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The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment

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Abstract

Rationale

Neuroleptic dysphoria encompasses a range of unpleasant subjective responses and, as a result, is difficult to study in preclinical animal models.

Objective

Based on the learned helplessness model of depression, increases in escape failures (EFs) in the drug-induced helplessness test (DH) are proposed to reflect drug-induced depressive-like state, a contributing factor to neuroleptic dysphoria in humans.

Materials and methods

Effects of the typical antipsychotic haloperidol and the atypical antipsychotics risperidone, olanzapine, aripiprazole, quetiapine, and clozapine were investigated in the DH test. We further characterized this test by examining compounds affecting motor function, cognition, anxiety, and those with antidepressant activity.

Results

The antipsychotics haloperidol, risperidone, aripiprazole, and olanzapine, all increased EFs, while quetiapine had no effect, and clozapine reduced EFs. Amphetamine, diazepam, and ciproxifan, had no effect on EFs. Scopolamine significantly reduced EFs and MK-801 showed a trend toward reducing EFs at doses not significantly sti mulating locomotor activity. Subchronic, but not acute, imipramine and subchronic fluoxetine significantly reduced EFs at doses significantly suppressing locomotor activity. Dissociation appears to exist between performance in the DH test and compound effects on catalepsy or locomotor activity.

Conclusions

After discussing potential alternative interpretations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria.

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Acknowledgements

The authors would like to thank Marlon Cowart for the synthesis of ciproxifan. We declare that the experiments comply with the current laws of the USA where the experiments were performed.

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Authors and Affiliations

  1. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, 60064, USA

    Michael E. Ballard, Ana M. Basso, Kelly B. Gallagher, Kaitlin E. Browman, Gerard B. Fox, Michael W. Decker, Lynne E. Rueter & Min Zhang

  2. Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Ludwigshafen, Germany

    Karla U. Drescher & Gerhard Gross

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  1. Michael E. Ballard
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  2. Ana M. Basso
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  3. Kelly B. Gallagher
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Correspondence to Min Zhang.

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Ballard, M.E., Basso, A.M., Gallagher, K.B. et al. The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment. Psychopharmacology 190, 1–11 (2007). https://doi.org/10.1007/s00213-006-0577-y

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