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Distinct Molecular Responses to Ketamine and Imipramine in Cortical and Striatal Regions Following Acute Swim Stress

Veronica Begni, Floriana de Cillis, Natascha Pfeiffer, Steven Roger Talbot, Peter Gass, Annamaria Cattaneo, Marco Andrea Riva, Anne Stephanie Mallien

Biomolecules March 24, 2026 DOI: 10.3390/biom16040484 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Preclinical experimental study Peer reviewed
Population Mice
Interventions Imipramine Ketamine
Topics Ketamine Neuroplasticity Esketamine
Keywords Imipramine Antidepressant Hippocampal formation Hippocampus Fluoxetine Pathophysiology Pharmacology
Key findings Imipramine dampened stress-induced cFOS expression in the cortex and striatum, whereas ketamine preserved it, indicating distinct molecular mechanisms underlying similar behavioral outcomes.

Abstract

Pharmacological antidepressant treatments alter the molecular and functional reactivity of stress-sensitive neural networks. However, how classical versus rapid-acting antidepressants differentially modulate acute stress-induced transcriptional responses across brain regions remains unclear. Here, we compared imipramine and ketamine in mice exposed to acute swim stress, assessing transcriptional adaptations across the frontal cortex, hippocampus, and striatum. Swim stress induced significant widespread activation of cFOS, which led to drug-specific modulations: imipramine primarily significantly dampened cortical and striatal cFOS expression, whereas ketamine preserved stress-evoked neuronal activation. In contrast, hippocampal activation was significantly robust but largely unaffected, indicating that acute antidepressant drug effects during stress coping preferentially target cortical and striatal plasticity mechanisms. In contrast, BDNF expression was altered only within the striatal region, where imipramine attenuated the stress-related increase in BDNF expression. Statistical analysis of behavioral outcomes during the swim stress confirmed a shared facilitation of active coping, yet these similar outcomes emerged from distinct molecular programs. Together, the data demonstrate that the treatment effects of the two substances diverge mechanistically, revealing cortical and striatal transcriptional signatures of classical versus rapid-acting antidepressant action. While these findings suggest potential translational relevance for understanding distinct mechanisms, further studies in humans are required to validate these signatures and their clinical implications.

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

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Ketamine Neuroplasticity Esketamine