1. Orexin A and B, recently identified in the rat hypothalamus are endogenous neuropeptide agonists for the G-protein coupled orexin-1 (OX1) and orexin-2 (OX2) receptors. 2. In the present study, we have examined the effects of orexin A, B and raised extracellular K(+) on noradrenaline release from the rat cerebrocortical slice. We have compared this with other sleep-wake-related (excitatory) neurotransmitters; dopamine, glutamate, serotonin and histamine. 3. Neurotransmitter release studies were performed in rat cerebrocortical slices incubated in modified Krebs buffer (with and without Ca(2+)+EGTA 1 mM) with various concentrations of orexin A, B and K(+) for various times. 4. Orexin A and B-evoked (10(-7) M) noradrenaline release was time-dependent reaching a maximum some 10 min after stimulation. K(+) (40 mM) evoked release was also time dependent but reached a maximum after 6 min. Orexin A, B and K(+) stimulation of release was concentration dependent with pEC(50) and E(max) (% of basal) values of 8.74+/-0.32 (1.8 nM) and 263+/-14% and 8.61+/-0.38 (2.4 nM) and 173+/-7% and 1.43+/-0.02 (37 mM) and 1430+/-70%, respectively. Orexin-evoked release was partially extracellular Ca(2+) dependent. 5. Of the other transmitters studied there was a weak orexin A and B stimulation of glutamate release. In contrast K(+) evoked dopamine, glutamate, histamine and serotonin release with pEC(50) and E(max) (% of basal) values of 1.47+/-0.05 (34 mM) and 3430+/-410%, 1.38+/-0.04 (42 mM) and 1240+/-50%, 1.47+/-0.02 (34 mM) and 480+/-10% and 1.40+/-0.05 (40 mM) and 560+/-60% respectively. 6. We conclude that the neuropeptides orexin A and B evoke noradrenaline release from rat cerebrocortical slices.