Venlafaxine is an antidepressant drug that inhibits the reuptake of serotonin and norepinephrine with different efficacies. The effects of repeated administration of this drug on the increase in the extracellular concentration of norepinephrine in the prefrontal cortex, induced by stress or by the anxiogenic drug FG 7142, were studied in freely moving rats. Exposure to foot-shock stress induced a marked increase (+120%) in the extracellular norepinephrine concentration in the prefrontal cortex of control rats. Long-term administration of venlafaxine (10 mg/kg i.p., once a day for 21 days) reduced the effect of stress on norepinephrine output by 75%. This effect of venlafaxine persisted for at least 5 days after discontinuation of drug treatment. Acute administration of FG 7142 (20 mg/kg i.p.), a benzodiazepine receptor inverse agonist, increased norepinephrine output (+90%) in control rats. Chronic treatment with venlafaxine prevented the effect of FG 7142. In contrast, the acute administration of this antidepressant had no effect on the stressor FG 7142-induced increase in norepinephrine output. These plastic changes in the sensitivity of norepinephrine neurones to foot-shock stress and to an anxiogenic drug may reveal an important neuronal mechanism for the physiological regulation of emotional state. Furthermore, this mechanism might be relevant to the anxiolytic and antidepressant effects of venlafaxine.
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