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

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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.

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Acknowledgement

This work was supported by USPHS grants MH25642, MH4548, by the Connecticut Mental Health Center and by the VA National PTSD Center. The lead author was supported by a NARSAD Young Investigator Award. The authors thank Brian M. Dow, Ph.D. for his assistance with data analysis.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University, New Haven, CT, USA

    Gerald Valentine, Mounira Banasr, Brian Pittman & Ronald Duman

  2. Department of Psychiatry, Harvard University, Cambridge, MA, USA

    Antonia Dow

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  1. Gerald Valentine
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  2. Antonia Dow
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  3. Mounira Banasr
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  4. Brian Pittman
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  5. Ronald Duman
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Correspondence to Gerald Valentine.

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Valentine, G., Dow, A., Banasr, M. et al. Differential effects of chronic antidepressant treatment on shuttle box escape deficits induced by uncontrollable stress. Psychopharmacology 200, 585–596 (2008). https://doi.org/10.1007/s00213-008-1239-z

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  • DOI: https://doi.org/10.1007/s00213-008-1239-z

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