en Experimental research article Experimental research article <span style="font-size: 12pt">Ketamine (KET) induced blockade of cortical spreading depression (CSD) declines with repeated KET applications in a way suggesting the development of tolerance. Possible mechanism of this process was studied in 31 rats anestheized with pentobarbital. CSD was elicited by injection of 1</span><span style="font-size: 12pt">µ</span><span style="font-size: 12pt">l of 5% KCl into cortex at 15 min intervals and monitored by recording the accompanying slow potential waves. After control recording, five injections of KET (50 mg/kg) were applied at 75 min intervals. The first KET injection elicited CSD blockade lasting for 30-45 min at the near and for 60- 75 min at the far electrode. The CSD blocking effect of subsequent injections gradually declined and was not recognizable after the fifth KET injection. MK-801 (2 & 5 mg/kg) injected to rats with marked KET tolerance 30 min after the last KET dose, failed to block CSD. Without KET pretreatment the same dosage of MK-801 induced CSD blockade lasting more than 1 h. KET tolerance did not prevent local CSD blockade in cortical area superfused with 10 mol/l AP5. It is concluded that repeated applications of KET may induce some conformational changes at binding site(s) in the N-methyl-D-aspartate (NMDA) controlled channels shared by both KET and MK-801</span> Spreading depression; Cerebral cortex; Ketamine; AP5; N-Methyl-D-Aspartate receptor; MK-801 1 8 http://ppj.phypha.ir/browse.php?a_code=A-10-67-1&slc_lang=en&sid=1 Ali Rashidipour 3200319475328460011611 3200319475328460011611 Yes Department of Physiology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, I.R. Iran