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)-alpha-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 elimination 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 neurons by a concomitant activation of H1 and H2 receptors. Histaminergic tuberomammillary 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.