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Caffeine and related compounds block inhibitory amino acid‐gated Cl − currents in freshly dissociated rat hippocampal neurones
Author(s) -
Uneyama Hisayuki,
Harata Nobutoshi,
Akaike Norio
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13591.x
Subject(s) - caffeine , inhibitory postsynaptic potential , glycine , chemistry , xanthine , theophylline , theobromine , glycine receptor , strychnine , ibmx , bicuculline , nmda receptor , biochemistry , biophysics , gabaa receptor , amino acid , pharmacology , receptor , endocrinology , biology , forskolin , enzyme
1 The effects of caffeine and related compounds on responses mediated by inhibitory amino acids were investigated in freshly dissociated rat hippocampal pyramidal neurones by conventional and nystatin perforated patch‐clamp techniques. 2 Glycine and γ‐aminobutyric acid (GABA) evoked Cl − currents in hippocampal neurones. The half‐maximum effective concentrations (EC 50 ) of glycine and GABA were 8.5 × 10 −5 and 5 × 10 −6 m , respectively. 3 Caffeine reversibly inhibited both 10 −4 m glycine‐ and 10 −5 m GABA‐induced Cl − currents in a concentration‐dependent manner. The half‐maximum inhibitory concentrations (IC 50 ) of caffeine were 4.5 × 10 −4 m for the glycine response and 3.6 × 10 −3 m for the GABA response. 4 Caffeine shifted the concentration‐response curve of I Gly to the right without affecting the maximum response. 5 The inhibitory action of caffeine did not show voltage‐dependency. 6 The blocking action of caffeine was not affected by intracellular perfusion with 5 m m BAPTA or by pretreatment with the protein kinase A inhibitor, H‐8. This excludes the participation of Ca 2+ or cyclic AMP in the inhibitory action of caffeine. 7 Caffeine failed to inhibit the augmentations of aspartate‐ and N ‐methyl‐ d ‐aspartate (NMDA) ‐gated current by glycine, suggesting that caffeine has no effect on the allosteric glycine binding site on the NMDA receptor. 8 The inhibitory effects of some xanthine derivatives on I Gly were compared. The inhibitory potency of those compounds on I Gly was in the order of pentoxifylline > theophylline ≥ caffeine > paraxanthine > IBMX ≥ theobromine > dyphylline. Xanthine had no effect. 9 The results indicate that methylxanthines including caffeine may act directly on the glycine receptor Cl − channel complex in rat hippocampal pyramidal neurones. The blockade of the inhibitory amino acid response by methylxanthines may be involved in the excitatory side effects of methylxanthines in the mammalian central nervous system.