Abstract
Chronic administration of theophylline (50 mg kg twice daily for 14 consecutive days) significantly increased the specific binding of [3H]CHA in membranes of the cerebral cortex and cerebellum of the rat, but not in membranes derived from the hippocampus or diencephalon. To characterize further the upregulation of A1 = adenosine receptors induced by theophylline, saturation analysis with [3H]CHA was performed in membranes of the cerebral cortex and cerebellum. In both saline- and theophylline-treated cortical membranes the binding isotherms for (3H]CHA could be resolved into receptor affinity states having respectively high (KH) and low (KL) affinity for [3H]CHA. The high and low affinity dissociation constants obtained from theophylline-exposed membranes of the cerebral cortex were 1.14 nM and 25.2 nM and did not differ significantly from the corresponding values in saline-treated animals. Chronic exposure to theophylline did, however, produce significant increases in the densities of both the high and low affinity forms of A1-adenosine receptors in the cerebral cortex. Qualitatively and quantitatively similar results were observed in cerebellar membranes. These results suggest that chronic exposure to theophylline increases the density of A1-receptor in the cerebral cortex and cerebellum with no concomitant changes in the ability of [3H]CHA to distinguish separate agonist affinity states of the receptor. The physiological significance of theophylline-induced upregulation was assessed by determining seizure thresholds for convulsants in rats treated chronically with saline or theophylline. Chronic exposure to theophylline resulted in significant increases in the doses of pentylenetetrazol, bicuculline and picrotoxinin required to elicit a clonic convulsion. Thus, these results suggest that the reduced susceptibility to seizures induced by change in convulsant animals treated chronically with theophylline represents a functional change.