Interaction of caffeine with the GABAA receptor complex: alterations in receptor function but not ligand binding.

Behavioral and neurochemical evidence indicates interactions between caffeine and other adenosine receptor ligands and the gamma-aminobutyric acid (GABA)-benzodiazepine system. To assess the effects of caffeine on binding and function at the GABAA receptor, we studied the effects of behaviorally-active doses of caffeine on benzodiazepine and Cl- channel binding and on overall function of the GABAA receptor as measured by Cl- uptake. There was no effect of caffeine on benzodiazepine receptor binding in cortical synaptosomal membranes at concentrations of 1-100 microM. No effects on benzodiazepine binding were found ex vivo in mice treated with caffeine, 20 and 40 mg/kg. At the putative Cl- channel site labeled by t-butylbicyclophosphorothionate (TBPS), binding was unchanged in vitro after caffeine treatment (1 and 10 microM) in washed and unwashed membranes. However, in ex vivo studies caffeine (20 and 40 mg/kg) increased numbers of TBPS sites in unwashed but not washed membranes. Muscimol-stimulated Cl- uptake into cortical synaptoneurosomes was decreased in mice treated with caffeine, 20 and 40 mg/kg. Similar results were observed in in vitro preparations treated with 50 microM but not 100 microM caffeine. These results indicate that caffeine administration significantly alters the Cl- transport function of the GABAA receptor complex.

[1]  Roland R. Griffiths,et al.  Interactions of diazepam and caffeine: Behavioral and subjective dose effects in humans , 1987, Pharmacology Biochemistry and Behavior.

[2]  H. Yamamura,et al.  Modulation of the chloride ionophore by benzodiazepine receptor ligands: influence of gamma-aminobutyric acid and ligand efficacy. , 1986, Molecular pharmacology.

[3]  D. Greenblatt,et al.  Current Status of Benzodiazepines , 1983 .

[4]  M. Airaksinen,et al.  Binding of beta-carbolines and caffeine on benzodiazepine receptors: correlations to convulsions and tremor. , 2009, Acta pharmacologica et toxicologica.

[5]  L. Pieri,et al.  Caffeine antagonizes several central effects of diazepam. , 1981, Life sciences.

[6]  J. Huff,et al.  Interaction of putative anxiolytic agents with central adenosine receptors. , 1981, Canadian journal of physiology and pharmacology.

[7]  G A McPherson,et al.  A practical computer-based approach to the analysis of radioligand binding experiments. , 1983, Computer programs in biomedicine.

[8]  D J Greenblatt,et al.  Relationship of plasma and brain concentrations of caffeine and metabolites to benzodiazepine receptor binding and locomotor activity. , 1989, The Journal of pharmacology and experimental therapeutics.

[9]  D. Greenblatt,et al.  Benzodiazepine receptor binding: Influence of physiologic and pharmacologic factors , 1987, Biopharmaceutics & drug disposition.

[10]  W. Turski,et al.  Aminophylline and CGS 8216 Reverse the Protective Action of Diazepam Against Electroconvulsions in Mice , 1985, Epilepsia.

[11]  B K Koe,et al.  [3H]Ro 15-1788 binding to benzodiazepine receptors in mouse brain in vivo: marked enhancement by GABA agonists and other CNS drugs. , 1987, European journal of pharmacology.

[12]  C. Braestrup,et al.  Benzodiazepine receptors in rat brain , 1977, Nature.

[13]  J. Phillis,et al.  The role of adenosine in the central actions of the benzodiazepines , 1988, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  S H Snyder,et al.  Adenosine receptors and behavioral actions of methylxanthines. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Snyder,et al.  Adenosine receptor interactions and anxiolytics , 1983, Neuropharmacology.

[16]  J. Phillis,et al.  Ro 15-1788 both antagonizes and potentiates adenosine-evoked depression of cerebral cortical neurons. , 1987, European journal of pharmacology.

[17]  D. Farb,et al.  Chronic caffeine or theophylline exposure reduces gamma-aminobutyric acid/benzodiazepine receptor site interactions. , 1988, Molecular pharmacology.

[18]  D. Greenblatt,et al.  Chronic benzodiazepine administration. I. Tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function. , 1988, The Journal of pharmacology and experimental therapeutics.

[19]  P. Wu,et al.  Up-regulation of brain [3H]diazepam binding sites in chronic caffeine-treated rats , 1984, Brain Research.

[20]  B. Ekström-jodal,et al.  AMINOPHYLLINE INHIBITION OF DIAZEPAM SEDATION: IS ADENOSINE BLOCKADE OF GABA-RECEPTORS THE MECHANISM? , 1984, The Lancet.

[21]  Weir Rl,et al.  Interaction between methylxanthines and the benzodiazepine receptor. , 1983 .

[22]  M J Mattila,et al.  Caffeine antagonizes diazepam effects in man. , 1982, Medical biology.

[23]  S. Paul,et al.  gamma-Aminobutyric acid (GABA)- and barbiturate-mediated 36Cl- uptake in rat brain synaptoneurosomes: evidence for rapid desensitization of the GABA receptor-coupled chloride ion channel. , 1986, Molecular pharmacology.

[24]  E. A. Swinyard,et al.  Benzodiazepine inhibition of [3H]flunitrazepam binding and caffeine-induced seizures in mice. , 1986, European journal of pharmacology.

[25]  S. Vellucci,et al.  Antagonism of caffeine-induced seizures in mice by Ro15-1788. , 1984, European journal of pharmacology.

[26]  Willy Haefely,et al.  Recent advances in the molecular pharmacology of Benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists , 1985 .

[27]  P. Seeburg,et al.  Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family , 1987, Nature.

[28]  S. Paul,et al.  Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions. , 1987, The Journal of pharmacology and experimental therapeutics.

[29]  G. Biggio,et al.  Foot‐Shock Stress and Anxiogenic β‐Carbolines Increase t‐[35S]Butylbicyclophosphorothionate Binding in the Rat Cerebral Cortex, an Effect Opposite to Anxiolytics and γ‐Aminobutyric Acid Mimetics , 1988, Journal of neurochemistry.

[30]  S H Snyder,et al.  Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. , 1981, Life sciences.

[31]  S. File,et al.  Interaction Between Effects of Caffeine and Lorazepam in Performance Tests and Self‐Ratings , 1982, Journal of clinical psychopharmacology.