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

Classical and rapid-acting antidepressants alter how the brain responds to acute stress through different molecular programs. In mice exposed to swim stress, imipramine dampened stress-induced neural activation in the cortex and striatum, while ketamine preserved it. Hippocampal activation remained robust and unaffected by either drug. BDNF expression changed only in the striatum, where imipramine reduced the stress-related increase. Both drugs similarly promoted active coping behaviors, but through distinct mechanisms. The findings suggest that cortical and striatal transcriptional signatures differentiate classical from rapid-acting antidepressant action, though human studies are needed to confirm clinical relevance.

Study at a glance

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.