Spreading depression (SD) in a flow-restricted area of the brain may be prolonged and may become potentially harmful by releasing glutamate. We induced SD in an oligemia model and examined the subsequent glutamate release. In 18 anesthetized male Fischer rats, a laser Doppler flowmeter, an electroenzymatic electrode for continuous measurement of glutamate, and a calomel electrode for measuring DC potential were placed through a cranial window positioned 3 mm away from a second window where KCl-soaked cotton was placed to initiate SD. The left carotid artery or both the common carotid arteries were ligated to suppress reactive hyperemia of SD. SD produced an increase in glutamate from 24.8 +/- 13.8 to 33.5 +/- 25.3 microM (peak value) (P < 0.0001). After ligation of both carotid arteries, the duration of SD increased from 1.5 +/- 0.6 min (before ligation) to 6.4 +/- 5.1 min (P < 0.05). Glutamate reached a peak level of 63.9 +/- 72.3 microM, then quickly returned to the control value. However, there was no positive correlation between the duration of SD and glutamate concentration. It is concluded that prolonged SD is not accompanied by a progressive increase in glutamate. Therefore, glutamate release induced by SD may not exert harmful effects on neurons.