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This study evaluates memantine's therapeutic potential against stress-induced alterations related to PTSD.

March 14, 2026CNS & Neurological Disorders - Drug Targets0 citations

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

SBSumadhura Bommaraju MDMrunali D. Dhokne PRPatel Parthkumar Rakeshkumar

Key Points

This study evaluates memantine's therapeutic potential against stress-induced alterations related to PTSD.
Adult male Sprague Dawley rats underwent foot shock to induce stress.
Animals received memantine prior to the stress procedure at dosages of 5 mg/kg or 10 mg/kg.
Behavioural outcomes included contextual fear assessments and sucrose intake for anhedonia measurement.
Neuroanatomical changes were examined via Golgi-Cox staining and synaptic function assessed by western blotting.
Cytokine and cortisol levels were measured using immunoassays.
Memantine prevented behavioural impairments indicated by reduced freezing behaviour.
It improved sucrose preference, suggesting reduced anhedonia.
Memantine reduced pro-inflammatory cytokine levels and enhanced synaptic plasticity markers.
HPA axis function was restored, supporting neuroprotective effects against stress.
Dendritic spine morphology improved with memantine treatment.

Abstract

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.

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