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Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway

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Abstract

Rationale

Acute low-dose administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST) and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB).

Objective

In this study, we tested the effects of ketamine on chronic stress-induced changes in cognitive flexibility and coping behavior on the AST and SPDB, respectively. Subsequently, we investigated vHipp-mPFC plasticity as a potential mechanism of ketamine’s therapeutic action.

Results

Ketamine reversed deficits in cognitive flexibility and restored active coping behavior in chronically stressed rats. Further, high frequency stimulation in the vHipp replicated ketamine’s antidepressant-like effects on the forced swim test and AST, but not on the SPDB.

Conclusion

These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.

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Acknowledgments

We would like to acknowledge and thank Lauren Evans for her superb technical assistance.

Funding

Funding for this work was provided by research grants MH090067 (DJL), MH053851, and MH072672 (DAM) from the National Institutes of Health and by a University of Texas Health Science Center President’s Council Faculty Scholar Award (DAM).

Conflict of interest

There are no conflicts of interest to report

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Authors and Affiliations

  1. Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7764, San Antonio, TX, 78229-3900, USA

    Julianne D. Jett, Angela M. Boley, Milena Girotti, Amiksha Shah, Daniel J. Lodge & David A. Morilak

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  1. Julianne D. Jett
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  2. Angela M. Boley
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  3. Milena Girotti
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  4. Amiksha Shah
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  5. Daniel J. Lodge
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  6. David A. Morilak
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Correspondence to David A. Morilak.

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Jett, J.D., Boley, A.M., Girotti, M. et al. Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology 232, 3123–3133 (2015). https://doi.org/10.1007/s00213-015-3957-3

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  • DOI: https://doi.org/10.1007/s00213-015-3957-3

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