Modelling post-traumatic stress disorder–major depressive disorder comorbidity in rats: impaired α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor signalling is consistent with synergistic behavioural and cognitive deficits

<b>Background:</b> Post-traumatic stress disorder comorbid with major depressive disorder (PTSD + MDD) is a multifactorial condition with significant individual and societal impacts. Although neuroimaging studies have highlighted large-scale neural circuit dysfunctions, the underlying pathogenic mechanisms at the synaptic level remain poorly understood. The glutamatergic system, particularly the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), is hypothesized to play a pivotal role in stress-induced pathologies, yet its specific role in PTSD + MDD comorbidity has not been elucidated. Furthermore, research has been hindered by a lack of validated experimental paradigms that accurately model this complex clinical state.<b>Objective:</b> This study aimed to establish a robust rat model of PTSD + MDD comorbidity and to investigate regional alterations of AMPAR subunits within this framework.<b>Method:</b> An animal model of PTSD + MDD comorbidity was constructed using single prolonged stress and electric foot shock (SPS&S) combined with chronic unpredictable mild stress (CUMS). The face, construct, and predictive validity of the model were verified through behavioural monitoring, molecular biological assessments, and drug treatment with paroxetine (PRX).<b>Results:</b> The combined SPS&S + CUMS paradigm resulted in core PTSD- and MDD-like behavioural deficits, including severe anhedonia and significant cognitive impairment. At the molecular level, we observed distinct, region-specific alterations in AMPAR subunits and mammalian target of rapamycin (mTOR): hippocampal glutamate receptor A1 (GluA1) and mTOR were downregulated, prefrontal GluA1 and GluA3 were reduced, while the amygdala showed decreased GluA2 with concurrent increases in GluA3 and mTOR. PRX treatment partially ameliorated both the behavioural abnormalities and protein-level dysregulation.<b>Conclusions:</b> The SPS&S + CUMS paradigm successfully induces core features of PTSD + MDD comorbidity and demonstrates robust validity. The observed alterations in AMPAR-related molecules are strictly characterized as significant correlates of the comorbid state, suggesting their potential involvement in the underlying pathophysiology. These findings identify AMPAR-related signalling as a promising correlative molecular signature, providing a necessary foundation for future investigations using region-specific manipulations to establish definitive causal links.