Hagit Cohen

Post-traumatic stress disorder (PTSD) remains difficult to prevent after trauma, highlighting the need for early interventions that reduce the risk of chronic symptom development. This controlled study investigated the preventive potential of 3,4-methylenedioxymethamphetamine (MDMA) in a validated rat model of PTSD induced by predator scent stress (PSS). Adult male Sprague–Dawley rats (N = 175) were exposed to PSS or sham-PSS and treated intraperitoneally with MDMA (2.5, 5, or 10 mg/kg) or saline. MDMA was administered either 30 min after PSS or 24 h later, with or without trauma-cue pairing. Behavioral outcomes included the elevated plus-maze and acoustic startle response assessments on day 7 for phenotypic classification, followed by contextual freezing on day 8. Urinary corticosterone and norepinephrine, hippocampal glucocorticoid receptor (GR) and norepinephrine transporter (NET), and c-Fos, tryptophan hydroxylase 2 (TPH2), GR, oxytocin, and tyrosine hydroxylase (TH) immunoreactivity were measured 1 h post-injection in stress-related brain regions. The 10 mg/kg MDMA dose significantly reduced anxiety-like behavior, startle amplitude, contextual freezing, and the prevalence of extreme behavioral responses when administered 30 min after PSS or 24 h later with trauma-cue pairing. Lower doses and unpaired delayed administration were largely ineffective. The effective dose increased urinary corticosterone and hippocampal GR levels, and enhanced c-Fos, TPH2, oxytocin, GR, and TH expression in stress-regulatory circuits. Trauma-cue pairing further strengthened MDMA-induced increases in GR, oxytocin, and TPH2. These findings suggest that MDMA was associated with dose-, timing-, and context-dependent reductions in PTSD-like outcomes, accompanied by neurochemical signatures consistent with enhanced stress regulation, neuroplasticity, and adaptive memory processing.