A rabbit spinal cord ischemia model was used to study the effects of focal ischemia on the tissue concentrations of serotonin, 5-hydroxyindole acetic acid, and norepinephrine. Ischemia induced by abdominal aorta occlusion caused both serotonin and norepinephrine concentrations to decline in the most ischemic areas of the spinal cord by 55 minutes. In marginally perfused adjacent areas, serotonin concentrations transiently declined at 14 and 20 min. After the onset of ischemia and then returned to normal. The minimum was reached at the same time when previous studies showed damage had become irreversible in more ischemic regions. Concentrations of 5-hydroxyindole acetic acid did not change at any time and norepinephrine declined only in the most ischemic areas after damage was irreversible. Thus, permanent serotonin and norepinephrine decreases occur only in areas destined to be destroyed by infarction, but the serotonin returns to normal in marginal tissue that remains viable. These studies suggest that serotonin may be involved in the early stages of irreversible changes during central nervous system ischemia.