Post-traumatic stress disorder (PTSD) is characterized by monoaminergic and hypothalamic-pituitary-adrenal (HPA)-axis abnormalities. Understanding monoamine-HPA-axis responses following stress and restress may provide a greater understanding of the neurobiology of PTSD and of its treatment. Hippocampal and frontal cortex serotonin, noradrenaline and dopamine, plasma corticosterone and aversive behavior were studied in rats on day 1 and day 7 post acute stress (AS = sequential restraint stress, swim stress and halothane exposure), and on day 1 and day 7 post restress (RS = swim stress). After AS, there was an early increase in both avoidant behavior and corticosterone (1 h after stress), with subsequent normalisation (day 7), suggesting an adequate adaptive response to the stressor. However, restress (RS) evoked a significant early HPA-axis hyporesponsiveness (1 h after RS) and a later significant increase in avoidant behavior on day 7 post RS. Hippocampal serotonin, noradrenaline and dopamine concentrations were unchanged 1 h post AS, but were significantly raised on day 7 post AS. Restress, however, reduced serotonin and noradrenaline levels 1 h after and on day 7 post RS, respectively, while dopamine was unchanged. In the frontal cortex only dopamine levels were altered, being significantly elevated 1 h after AS, and reduced on day 7 post RS. AS and RS thus differently effect the HPA-axis, evoking regional-specific brain monoamine changes that underlie maladaptive behavior and other post stress-related sequelae.