The effects of cyclothiazide, a drug that blocks AMPA receptor desensitization, on synaptic responses were studied in field CA1 of hippocampal slices from adult and neonatal rats. Cyclothiazide (100 microM) reliably increased AMPA receptor-mediated field EPSP decay times in adult slices but only after prolonged (60-120 min) applications. In neonatal slices, 30 min applications of cyclothiazide were sufficient to produce large and long-lasting increases in response decay times. Since the effects of cyclothiazide on AMPA receptor binding properties were similar in adult and neonatal forebrain membranes, the data indicate that the slow action of the drug in adult slices is probably due to diffusion barriers. The prolongation of EPSP decay by cyclothiazide suggests that AMPA receptor-mediated synaptic responses in hippocampus are terminated by receptor desensitization.