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Title: Role of adenosine receptors in caffeine tolerance

Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increasesmore » (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.« less
Authors:
; ;  [1]
  1. (Emory Univ. School of Medicine, Atlanta, GA (USA))
Publication Date:
OSTI Identifier:
5961664
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Pharmacology and Experimental Therapeutics; (USA); Journal Volume: 256:1
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; ADENOSINE; RECEPTORS; CAFFEINE; BIOLOGICAL EFFECTS; BIOCHEMICAL REACTION KINETICS; AMP; BIOLOGICAL FUNCTIONS; CEREBRAL CORTEX; CHRONIC EXPOSURE; DOSE-RESPONSE RELATIONSHIPS; NEUROREGULATORS; ORAL ADMINISTRATION; RATS; TRACER TECHNIQUES; TRITIUM COMPOUNDS; ANALEPTICS; ANIMALS; AROMATICS; AUTONOMIC NERVOUS SYSTEM AGENTS; AZAARENES; BODY; BRAIN; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM AGENTS; CEREBRUM; DRUGS; FUNCTIONS; HETEROCYCLIC COMPOUNDS; HYDROGEN COMPOUNDS; ISOTOPE APPLICATIONS; KINETICS; MAMMALS; MEMBRANE PROTEINS; NERVOUS SYSTEM; NUCLEOSIDES; NUCLEOTIDES; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC OXYGEN COMPOUNDS; ORGANS; PROTEINS; PURINES; REACTION KINETICS; RIBOSIDES; RODENTS; VERTEBRATES; XANTHINES 550201* -- Biochemistry-- Tracer Techniques; 560300 -- Chemicals Metabolism & Toxicology; 550101 -- Behavioral Biology-- Tracer Techniques