Protective Effects of Memantine Against Acute Stress-Induced Fear Memory and Synaptic Dysfunction via NMDA Receptor Antagonism.

INTRODUCTION

Post-traumatic stress disorder (PTSD) is a complex mental health condition that arises following exposure to severe psychological trauma. Dysregulation of excitatory transmission, especially involving N-methyl-D-aspartate (NMDA) receptors, has been increasingly linked to its development. This study aimed to evaluate the therapeutic potential of memantine, a noncompetitive antagonist of NMDA receptors, in a rodent model of PTSD, with a focus on its effects at the cellular and molecular levels.

METHODS

Adult male Sprague Dawley rats were exposed to an unavoidable foot shock paradigm to induce stress-related behavioural alterations. Animals received memantine at either 5 mg/kg or 10 mg/kg, one hour before the stress procedure. Behavioural outcomes included a multi-day contextual fear paradigm and a sucrose intake measure to evaluate anhedonia. Neuroanatomical alterations linked to synaptic plasticity were analysed using Golgi-Cox staining, while molecular markers of synaptic function were assessed via western blotting. Additionally, pro-inflammatory cytokines and cortisol levels were measured through immunoassays.

RESULTS

A single administration of memantine effectively prevented behavioural impairments, as evidenced by reduced freezing behaviour and preserved sucrose preference. Memantine attenuated NMDA receptor overactivation, restored hypothalamic-pituitary-adrenal (HPA) axis function, decreased proinflammatory cytokine levels, and improved dendritic spine morphology. Molecular analyses further showed improved expression of synaptic proteins involved in plasticity.

DISCUSSION: The findings indicate that NMDA receptor blockade during acute stress can prevent the development of PTSD-like behavioural and molecular alterations. The observed protection against neuroinflammation and synaptic deficits aligns with previous evidence supporting NMDA antagonism as a neurotherapeutic strategy.

CONCLUSION

Memantine provided significant protection against FS-stress-induced behavioural, inflammatory, and synaptic abnormalities, suggesting its potential utility as a pharmacological intervention for PTSD.