These experiments were designed to assess the ability of norepinephrine and its beta-receptor agonist, isoproterenol, to modulate responses induced by activation of excitatory amino acid receptors in brain slices obtained from developing human cortex or adult rat cortex. Human cortical slices were obtained from children undergoing surgery for intractable epilepsy (9 months to 10 yr of age). For comparison, slices were also obtained from rats (2-3 months of age). Iontophoretic application of glutamate, N-methyl-D-aspartate or alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) produced excitatory responses consisting of membrane depolarizations accompanied by action potentials. Iontophoretic or bath application of norepinephrine or isoproterenol enhanced responses evoked by glutamate or N-methyl-D-aspartate. Depolarizations occurred with shorter latencies and their amplitudes increased. Action potential frequency was also increased and responses were of longer duration. In contrast, norepinephrine or isoproterenol had no effect on responses induced by AMPA. The enhancement of responses induced by N-methyl-D-aspartate or glutamate was antagonized by the beta-adrenergic receptor antagonist propranolol. Similar findings were obtained from neurons in humans or rats. These results suggest that norepinephrine, possibly via beta-receptors, potentiates responses mediated by glutamate and N-methyl-D-aspartate receptors without affecting those mediated by AMPA receptors. These effects were observed at all ages studied, indicating that the ability of norepinephrine to modulate excitatory neuronal transmission is well developed in human cortex by 9 months of age.