Memantine Alleviates PTSD-like Symptoms and Improves Dendritic Arborization through Modulation of the HPA Axis and Neuroinflammation in Rats

Abstract

Post-traumatic stress disorder (PTSD) poses significant neurological and psychiatric challenges. Investigations into the glutamatergic system, particularly the N-methyl-D-aspartate (NMDA) receptor, are crucial for understanding PTSD mechanisms. This study aimed to evaluate the therapeutic potential of the non-competitive NMDA receptor antagonist memantine in mitigating PTSD symptoms and to explore its underlying cellular and molecular impacts. Male Sprague Dawley rats were subjected to inescapable foot shock stress (FS-stress) to model PTSD. Following stress exposure, memantine was administered at doses of 5 mg/kg and 10 mg/kg six hours post-stress. Behavioural assessments, including fear conditioning and sucrose preference tests, were conducted. Golgi-Cox staining was used to assess neuroanatomical changes related to synaptic plasticity. Western blotting was used to analyse molecular markers associated with synaptic plasticity, while immunoassays measured proinflammatory cytokines and cortisol levels. Memantine treatment improved behavioral outcomes, restoring sucrose preference and reducing freezing behavior. Morphological analysis demonstrated that memantine enhanced dendritic spine structure, particularly increasing the proportion of mature mushroom spines, which are critical for synaptic stability. Additionally, memantine normalized cortisol levels, suggesting a regulatory effect on the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, memantine treatment improved the inflammatory cytokine profile, reducing IL-6 and TNF-α levels. These results suggest that memantine has potential as a therapeutic intervention for PTSD by targeting critical pathways involved in stress responses.The findings indicate that memantine, an NMDA receptor antagonist, can counteract behavioral and functional disturbances induced by FS-stress.