ABSTRACT
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.
