Chronic treatment of rats with theophylline (75mg/kg twice-daily for 21 consecutive days) significantly increased the specific binding of [3H]CHA and [3H]DPCPX in cerebral cortical membranes. The absolute increase in the number of binding sites following theophylline treatment was approximately the same for each ligand, although this number represents a larger percentage of the total sites available to [3H]CHA. Saturation analysis of [3H]DPCPX binding indicated that theophylline treatment increased the maximum number of binding sites from 799 +/- 13 to 920 +/- 22 fmol/mg protein, while the affinity of [3H]DPCPX for A1 receptors was unaltered. These results suggest that chronic theophylline exposure produces both an increase in the number of A1 adenosine receptors and an enhancement of coupling of these receptors to G proteins.