The medial prefrontal cortex receives converging projections from the mediodorsal thalamic nucleus, dopaminergic cells from the ventral tegmental area dn noradrenergic cells from the locus coeruleus. Stimulation of the ventral tegmental area inhibits the spontaneous activity of prefrontal cortical neurons and blocks the excitatory response evoked by stimulation of the mediodorsal thalamic nucleus (10 Hz). The aim of the present study was to compare the influence of dopaminergic and noradrenergic afferents on the spontaneous and evoked activity of medial prefrontal cortical neurons. In ketamine-anaesthetized rats, repetitive stimulation (20 Hz, 10 s) of the locus coeruleus produced a long-lasting post-stimulus inhibition (mean duration: 45 s) of the spontaneous activity of 56% of the tested cells. This effect was decreased markedly following selective destruction of the ascending noradrenergic pathways (local 6-hydroxy-dopamine injection) or depletion of cortical catecholamines by alpha-methyl-para-tyrosine pretreatment, suggesting that these inhibitory responses are mediated by noradrenergic neurons. The excitatory response to mediodorsal thalamus nucleus stimulation (10 Hz) could still be evoked during the post-stimulus inhibitory period induced by locus coeruleus stimulation (20 Hz, 10 s) resulting in the enhancement of signal-to-noise ratio. On the other hand, a population of prefrontal cortex neurons (26%) was found to be reproducibly activated by noxious tail pinch. This evoked response was still present during the post-stimulus inhibitory period induced by locus coeruleus stimulation but was completely suppressed during stimulation of the ventral tegmental area (10 Hz). In conclusion, these results indicate that the dopaminergic and noradrenergic systems exert a completely distinct control of information transfer in the medial prefrontal cortex.