Alcohol consumption before trauma is a prevalent but understudied risk factor for posttraumatic stress disorder (PTSD). This study investigated whether acute ethanol exposure prior to trauma modulates PTSD-like symptom development in rats, identified hippocampal mechanisms involved, and tested an early post-trauma intervention. Adult male Sprague-Dawley rats received ethanol (1.6 g/kg, 40% v/v, intraperitoneal) or saline 4 h or 30 min before predator scent stress (PSS) or sham-PSS exposure. Seven days post-exposure, anxiety-like behavior (elevated plus-maze), acoustic startle response, and cue-induced freezing were assessed using validated cut-off behavioral criteria to classify PTSD-like phenotypes. Hippocampal CA1 dendritic morphology was examined in relation to behavioral outcomes. In parallel cohorts, immunofluorescence quantified hippocampal hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), neuropeptide Y (NPY), NPY-Y1 receptor (NPY-Y1-R), and brain-derived neurotrophic factor (BDNF) 1 h post-PSS. A separate ethanol-pretreated group received subanesthetic intranasal ketamine (0.6 mg/kg) via amylolipid nanovesicles (ketamine-ALN) 1 h after PSS. Rats administered ethanol 4 h-but not 30 min-before PSS showed a higher prevalence of PTSD-like phenotypes at 7 days and significantly greater CA1 dendritic retraction. Combined ethanol and PSS exposure was associated with reduced BDNF and NPY levels, increased HCN1, and loss of NPY-Y1-R immunoreactivity, consistent with a hypoexcitable, plasticity-resistant state in the hippocampus. Rats that received early post-PSS ketamine-ALN showed lower cue-induced freezing, a more resilient behavioral profile, and less dendritic atrophy than unloaded-ALN-treated rats. Pre-trauma timed ethanol exposure was associated with a hippocampal "double-hit" involving HCN1 and NPY-Y1-R circuits, together with greater PTSD-like vulnerability. A single early post-trauma intranasal subanesthetic dose of ketamine was associated with a lower prevalence of PTSD-like phenotype, suggesting a promising preventive strategy for alcohol-exposed trauma survivors.
