THE effect of the AMPA antagonist NBQX (10 μM), NMDA antagonist ketamine (100 μM) and 5-HT1A agonist 8-OH-DPAT (1, 10 and 100 μM) on the properties of a KCl-induced spreading depression (SD) was studied in parietal cortical slices of adult rats. Whereas NBQX did not significantly affect the SD, ketamine significantly (p < 0.01) reduced the amplitude of the first SD peak (12.8 ± 4.6 mV) and blocked the second SD peak when compared with the controls (19.8 ± 5.2 mV and 25 ±5 mV, respectively). Ketamine also decreased the SD duration at half maximal amplitude from 34.9 ± 12.4 s to 22.2 ± 12 s (p < 0.05). 8-OH-DPAT attenuated the duration of the SD from 42 ± 15.6 s to 21.2 ± 10.6 s (p < 0.05, 100 μM). These data indicate that not only NMDA receptor blockade, but also activation of the 5-HT1A receptor attenuates the SD and may be beneficial in the reduction of ischemic injury following focal cerebral ischemia.