Long-lasting cognitive deficit induced by stress is alleviated by acute administration of antidepressants

Deficits in executive control associated with frontal lobe dysfunction have been reported in affective disorder, which is often precipitated by stressful life events. Here we examined the impact of repeated restraint stress (1h daily for 7 days) on rats' performance in the attentional set-shifting task (ASST). To evaluate the persistence of cognitive deficits, the performance of separate groups of rats was assessed on the 4th, 7th, 14th and 21st day following stress cessation. Stressed rats exhibited unusually long-lasting extra-dimensional (ED) set-shifting impairments, since these deficits were demonstrated even 3 weeks following stress termination. An inhibitor of corticosterone synthesis, the drug metyrapone (50mg/kg, IP) protected rats from the cognitive impairment suggesting an involvement of endogenous adrenal steroids in the debilitating effects of stress. Acute intraperitoneal administration of four different antidepressants (desipramine, nomifensine, fluoxetine and escitalopram) at the minimum effective doses of 3, 0.3, 1 and 1mg/kg, respectively, reversed the deficits of ED set-shifting in stressed animals. Desipramine, nomifensine, fluoxetine and escitalopram at the minimum effective doses of 6, 1, 1 and 1mg/kg, IP, respectively, promoted also cognitive flexibility in unstressed groups. We conclude that stress-induced long-term set-shifting impairment may represent a useful model mimicking clinically relevant aspects of depression, i.e., the persistence of executive dysfunction. The potential utility of antidepressants in treating frontal-like cognitive impairments is suggested.