Efferents from the pedunculopontine tegmentum (PPTg) exert widespread control over neocortical electrocorticographic (ECoG) activity and aid in maintaining high-frequency ECoG activation during waking and rapid eye movement sleep. The mechanisms and subcortical routes that allow the PPTg to influence cortical activity remain controversial. We examined the relative contributions of the thalamus and basal forebrain in ECoG activation elicited by PPTg stimulation in urethane-anesthetized rats. Stimulation (100 Hz, 2 s) of the PPTg suppressed large-amplitude, low-frequency oscillations, replacing them with high-frequency beta-gamma activity. Systemic administration of the anti-muscarinic drug scopolamine (1 mg/kg, i.p.) abolished activation elicited by PPTg stimulation, suggestive of an essential role of acetylcholine in this effect. Local infusions of lidocaine (1 microl, 1%) into the region of the cholinergic basal forebrain complex produced a strong reduction in activation elicited by PPTg stimulation. Lidocaine infusions into the reticular thalamic nucleus had no effect, but infusions into central thalamus produced a small attenuation of PPTg-evoked cortical activation. Combined basal forebrain-central thalamic infusions (1 microl/site) produced roughly additive effects, leading to a greater loss of activation than single-site infusions. These results indicate that, under the present experimental conditions, high-frequency cortical ECoG activation elicited by the PPTg involves relays in both the basal forebrain and central thalamus, with a predominant role of the basal forebrain. After concurrent central thalamic-basal forebrain inactivation, the forebrain can maintain only limited, short-lasting activation in response to PPTg stimulation. The additivity of infusion effects suggests that, rather than participating in one serial system, basal forebrain and central thalamus constitute parallel activating pathways. These findings aid in resolving previous controversies regarding the role of thalamus and basal forebrain in activation by emphasizing the importance of multiple, large-scale networks between brainstem and cortex in regulating the activation state of the mammalian neocortex.