Considerable evidence has shown that both cholinergic and histaminergic neurons in the brain may act to facilitate processes of cortical activation that occur during wakefulness. In the present study, the potential influence of histaminergic neurons upon cholinergic neurons of the basal forebrain was investigated in guinea-pig basal forebrain slices. We found that electrophysiologically identified and immunohistochemically verified cholinergic neurons of the nucleus basalis were depolarized and excited by histamine, as manifested by an increase in tonic firing. The depolarization was associated with an increase in membrane input resistance. The effect of histamine persisted in the presence of either tetrodotoxin or a high-magnesium/low-calcium solution, indicating that it is postsynaptic. By a process of elimination, the participation in this response of the three described histamine receptors was examined. Involvement of H₃ receptors was excluded on the basis that the H₃ agonist (R)-α-methyl-histamine had no direct effect, and the H₃ antagonist, thioperamide, did not block the effect of histamine. In contrast, the presence of a small response to impromidine, a selective agonist of H₂ receptors, and the partial block of the response to histamine by the H₂ receptor antagonist, cimetidine, indicated the participation of H₂ receptors. Finally, the complete elomination of histamine's effect occurred when low doses of the H₁ antagonist, mepyramine, were added to the H₂ antagonist, cimetidine, indicating the involvement and predominance of H₁ receptors in the response. Our data thus suggest that histamine excites nucleus basalis cholinergic neurones by a concomitant activation of H₁ and H₂ receptors. Histaminergic tuberomammilary neurons may accordingly facilitate tonic firing of cholinergic neurons during wakefulness. Cholinergic basalis neurons could thus act in tandem with histaminergic neurons during periods of arousal to collectively promote widespread cortical activation.