Chronic exposure to subcutaneously implanted methylxanthines. Differential elevation of A1-adenosine receptors in mouse cerebellar and cerebral cortical membranes.

Upregulation of brain adenosine receptors in DBA/2J mice as affected by theophylline and caffeine, adenosine antagonists, was examined following subcutaneous drug implantation to ensure chronic exposure. Scatchard analysis of binding to membranes of cerebral cortex and cerebellum from individual mice showed a differential upregulation of (-)-N6-R-[G-3H]phenylisopropyladenosine ([3H]-L-PIA) binding density by theophylline. After 14 days of exposure to theophylline (serum concentration of 1.2 +/- 0.01 micrograms/ml measured by HPLC analysis), the Bmax for L-PIA binding to cerebellar membranes increased 22% over the control mice (statistically significant at P less than 0.01 level). Theophylline had no effect on the Bmax for L-PIA binding to cerebral cortical membranes. The observed increases in Bmax values of cerebellar (13.2%) and cerebral cortical membrane binding (14.2%) on chronic exposure to caffeine (7.1 +/- 0.5 micrograms/ml) were not statistically significant at the P less than or equal to 0.05 level. Neither methylxanthine affected the dissociation constant, KD, for L-PIA. The increased potential for adenosine receptor upregulation by theophylline compared to caffeine following chronic, low level exposure suggests that caffeine treatment for sleep apnea may be preferred to the standard theophylline therapy.