Acute pretrauma ethanol exacerbates PTSD-like phenotype in rats and is reversed by early intranasal ketamine
Bar Eilat Yogev, Gal Levi, Noa Efroni, Amnon Sintov, Doron Todder, Joseph Zohar, Hagit Cohen
Scientific Reports June 14, 2026 DOI: 10.1038/s41598-026-56757-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort with experimental manipulation Peer reviewed |
|---|---|
| Population | Adult male Sprague-Dawley rats |
| Interventions | Ethanol Ketamine |
| Dose | 1.6 g/kg, 40% v/v, intraperitoneal; 0.6 mg/kg intranasal via amylolipid nanovesicles |
| Duration | 7 days post-exposure |
| Topics | Ketamine Esketamine PTSD |
| Keywords | Nasal administration Ethanol Phenotype Alcohol Pharmacology Anesthesia Drug |
| Key findings | Pre-trauma ethanol exposure four hours before stress increased PTSD-like phenotype prevalence and hippocampal dendritic retraction, while early post-trauma intranasal ketamine reduced these effects. |
Abstract
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.