes in the rat. Behav Brain Res 62: 171–175
Plata-Salaman CR, Oomura Y, Kai Y (1988) Tumor necrosis factor and interleukin-1β: suppression of food intake by direct action in the central nervous system. Brain Res 448: 106–114
Rueter LE, Jacobs BL (1996) A microdialyses examination of serotonin release in the rat forebrain induced by behavioural/environmental manipulations. Brain Res 739: 57–69
Sakai N, Kaufman S, Milstien S (1995) Parallel induction of nitric oxide and tetrahydrobiopterin synthesis by cytokines in rat glial cells. J Neurochem 65: 895–902
Sawada M, Suzumura A, Itoh Y, Marunouchi T (1993) Production of interleukin-5 by mouse astrocytes and microglia in culture. Neurosci Lett 155: 175–178
Schöbitz B, De Kloet ER, Holsboer F (1994) Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain. Prog Neurobiol 44: 397–432
Shintani F, Kanba S, Nakaki T, Nibuya M, Kinoshita N, Suzuki E, Yagi G, Kato R, Asai M (1993) Interleukin-1β augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus. J Neurosci 13: 3574–3581
Strijbos PJ, Hardwick AJ, Relton JK, Carey F, Rothwell NJ (1992) Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF. Am J Physiol 263: E632-E636
Tada M, Diserens AC, Desbaillets I, de Triboledt N (1994) Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymersase chain reaction. J Neurosurg 80: 1063–1073
Vankelecom H, Carmeliet P, Heremans H, van Damme J, Dijkmans R, Biliau A, Denef C (1990) Interferon-γ inhibits stimulated adrenocorticotropin, prolactin, and growth hormone secretion in normal rat anterior pituitary cell cultures. Endocrinology 126: 2919–2926
Waguespack PJ, Banks WA, Kastin AJ (1994) Interleukin-2 does not cross the blood-brain barrier by a saturable transport system. Brain Res Bull 34: 103–109
Watkins LR, Goehler LE, Relton JK, Tartaglia N, Silbert L, Martin D, Maier SF (1995a) Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett 183: 27–31
Watkins LR, Maier SF, Goehler LE (1995b) Cytokine-to-brain communication: a review & analyses of alternative mechanisms. Life Sci 57: 1011–1026
Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH (1994) Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and 6. Brain Res 643: 40–49
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Clement, H.W., Buschmann, J., Rex, S. et al. Effects of interferon-γ, interleukin-1β, and tumor necrosis factor-α on the serotonin metabolism in the nucleus raphe dorsalis of the rat. J. Neural Transmission 104, 981–991 (1997). https://doi.org/10.1007/BF01273312
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01273312