Differential effects of chronic antidepressant treatment on shuttle box escape deficits induced by uncontrollable stress

Abstract

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.

Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness

“…The helpless condition characterizes a depressive-like phenotype with changes in animal behavior that simulate the symptomatology of major depression patients (Dess et al 1988;Greenberg et al 1989;Adrien et al 1991). Chronic and acute treatment with several classes of antidepressants prevents or reverses this depressive-like behavior (Telner et al 1981;Sherman et al 1982;Martin et al 1987;Takamori et al 2001;Chourbaji et al 2005;Joca et al 2006;Valentine et al 2008;Zazpe et al 2007). …”

Behaviour of a genetic mouse model of depression in the learned helplessness paradigm

“…Previous studies reported that the helpless period lasted at least 10 days (Chourbaji et al 2005) and up to 21 days (Valentine et al 2008) depending on the protocol used. In our experiment, we noticed that animals exposed to a shock reminder presented a high and stable behavioural deficit 24 h after training until the final escape test, compared to animals with no reminder.…”

Animal models of psychopathology: Historical models and the pavlovian contribution

“…Electroconvulsive shocks (Dorworth & Overmier, 1977) and select drugs (e.g., desmethylimipramine; Leshner, Remler, Biegon, & Samuel, 1979) have also been shown to disrupt the interference produced by uncontrollable shock. Of translational importance, releasing learned helplessness animals from their deficits has been widely used as a criterion for testing the efficacy of anti-depressive drugs (e.g., Reed, Happe, Petty, & Bylund, 2008;Reed et al, 2009;Valentine, Dow, Banasr, Pittman, & Duman, 2008).…”