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Norepinephrine–gamma-aminobutyric acid (GABA) interaction in limbic stress circuits: effects of reboxetine on GABAergic neurons

  • James P Herman
    Correspondence
    Address reprint requests to James P. Herman, Ph.D., University of Cincinnati Medical Center, Department of Psychiatry, 231 Albert Sabin Way, Cincinnati OH 45267-0559, USA.
    Affiliations
    Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, USA (JPH, BB)

    Department of Anatomy and Neurobiology, University of Kentucky School of Medicine, Lexington, Kentucky, USA (JPH, AR)
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  • Andrew Renda
    Affiliations
    Department of Anatomy and Neurobiology, University of Kentucky School of Medicine, Lexington, Kentucky, USA (JPH, AR)
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  • Bryan Bodie
    Affiliations
    Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, USA (JPH, BB)
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      Abstract

      Background

      Reboxetine is a selective norepinephrine (NE) reuptake inhibitor that exerts significant antidepressant action. The current study assessed norepinephrine–γ-aminobutyric acid (GABA)-ergic mechanisms in reboxetine action, examining glutamic acid decarboxylase (GAD) mRNA expression in limbic neurocircuits following reboxetine within the context of chronic stress.

      Methods

      Male rats received 25 mg/kg reboxetine/day, p.o. Reboxetine and vehicle animals were exposed to 1 week of variable stress exposure or handling. Behavioral responses to stress (open field) were tested on day 7, and animals were killed on day 8 to assess neuroendocrine stress responses and limbic GAD65/67 mRNA regulation (in situ hybridization).

      Results

      Reboxetine significantly decreased behavioral reactivity in the open field. Reboxetine administration did not affect expression of GAD65/67 mRNA in handled rats; however, administration to stressed animals reduced GAD67 (but not GAD65) mRNA in the medial amygdaloid nucleus, posteromedial bed nucleus of the stria terminalis, and dentate gyrus. In contrast, GAD65 mRNA expression was increased by reboxetine in the lateral septum of stressed animals.

      Conclusions

      Norepinephrine pathways appear to modulate synthesis of GABA in central limbic stress circuits. Decreases in GABA synthetic capacity suggest reduced activation of stress-excitatory pathways and enhanced activation of stress-inhibitory circuits, and is consistent with a role for GABA in the antidepressant efficacy of NE reuptake inhibitors.

      Keywords

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      References

        • Anand A.
        • Charney D.S.
        Norepinephrine dysfunction in depression.
        J Clin Psychiatry. 2000; 61: 16-24
        • Bowers G.
        • Cullinan W.E.
        • Herman J.P.
        Region-specific regulation of glutamic acid decarboxylase (GAD) mRNA expression in central stress circuits.
        J Neurosci. 1998; 18: 5938-5947
        • Casada J.H.
        • Dafny N.
        Restraint and stimulation of the bed nucleus of the stria terminalis produce similar stress-like behaviors.
        Brain Res Bull. 1991; 27: 207-212
        • Casada J.H.
        • Dafny N.
        Responses of neurons in bed nucleus of the stria terminalis to microiontophoretically applied morphine, norepinephrine and acetylcholine.
        Neuropharmacology. 1993; 32: 279-284
        • Chozick B.S.
        The behavioral effects of lesions of the septum.
        Int J Neurosci. 1985; 26: 197-217
        • Connor T.J.
        • Kelliher P.
        • Harkin A.
        • Kelly J.P.
        • Leonard B.E.
        Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat.
        Eur J Pharmacol. 1999; 379: 125-133
        • Cullinan W.E.
        • Herman J.P.
        • Battaglia D.F.
        • Akil H.
        • Watson S.J.
        Pattern and time course of immediate early gene expression in rat brain following acute stress.
        Neuroscience. 1995; 64: 477-505
        • Cullinan W.E.
        • Herman J.P.
        • Watson S.J.
        Ventral subicular interaction with the hypothalamic paraventricular nucleus.
        J Comp Neurol. 1993; 332: 1-20
        • Davis M.
        Are different parts of the extended amygdala involved in fear versus anxiety?.
        Biol Psychiatry. 1998; 44: 1239-1247
        • Delgado P.L.
        • Moreno F.A.
        Role of norepinephrine in depression.
        J Clin Psychiatry. 2000; 61: 5-12
        • Dunn J.D.
        Plasma corticosterone responses to electrical stimulation of the bed nucleus of the stria terminalis.
        Brain Res. 1987; 407: 327-331
        • Dunn J.D.
        • Whitener J.
        Plasma corticosterone responses to electrical stimulation of the amygdaloid complex.
        Neuroendocrinology. 1986; 42: 211-217
        • Dunn J.D.
        • Williams T.J.
        Cardiovascular responses to electrical stimulation of the bed nucleus of the stria terminalis.
        J Comp Neurol. 1995; 352: 227-234
        • Emmert M.H.
        • Herman J.P.
        Differential forebrain c-fos mRNA induction by ether inhalation and novelty.
        Brain Res. 1999; 845: 60-67
        • Esclapez M.
        • Tillakaratne N.J.K.
        • Kaufman D.L.
        • Tobin A.J.
        • Houser C.R.
        Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms.
        J Neurosci. 1994; 14: 1835-1855
        • Feldblum S.
        • Erlander M.G.
        • Tobin A.J.
        Different distributions of GAD65 and GAD67 mRNAs suggest that the two glutamate decarboxylases play distinctive functional roles.
        J Neurosci Res. 1993; 34: 689-706
        • Feldman S.
        • Conforti N.
        • Itzik A.
        • Weidenfeld J.
        Differential effect of amygdaloid lesions of CRF-41, ACTH and corticosterone responses following neural stimuli.
        Brain Res. 1994; 658: 21-26
        • Feldman S.
        • Conforti N.
        • Saphier D.
        The preoptic area and bed nucleus of the stria terminalis are involved in the effects of the amygdala on adrenocortical secretion.
        Neuroscience. 1990; 37: 775-779
        • Gray T.S.
        • Piechowski R.A.
        • Yracheta J.M.
        • Rittenhouse P.A.
        • Bethea C.L.
        • Van de Kar L.D.
        Ibotenic acid lesions in the bed nucleus of the stria terminalis attenuate conditioned stress-induced increases in prolactin, ACTH and corticosterone.
        Neuroendocrinology. 1993; 57: 517-524
        • Graybiel A.M.
        The basal ganglia.
        Curr Biol. 2000; 10: R509-R511
        • Herman J.P.
        • Adams D.
        • Prewitt C.M.
        Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm.
        Neuroendocrinology. 1995; 61: 180-190
        • Herman J.P.
        • Cullinan W.E.
        • Watson S.J.
        Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression.
        J Neuroendocrinol. 1994; 6: 433-442
        • Herman J.P.
        • Schäfer M.K.-H.
        • Young E.A.
        Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamo-pituitary-adrenocortical axis.
        J Neurosci. 1989; 9: 3072-3082
        • Jacobson L.
        • Sapolsky R.M.
        The role of the hippocampus in feedback regulation of the hypothalamo-pituitary-adrenocortical axis.
        Endocrine Rev. 1991; 12: 118-134
        • Kirby L.G.
        • Lucki I.
        The effect of repeated exposure to forced swimming on extracellular levels of 5-hydroxytryptamine in the rat.
        Stress. 1998; 2: 251-263
        • Lopez J.F.
        • Vazquez D.M.
        • Chalmers D.T.
        • Watson S.J.
        Regulation of 5-HT receptors and the hypothalamic-pituitary-adrenal axis.
        Ann N Y Acad Sci. 1997; 836: 106-134
        • Massana J.
        Reboxetine versus fluoxetine.
        J Clin Psychiatry. 1998; 59: 8-10
        • Montgomery S.A.
        • Schatzberg A.F.
        Introduction. Reboxetine.
        J Clin Psychiatry. 1998; 59: 3
        • Moore R.Y.
        • Bloom F.E.
        Central catecholamine neuron systems.
        Annu Rev Neurosci. 1979; 2: 113-168
        • Moore R.Y.
        • Card J.P.
        Noradrenaline-containing neuron systems.
        in: Björklund A. Hökfelt T. Handbook of Chemical Neuroanatomy, Vol. 2: Classical Transmitters in the CNS, Part II. Elsevier, Amsterdam1984: 1-124
        • Mugnaini E.
        • Oertel W.H.
        An atlas of the distribution of GABAergic neurons and terminals in the rat CNS as revealed by GAD immunohistochemistry.
        in: Björklund A. Hökfelt T. GABA and Neuropeptides in the CNS. Vol. 1. Elsevier, Amsterdam1985: 436-622
        • Nestler E.J.
        • Alreja M.
        • Aghajanian G.K.
        Molecular control of locus coeruleus neurotransmission.
        Biol Psychiatry. 1999; 46: 1131-1139
        • Nisenbaum L.K.
        • Abercrombie E.D.
        Presynaptic alterations associated with enhancement of evoked release and synthesis of norepinephrine in hippocampus of chronically cold-stressed rats.
        Brain Res. 1993; 608: 280-287
        • Paskitti M.E.
        • McCreary B.J.
        • Herman J.P.
        Stress regulation of adrenocorticosteroid receptor gene transcription and mRNA expression in rat hippocampus.
        Brain Res Mol Brain Res. 2000; 80: 142-152
        • Paxinos G.
        • Watson C.
        The Rat Brain in Stereotaxic Coordinates. 2nd ed. Academic Press, New York1986
        • Petty F.
        GABA and mood disorders.
        J Affect Disord. 1995; 34: 275-281
        • Sacchetti G.
        • Bernini M.
        • Bianchetti A.
        • Parini S.
        • Invernizzi R.W.
        • Samanin R.
        Studies on the acute and chronic effects of reboxetine on extracellular noradrenaline and other monoamines in the rat brain.
        Br J Pharmacol. 1999; 128: 1332-1338
        • Schatzberg A.F.
        Clinical efficacy of reboxetine in major depression.
        J Clin Psychiatry. 2000; 61: 31-38
        • Segovia J.
        • Tillakaratne N.J.
        • Whelan K.
        • Tobin A.J.
        • Gale K.
        Parallel increases in striatal glutamic acid decarboxylase activity and mRNA levels in rats with lesions of the nigrostriatal pathway.
        Brain Res. 1990; 529: 345-348
        • Shiah I.S.
        • Yatham L.N.
        GABA function in mood disorders.
        Life Sci. 1998; 63: 1289-1303
        • Steciuk M.
        • Kram M.
        • Kramer G.L.
        • Petty F.
        Decrease in stress-induced c-Fos-like immunoreactivity in the lateral septal nucleus of learned helpless rats.
        Brain Res. 1999; 822: 256-259
        • Swanson L.W.
        • Petrovich G.D.
        What is the amygdala?.
        Trends Neurosci. 1998; 21: 323-331
        • Tanaka M.
        • Yoshida M.
        • Emoto H.
        • Ishii H.
        Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety.
        Eur J Pharmacol. 2000; 405: 397-406
        • Thrivikraman K.V.
        • Su Y.
        • Plotsky P.M.
        Patterns of fos-immunoreactivity in the CNS induced by repeated hemorrhage in conscious rats.
        Stress. 1997; 2: 145-158
        • Valentino R.J.
        • Curtis A.L.
        • Page M.E.
        • Pavcovich L.A.
        • Florin-Lechner S.M.
        Activation of the locus ceruleus brain noradrenergic system during stress.
        Adv Pharmacol. 1998; 42: 781-784
        • Versiani M.
        • Mehilane L.
        • Gaszner P.
        • Arnaud-Castiglioni R.
        Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term treatment of major depressive disorder.
        J Clin Psychiatry. 1999; 60: 400-406
        • Watanabe Y.
        • McKittrick C.R.
        • Blanchard D.C.
        • Blanchard R.J.
        • McEwen B.S.
        • Sakai R.R.
        Effects of chronic social stress on tyrosine hydroxylase mRNA and protein levels.
        Mol Brain Res. 1995; 32: 176-180
        • Wong E.H.
        • Sonders M.S.
        • Amara S.G.
        • Timholt P.M.
        • Piercey M.F.
        • Hoffman W.P.
        • et al.
        Reboxetine.
        Biol Psychiatry. 2000; 47: 818-829
        • Woodson W.
        • Nitecka L.
        • Ben-Ari Y.
        Organization of the GABAergic system in the rat hippocampal formation.
        J Comp Neurol. 1989; 280: 254-271