In a slice preparation of rat visual cortex, we discovered that paired-pulse stimulation (PPS) elicits a form of homosynaptic long-term depression (LTD) in the superficial layers when carbachol (CCh) or norepinephrine (NE) is applied concurrently. PPS by itself, or CCh and NE in the absence of synaptic stimulation, produced no lasting change. The LTD induced by PPS in the presence of NE or CCh is of comparable magnitude with that obtained with prolonged low-frequency stimulation (LFS) but requires far fewer stimulation pulses (40 vs 900). The cholinergic facilitation of LTD was blocked by atropine and pirenzepine, suggesting involvement of M1 receptors. The noradrenergic facilitation of LTD was blocked by urapidil and was mimicked by methoxamine, suggesting involvement of alpha1 receptors. beta receptor agonists and antagonists were without effect. Induction of LTD by PPS was inhibited by NMDA receptor blockers (completely in the case of NE; partially in the case of CCh), suggesting that one action of the modulators is to control the gain of NMDA receptor-dependent homosynaptic LTD in visual cortex. We propose that this is a mechanism by which cholinergic and noradrenergic inputs to the neocortex modulate naturally occurring receptive field plasticity.