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

  • James P Herman
    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.
    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
    Department of Anatomy and Neurobiology, University of Kentucky School of Medicine, Lexington, Kentucky, USA (JPH, AR)
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  • Bryan Bodie
    Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, USA (JPH, BB)
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      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.


      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).


      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.


      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.


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