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Proc Natl Acad Sci U S A. Sep 12, 1995; 92(19): 8788–8792.

Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus.


The mechanisms by which stress and anti-depressants exert opposite effects on the course of clinical depression are not known. However, potential candidates might include neurotrophic factors that regulate the development, plasticity, and survival of neurons. To explore this hypothesis, we examined the effects of stress and antidepressants on neurotrophin expression in the locus coeruleus (LC), which modulates many of the behavioral and physiological responses to stress and has been implicated in mood disorders. Using in situ hybridization, we demonstrate that neurotrophin 3 (NT-3) is expressed in noradrenergic neurons of the LC. Recurrent, but not acute, immobilization stress increased NT-3 mRNA levels in the LC. In contrast, chronic treatment with antidepressants decreased NT-3 mRNA levels. The effect occurred in response to antidepressants that blocked norepinephrine uptake, whereas serotonin-specific reuptake inhibitors did not alter NT-3 levels. Electroconvulsive seizures also decreased NT-3 expression in the LC as well as the hippocampus. Ntrk3 (neurotrophic tyrosine kinase receptor type 3; formerly TrkC), the receptor for NT-3, is expressed in the LC, but its mRNA levels did not change with stress or antidepressant treatments. Because, NT-3 is known to be trophic for LC neurons, our results raise the possibility that some of the effects of stress and antidepressants on LC function and plasticity could be mediated through NT-3. Moreover, the coexpression of NT-3 and its receptor in the LC suggests the potential for autocrine mechanisms of action.

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  • Gold PW, Goodwin FK, Chrousos GP. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2) N Engl J Med. 1988 Aug 18;319(7):413–420. [PubMed]
  • Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry. 1992 Aug;149(8):999–1010. [PubMed]
  • Weiss JM, Glazer HI, Pohorecky LA, Brick J, Miller NE. Effects of chronic exposure to stressors on avoidance-escape behavior and on brain norepinephrine. Psychosom Med. 1975 Nov-Dec;37(6):522–534. [PubMed]
  • Foote SL, Bloom FE, Aston-Jones G. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev. 1983 Jul;63(3):844–914. [PubMed]
  • Thoenen H. Induction of tyrosine hydroxylase in peripheral and central adrenergic neurones by cold-exposure of rats. Nature. 1970 Nov 28;228(5274):861–862. [PubMed]
  • Zigmond RE, Schon F, Iversen LL. Increased tyrosine hydroxylase activity in the locus coeruleus of rat brain stem after reserpine treatment and cold stress. Brain Res. 1974 Apr 26;70(3):547–552. [PubMed]
  • Smith MA, Brady LS, Glowa J, Gold PW, Herkenham M. Effects of stress and adrenalectomy on tyrosine hydroxylase mRNA levels in the locus ceruleus by in situ hybridization. Brain Res. 1991 Mar 22;544(1):26–32. [PubMed]
  • Melia KR, Rasmussen K, Terwilliger RZ, Haycock JW, Nestler EJ, Duman RS. Coordinate regulation of the cyclic AMP system with firing rate and expression of tyrosine hydroxylase in the rat locus coeruleus: effects of chronic stress and drug treatments. J Neurochem. 1992 Feb;58(2):494–502. [PubMed]
  • Abercrombie ED, Jacobs BL. Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. II. Adaptation to chronically presented stressful stimuli. J Neurosci. 1987 Sep;7(9):2844–2848. [PubMed]
  • Svensson TH, Usdin T. Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressants: alpha-receptor mediation. Science. 1978 Dec 8;202(4372):1089–1091. [PubMed]
  • Nestler EJ, McMahon A, Sabban EL, Tallman JF, Duman RS. Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7522–7526. [PMC free article] [PubMed]
  • Brady LS, Whitfield HJ, Jr, Fox RJ, Gold PW, Herkenham M. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Invest. 1991 Mar;87(3):831–837. [PMC free article] [PubMed]
  • Melia KR, Nestler EJ, Duman RS. Chronic imipramine treatment normalizes levels of tyrosine hydroxylase in the locus coeruleus of chronically stressed rats. Psychopharmacology (Berl) 1992;108(1-2):23–26. [PubMed]
  • Arenas E, Persson H. Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo. Nature. 1994 Jan 27;367(6461):368–371. [PubMed]
  • Friedman WJ, Ibáez CF, Hallbök F, Persson H, Cain LD, Dreyfus CF, Black IB. Differential actions of neurotrophins in the locus coeruleus and basal forebrain. Exp Neurol. 1993 Jan;119(1):72–78. [PubMed]
  • Nawa H, Bessho Y, Carnahan J, Nakanishi S, Mizuno K. Regulation of neuropeptide expression in cultured cerebral cortical neurons by brain-derived neurotrophic factor. J Neurochem. 1993 Feb;60(2):772–775. [PubMed]
  • Sakaguchi T, Nakamura S. Duration-dependent effects of repeated restraint stress on cortical projections of locus coeruleus neurons. Neurosci Lett. 1990 Oct 16;118(2):193–196. [PubMed]
  • Hohn A, Leibrock J, Bailey K, Barde YA. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature. 1990 Mar 22;344(6264):339–341. [PubMed]
  • Ernfors P, Wetmore C, Olson L, Persson H. Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron. 1990 Oct;5(4):511–526. [PubMed]
  • Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME, Lindsay RM, Yancopoulos GD. NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron. 1990 Oct;5(4):501–509. [PubMed]
  • Kokaia Z, Bengzon J, Metsis M, Kokaia M, Persson H, Lindvall O. Coexpression of neurotrophins and their receptors in neurons of the central nervous system. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6711–6715. [PMC free article] [PubMed]
  • Miranda RC, Sohrabji F, Toran-Allerand CD. Neuronal colocalization of mRNAs for neurotrophins and their receptors in the developing central nervous system suggests a potential for autocrine interactions. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6439–6443. [PMC free article] [PubMed]
  • Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature. 1995 Mar 30;374(6521):450–453. [PubMed]
  • Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995 Mar;15(3 Pt 1):1768–1777. [PubMed]
  • Ernfors P, Bengzon J, Kokaia Z, Persson H, Lindvall O. Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron. 1991 Jul;7(1):165–176. [PubMed]
  • Gall C, Lauterborn J. The dentate gyrus: a model system for studies of neurotrophin regulation. Epilepsy Res Suppl. 1992;7:171–185. [PubMed]
  • Lindvall O, Ernfors P, Bengzon J, Kokaia Z, Smith ML, Siesjö BK, Persson H. Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):648–652. [PMC free article] [PubMed]
  • Takeda A, Onodera H, Yamasaki Y, Furukawa K, Kogure K, Obinata M, Shibahara S. Decreased expression of neurotrophin-3 mRNA in the rat hippocampus following transient forebrain ischemia. Brain Res. 1992 Jan 8;569(1):177–180. [PubMed]
  • Kvetnansky R, Mikulaj L. Adrenal and urinary catecholamines in rats during adaptation to repeated immobilization stress. Endocrinology. 1970 Oct;87(4):738–743. [PubMed]
  • Maisonpierre PC, Le Beau MM, Espinosa R, 3rd, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics. 1991 Jul;10(3):558–568. [PubMed]
  • Ernfors P, Ibáez CF, Ebendal T, Olson L, Persson H. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5454–5458. [PMC free article] [PubMed]
  • Whitfield HJ, Jr, Brady LS, Smith MA, Mamalaki E, Fox RJ, Herkenham M. Optimization of cRNA probe in situ hybridization methodology for localization of glucocorticoid receptor mRNA in rat brain: a detailed protocol. Cell Mol Neurobiol. 1990 Mar;10(1):145–157. [PubMed]
  • Lewis EJ, Tank AW, Weiner N, Chikaraishi DM. Regulation of tyrosine hydroxylase mRNA by glucocorticoid and cyclic AMP in a rat pheochromocytoma cell line. Isolation of a cDNA clone for tyrosine hydroxylase mRNA. J Biol Chem. 1983 Dec 10;258(23):14632–14637. [PubMed]
  • Merlio JP, Ernfors P, Jaber M, Persson H. Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system. Neuroscience. 1992 Dec;51(3):513–532. [PubMed]
  • Castren E, Thoenen H, Lindholm D. Brain-derived neurotrophic factor messenger RNA is expressed in the septum, hypothalamus and in adrenergic brain stem nuclei of adult rat brain and is increased by osmotic stimulation in the paraventricular nucleus. Neuroscience. 1995 Jan;64(1):71–80. [PubMed]
  • Seroogy KB, Lundgren KH, Tran TM, Guthrie KM, Isackson PJ, Gall CM. Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J Comp Neurol. 1994 Apr 15;342(3):321–334. [PubMed]
  • Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay RM. Overlapping and distinct actions of the neurotrophins BDNF, NT-3, and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci. 1994 Jan;14(1):335–347. [PubMed]
  • Louis JC, Magal E, Burnham P, Varon S. Cooperative effects of ciliary neurotrophic factor and norepinephrine on tyrosine hydroxylase expression in cultured rat locus coeruleus neurons. Dev Biol. 1993 Jan;155(1):1–13. [PubMed]
  • Bondareff W, Mountjoy CQ, Roth M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology. 1982 Feb;32(2):164–168. [PubMed]
  • Brady LS. Stress, antidepressant drugs, and the locus coeruleus. Brain Res Bull. 1994;35(5-6):545–556. [PubMed]
  • Kety SS, Javoy F, Thierry AM, Julou L, Glowinski J. A sustained effect of electroconvulsive shock on the turnover of norepinephrine in the central nervous system of the rat. Proc Natl Acad Sci U S A. 1967 Sep;58(3):1249–1254. [PMC free article] [PubMed]
  • Schultzberg M, Austin MC, Crawley JN, Paul SM. Repeated administration of desmethylimipramine blocks the reserpine-induced increase in tyrosine hydroxylase mRNA in locus coeruleus neurons of the rat. Brain Res Mol Brain Res. 1991 Jul;10(4):307–314. [PubMed]
  • Barden N, Reul JM, Holsboer F. Do antidepressants stabilize mood through actions on the hypothalamic-pituitary-adrenocortical system? Trends Neurosci. 1995 Jan;18(1):6–11. [PubMed]

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