Because the excitable properties of neurons in the neocortex depend on the characteristics of voltage-gated Na(+) channels, factors which regulate those characteristics can fundamentally modify the dynamics of cortical circuits. Here, we report on a novel neuromodulatory mechanism that links the availability of Na(+) channels to metabolism of polyamines (PAs) in the cerebral cortex. Using single channel and whole-cell recordings, we found that products of PA metabolism, the ubiquitous aliphatic polycations spermine and spermidine, are endogenous blockers of Na(+) channels in layer 5 pyramidal cells. Because the blockade is activity-dependent, it is particularly effective against Na(+) channels which fail to inactivate rapidly and thus underlie the persistent Na(+) current. At the level of the local cortical circuit, pharmacological depletion of PAs led to increased spontaneous spiking and periods of hypersynchronous discharge. Our data suggest that changes in PA levels, whether associated with normal brain states or pathological conditions, profoundly modify Na(+) channel availability and thereby shape the integrative behavior of single neurons and neocortical circuits.