Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving rats

Synapse. 2002 Jan;43(1):70-7. doi: 10.1002/syn.10024.


The effect of repeated administration of imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, was studied on the stress-induced increase in the extracellular concentration of norepinephrine in the prefrontal cortex of freely moving rats. Exposure to footshock in control rats induced a marked increase in extracellular norepinephrine concentrations in the prefrontal cortex (+120%). Long-term administration with imipramine or mirtazapine (10 mg/kg, i.p., twice or once a day, respectively, for 14 days) reduced (+50%) the effect of stress on basal norepinephrine output. Acute administration of FG7142 (30 mg/kg, i.p.), an anxiogenic benzodiazepine receptor inverse agonist, induced a marked increase in norepinephrine output (+90%) in control rats. In rats chronically treated with imipramine or mirtazapine this effect was completely antagonized. On the contrary, acute administration of these antidepressant drugs failed to reduce stress- and FG7142-induced increase in norepinephrine output. The plastic changes in the sensitivity of norepinephrine neurons to footshock stress and drug-induced anxiogenic stimuli may reveal a new important neuronal mechanism involved in the long-term modulation of emotional state. This action might be relevant for the anxiolytic and antidepressant effect of antidepressant drugs.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Antidepressive Agents, Tricyclic / pharmacology*
  • Anxiety / chemically induced
  • Anxiety / metabolism
  • Anxiety / physiopathology
  • Carbolines / pharmacology
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Depression / drug therapy*
  • Depression / etiology
  • Depression / metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Electric Stimulation
  • GABA Antagonists / pharmacology
  • Imipramine / pharmacology*
  • Male
  • Mianserin / analogs & derivatives*
  • Mianserin / pharmacology*
  • Mirtazapine
  • Norepinephrine / metabolism*
  • Rats
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism
  • Stress, Physiological / complications
  • Stress, Physiological / drug therapy*
  • Stress, Physiological / metabolism


  • Anti-Anxiety Agents
  • Antidepressive Agents, Tricyclic
  • Carbolines
  • GABA Antagonists
  • Receptors, GABA-A
  • Mianserin
  • FG 7142
  • Mirtazapine
  • Imipramine
  • Norepinephrine