Theophylline-induced upregulation of A1-adenosine receptors associated with reduced sensitivity to convulsants.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Szot
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College of Pharmacy, Oregon State University, Corvallis 97331.
Sanders
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RC
Murray
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TF
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D003292:Convulsants / Q000494:pharmacology*; D004361:Drug Tolerance; D007700:Kinetics; D008297:Male; D008433:Mathematics; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology*
D003292:Convulsants; D011983:Receptors, Purinergic; C027513:N(6)-cyclohexyladenosine; D013806:Theophylline; D000241:Adenosine; D010433:Pentylenetetrazole