In the p50 suppression paradigm, when two auditory stimuli are presented 500 ms apart, the amplitude of the second response (S2), compared with the first (S1), is markedly attenuated in healthy subjects. This is an index of sensory gating. Most schizophrenic patients fail to inhibit the p50 response to the second stimulus, which is assumed to reflect an inhibitory deficit. Adenosine is a neuromodulator with mostly inhibitory activity which is released by physiological stimuli. Since this inhibitory pattern resembles the phenomenon of sensory gating, the contribution of adenosine to p50 suppression was investigated in normal volunteers after treatment with the adenosine antagonist theophylline or placebo. P50 recordings were conducted in thirteen healthy subjects at baseline and 5, 30, 60, and 90 min after oral administration of theophylline (0.66 mg/kg, maximum dose of 500 mg) or placebo in a cross-over design. Baseline results from 17 drug-treated schizophrenic patients were included for comparison. Compared with placebo, theophylline treatment significantly increased P50 ratio (S2/S1) from 0.28 +/- 0.03 to 0.82 +/- 0.11 at 30 min and 0.61 +/- 0.07 at 60 min (mean +/- SEM), which were not significantly different from the schizophrenia group (0.74 +/- 0.05). The increased p50 ratio by theophylline was due to a combined decrease in S1 and increase in S2 amplitude. The impairment of p50 suppression by theophylline in normal subjects suggests a modulatory role of adenosine in sensory gating, which may be related to p50 suppression deficit in schizophrenia and is in agreement with a hypoadenosinergic model of schizophrenia.