Histamine-containing neurons of the tuberomammillary nucleus (TMN) are implicated in facilitating wakefulness. They project to many brain areas, including the cholinergic basal forebrain (BF). The cholinergic magnocellular regions of the BF are important in the regulation of cortical arousal and wakefulness, and a role for histamine in this activity is suggested by in vitro data indicating histamine excites BF cholinergic and non-cholinergic neurons. To test the hypothesis that histamine induces wakefulness via actions in the BF, we performed microdialysis perfusion of different concentrations of histamine (100, 500 and 1000 microM) in the BF of Sprague-Dawley rats. A MANOVA analysis showed that histamine produced a highly statistically significant and dose-dependent increase in wakefulness and decrease in non-rapid eye movement (NREM) sleep compared with artificial cerebrospinal fluid perfusion. From a wakefulness baseline percentage time of about 12% with artificial cerebrospinal fluid, histamine perfusion increased this value to 26% (100 microM), 36% (500 microM), or 47% (1000 microM). There was no statistically significant change in rapid eye movement (REM) sleep. Histamine perfusion (500 microM) in a control site, the centromedian thalamic nucleus, did not produce any change in behavioral state. The results indicate a prominent role of histamine in wakefulness regulation via the BF and further support the hypothesis that the BF has an important role in EEG activation and wakefulness.