Noradrenergic projections to the cortex modulate a variety of cortical activities and calcium channels are one likely target for such modulation. We used the whole-cell patch-clamp technique to study noradrenergic modulation of barium currents in acutely dissociated pyramidal neurons from rat sensorimotor cortex. Extracellular application of specific agonists and antagonists revealed that norepinephrine (NE) reduced Ca2+ current. A major component of this modulation was due to activation of alpha2 receptors. Activation of alpha2-adrenergic receptors resulted in a fast, voltage-dependent pathway involving Gi/Go G-proteins. This pathway targeted N- and P-type calcium channels The alpha2 modulation was partially reversed by repeated action potential waveforms (APWs). N- and P-type channels have been implicated in synaptic transmission and activation of afterhyperpolarizations in these cells. Our findings suggest that NE can regulate these cellular processes by mechanisms sensitive to spike activity.