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

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

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3123-3133
Number of pages11
JournalPsychopharmacology
Volume232
Issue number17
DOIs
StatePublished - Sep 14 2015

Keywords

  • Chronic stress
  • Cognitive flexibility
  • Ketamine
  • Medial prefrontal cortex
  • Ventral hippocampus

ASJC Scopus subject areas

  • Pharmacology

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