Differential Actions of Ketamine on CA3-Prelimbic and CA3-Infralimbic Connection Responsivity Depend on Prior Exposure to Stress.
Carlos M Contreras, Ana G Gutiérrez-García
Behavioural Brain Research June 27, 2025 DOI: 10.1016/j.bbr.2025.115712 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male Wistar rats |
| Interventions | ketamine saline |
| Duration | 15-min forced swim test session, 60 minutes post-stress injection, 24-hour delay before testing |
| Topics | Ketamine Esketamine |
| Keywords | Forced swim test Infralimbic cortex Stress-sensitive Stress-induced changes Prior stress Potential antidepressants Beneficial antidepressant-like effects Effectively reversed Precise action Brain circuitry: hippocampus Brain circuits Hippocampus-prelimbic cortex connections |
| Citations | 1 |
| Key findings | The CA3-prelimbic connection is sensitive to stress regardless of drug treatment, while the CA3-infralimbic connection is sensitive to ketamine but only after prior stress exposure. |
Abstract
The present study explored the behavioral stressing action of a 15-min forced swim test (FST) session, changes in CA3-medial prefrontal cortex (mPFC) connection responsivity, and whether ketamine reverses such changes. Two groups of male Wistar rats were subjected to a 15-min FST session. Sixty minutes later, they were injected with either saline (stress [STR] SAL group) or ketamine (STR KET group). Twenty-four hours later, these two groups underwent an open field test (OFT) and a 5-min FST session. The other two groups received similar treatments (SAL group and KET group) without being subjected to the FST. In all four groups, single-unit extracellular recordings from the prelimbic (PL) and infralimbic (IL) regions of the mPFC were obtained while the CA3 hippocampal region was stimulated. Ketamine decreased the time spent immobile in the FST without altering behavior in the OFT. In the SAL group, CA3 stimulation produced an inhibitory response in the PL but a strong excitatory response in the IL. In the KET group, there were no changes in connection responsivity in the CA3-PL connection, but an inhibitory response was observed in the CA3-IL connection. Responsivity of the CA3-PL connection was similar between the STR KET and STR SAL groups. In the SAL group, CA3 stimulation produced an inhibitory response in the IL, which was accentuated in the STR SAL group. In the STR KET group, the inhibitory response was abolished. These findings indicate that the CA3-PL connection is sensitive to stress, independent of drug treatment, whereas the CA3-IL connection is sensitive to ketamine, but its action depends on prior stress exposure.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 13
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacology & Therapeutics July 1, 2019
- Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review Journal of Psychopharmacology June 26, 2021
- Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Molecular Brain June 16, 2020
- Inflammation, stress and depression: an exploration of ketamine’s therapeutic profile Drug Discovery Today February 1, 2023
and 8 more in the library