Norepinephrine (NE) is a regulatory neurotransmitter widely distributed throughout the central nervous system. It modulates intrinsic currents as well as amplitude and frequency of synaptic transmission affecting the 'signal-to-noise' ratio of sensory responses. The mechanisms of NE action are diverse and depend on adrenergic receptor subtypes and their cellular distribution. In cortical pyramidal cells, pharmacological activation of a₁- or b- adrenergic receptors (AR) depresses or potentiates synaptic excitatory transmission, respectively. Yet, it remains unclear whether these two receptor subtypes are co-expressed and whether their activation by NE leads to relevant interactions. Here, we tested the effects of bath applied AR-agonists on excitatory postsynaptic currents (EPSCs) evoked by stimulating ascending fibers to layer II/III pyramidal cells from acute slices. We found that activation of b-AR increased, while subsequent activation of a₁-AR decreased the amplitude of EPSCs. These changes were reversible and did not affect the paired-pulse ratio. Similarly, by blocking either a₁- or b-AR, we found that low doses of NE could potentiate or depress EPSCs, respectively. Modulation was dose-dependent and with almost a tenfold difference in half maximal effective concentration for putative a₁- and b-AR-dependent components. No changes were detected when both receptor subtypes were blocked. In control conditions, appropriate concentrations of NE lead to opposite modulation of EPSCs, as expected by linear interactions between a₁- and b-AR modules. Diffusion of NE through the extracellular space could favor EPSC potentiation in proximal regions of higher [NE] and depression in distal regions of lower [NE], shaping the propagation of cortical transmission.