The neuromodulator histamine plays an important role in the regulation of behavioural state and the neocortical electrocorticogram (ECoG). With the present experiments, we characterized the anatomical targets that mediate the cortical-activating effects of histamine. Urethane-anaesthetized rats displayed continuous large-amplitude, low-frequency oscillations with a maximal spectral power in the delta (0.5-3.9 Hz) frequency band. Electrical (100 Hz) stimulation of the pontine-tegmentum suppressed slow, large-amplitude oscillations and induced ECoG activation. Application of histamine (1 mm) into the basal forebrain cholinergic complex by reverse microdialysis enhanced ECoG activation elicited by tegmental stimulation without changing resting ECoG activity. Ventrolateral or central thalamic application of histamine had no effect on resting ECoG activity, and ventrolateral thalamic application produced only a slight enhancement of brainstem-induced activation. Neocortical application of histamine in close proximity (< 500 micro m) to the recording electrode reduced low-frequency delta power in the resting ECoG without affecting stimulation-induced ECoG activation. These data suggest that, under the present experimental conditions, histamine facilitates ECoG activation primarily by potentiating the excitatory influence of brainstem fibers at the level of the basal forebrain. Histamine release in some parts of the thalamus results in a minor enhancement of ECoG activation, and cortical histamine release produces a small but consistent suppression of slow delta oscillations in the resting ECoG. These concurrent subcortical and cortical actions probably permit histamine to effectively modulate cortical activation and excitability across different behavioural states.