Rationale: The transient behavioral deficit produced in rodents by typical learned helplessness (LH) procedures limits the utility of LH in identifying the therapeutic mechanisms associated with chronic antidepressant administration. In addition, LH procedures do not differentiate between different antidepressant classes as observed in the forced swim test.
Objectives: To produce both a long lasting and antidepressant reversible behavioral deficit in a modified LH procedure that administers inescapable shock (IS) in the same operant chamber used for shuttle box escape testing.
Results: A single IS session produced a robust increase in the number of escape failures (FR-2 escape contingency) that endured for at least 21 days. This escape deficit was reversed by desipramine (24 mg/kg/day, 6 days) at the first shuttle box session. Fluoxetine (5 mg/kg/day, 6 and 21 days) improved escape performance only after repeated test sessions. In contrast, fluoxetine (5 mg/kg/day, 21 days) completely reversed the first shuttle box test escape deficit induced by exposure to a chronic unpredictable stress procedure devoid of shocks or exposure to operant chambers. These differential drug effects may be due to the presence or absence of contextual cues during escape testing. Repeated re-exposure to the IS context enhanced the FR-2 escape deficit.
Conclusions: These data suggest that performing escape testing and IS in the same environment improves the preclinical modeling of the time-dependency and behavioral pattern of antidepressant response observed clinically. Additionally, contextual information associated with the IS environment modulates escape performance and may interact differentially with discrete antidepressant classes.