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

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

doi:10.1007/s00213-015-3957-3

Cited by 75Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

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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Jett, Julianne D., Boley, Angela M., Girotti, Milena, Shah, Amiksha, Lodge, Daniel J., Morilak, David A.·2015·Psychopharmacology

DOI 10.1007/s00213-015-3957-3PMC PMC4536154

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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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Two studies in rats extend molecular findings in animal models to behavioral indices with possible relevance to cognitive flexibility in human patients.
“Two studies in rats 130,131 extend molecular findings in animal models to behavioral indices with possible relevance to cognitive flexibility in human patients.”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [130]
Following stress, rats randomized to ketamine compared to saline exhibited enhanced cognitive flexibility, as indexed by improved set-shifting task performance.
“Following stress, rats randomized to ketamine (compared to saline) exhibited enhanced cognitive flexibility, as indexed by improved set-shifting task performance.”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [130]
Two weeks of chronic unpredictable stress produces significant deficits in reversal learning measured by the AST or a Morris water maze spatial reversal task.
“Similarly, two weeks of chronic unpredictable stress also produces significant deficits in reversal learning, measured using the AST (Bondi et al 2007, Bondi et al 2010, Jett et al 2015, Jett & Morilak 2013) or using a Morris water maze spatial reversal task (Hill et al 2005, Quan et al 2011, Yu et al 2016).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Jett et al 2015
Systemic sub-anesthetic ketamine given 24 hours before testing reverses stress effects on extradimensional set-shifting.
“Ketamine given systemically at a sub-anesthetic dose 24 hours before testing has been shown to reverse the effects of stress on ED set-shifting (Jett et al 2015).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Jett et al 2015

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Authors: Jett, J. D., Boley, A. M., Girotti, M., Shah, A., Lodge, D. J., & Morilak, D. A.
Affiliations: The University of Texas at San Antonio Health Science Center (US)
Corresponding author: Morilak, David A.
ORCID: Jett, Julianne D.
Boley, Angela M.
Girotti, Milena
Lodge, Daniel J.
Morilak, David A.
Venue: Psychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2015-05-20
Volume: 232
Issue: 17
Pages: 3123-3133
ISSN: 0033-3158 (ISSN-L)
1432-2072
DOI: 10.1007/s00213-015-3957-3
PMC: PMC4536154
OpenAlex: W1920890253
Cited by: 75
References: 62
Citations by year: 2026: 3 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 9 · 2019: 14 · 2018: 3 · 2017: 6 · 2016: 7
FWCI: 3.84
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Psychopharmacology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5r01mh090067-10)
National Institute of Mental Health (MH072672, MH053851, R01: MH090067, R56MH053851, MH090067, R29MH053851, R01MH072672, R01MH053851)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: ketamine, antidepressant-like effects, cognitive flexibility, chronic stress, ventral hippocampus, medial prefrontal cortex, set-shifting, forced swim test, defensive burying, NMDA receptor antagonists, depression
MeSH terms: Adaptation, Psychological, Animals, Antidepressive Agents, Attention, Behavior, Animal, Cognition, Electroshock, Hippocampus, Ketamine, Male, Neural Pathways, Neuronal Plasticity, Stress, Psychological, Swimming, Rats, Sprague-Dawley, Prefrontal Cortex, Long-Term Potentiation, Excitatory Amino Acid Antagonists, Rats

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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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