Ketamine blockade of spreading depression: rapid development of tolerance

Persistence of the ketamine-induced blockade of spreading depression (SD) was studied in 15 rats, anesthetized with 200 mg/kg ketamine followed at 50- to 60-min intervals by 3-5 injections of 100 mg/kg of the drug. Cortical or caudate SDs evoked 10 min after the first ketamine injection were blocked but the amplitude of SD waves elicited at regular 10-min intervals gradually increased while the blockade induced by subsequent ketamine injections weakened and became unrecognizable after the fifth injection. The result was not due to prolonged action of ketamine alone but rather to combined effect of ketamine and SD repetition. The development of tolerance is probably due to use-dependence of NMDA-gated channels which must be taken into account when assessing the therapeutic value of NMDA antagonists in treatment of brain ischemia.