, Volume 47, Issue 2, pp 108–114 | Cite as

Caffeine Suppresses GABA Receptor-Mediated Current in Rat Primary Sensory Neurons via Inhibition of Intracellular Phosphodiesterase

  • J. Y. Yang
  • G. Yang
  • J. Ren
  • J. Zhao
  • Sh. Li

In acutely isolated rat primary sensory neurons, the effects of caffeine on GABA receptormediated current (I GABA) were investigated using a whole-cell patch clamp technique. We found that applications of GABA (10-1000 μM) induced inward currents in a concentration-dependent manner; the currents manifested obvious desensitization. Pretreatment with caffeine (0.01-100 μM) suppressed I GABA in a noncompetitive manner; caffeine shifted the concentration–response curve for GABA downwards compared to the control. Theophylline showed a similar and stronger inhibitory effect on I GABA. Isolated application of 1 μM diazepam enhanced I GABA, while pretreatment with 10 μM caffeine and 1 μM diazepam suppressed this current. Intracellular application of the protein kinase A inhibitor H-8 dramatically weakened the inhibitory effect of caffeine on I GABA. Because primary afferent depolarization is related to GABAA receptors, our results suggest that caffeine might antagonize presynaptic inhibitory effects of primary afferents, probably via inhibition of intracellular phosphodiesterase.


GABA receptor-mesiated current primary sensory (DRG) neurons whole-cell patch clamp caffeine phosphodiesterase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    T. Somekawa-Kondo, K. Yamaguchi, Y. Ishitsuka, et al., “Aminophylline, administered at usual doses for rodents in pharmacological studies, induces hippocampal neuronal cell injury under low tidal volume hypoxic conditions in guinea-pigs,” J. Pharm. Pharmacol., 65, No. 1, 102-114 (2013).PubMedCrossRefGoogle Scholar
  2. 2.
    N. P. Riksen, P. Smits, and G. A. Rongen, “The cardiovascular effects of methylxanthines,” Handbook Exp. Pharmacol., 200, 413-437 (2011).CrossRefGoogle Scholar
  3. 3.
    H. Uneyama, M. Munakata, and N. Akaike,“Caffeine response in pyramidal neurons freshly dissociated from rat hippocampus,” Brain Res., 604, Nos. 1/2, 24-31 (1993)PubMedCrossRefGoogle Scholar
  4. 4.
    C. C. Chou and T. W. Vickroy,“Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine forebrain tissues,” Am. J. Vet. Res., 64, No. 2, 216-224 (2003).PubMedCrossRefGoogle Scholar
  5. 5.
    C. W. Hsu, C. S. Wang, and T. H. Chiu,“Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice,” J. Biomed. Sci., 17, 4 (2010).PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    M. El Yacoubi, C. Ledent, M. Parmentier, et al., “In vivo labelling of the adenosine A2A receptor in mouse brain using the selective antagonist [3H]SCH 58261,” Eur. J. Neurosci., 14, No. 9, 1567-1570 (2001).PubMedCrossRefGoogle Scholar
  7. 7.
    O. Pauvert, C. Lugnier, T. Keravis, et al.,“Effect of sildenafil on cyclic nucleotide phosphodiesterase activity, vascular tone and calcium signaling in rat pulmonary artery,” Br. J. Pharmacol., 139, No. 3, 513-522 (2003).PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    F. A. Belibi, D. P. Wallace, T. Yamaguchi, et al., “The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease,” J. Am. Soc. Nephrol., 13, No. 11, 2723-2729 (2002).PubMedCrossRefGoogle Scholar
  9. 9.
    D. Shi, W. L. Padgett, and J. W. Daly,“Caffeine analogs: effects on ryanodine-sensitive calcium-release channels and GABAA receptors,” Cell. Mol. Neurobiol., 23, No. 3, 331-347 (2003).PubMedCrossRefGoogle Scholar
  10. 10.
    S. S. Kang, K. S. Han, B. M. Ku, et al., “ Caffeinemediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival,” Cancer Res., 70, No. 3, 1173-1183 (2010).PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    C. Yang, S. Franciosi, and R. E. Brown, “Adenosine inhibits the excitatory synaptic inputs to basal forebrain cholinergic, GABAergic, and parvalbumin neurons in mice,” Front. Neurol., 20, No. 4, 77 (2013)Google Scholar
  12. 12.
    J. A. Ribeiro and A. M. Sebastião, “Caffeine and adenosine,” J. Alzheimer´s Dis., 20, Suppl. 1, S3-S15 (2010)Google Scholar
  13. 13.
    Q. X. Chen, A. Stelzer, A. R. Kay, et al., “GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea-pig hippocampal neurones,” J. Physiol., 420, 207-221 (1990).PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    M. Gyenes, Q. Wang, T. T. Gibbs, et al., “Phosphorylation factors control neurotransmitter and neuromodulator actions at the gamma-aminobutyric acid type A receptor,” Mol. Pharmacol., 46, No. 3, 542-549 (1994).PubMedGoogle Scholar
  15. 15.
    C. S. Huang, J. Y. Ma, W. Marszalec, et al., “Effects of the nootropic drug nefiracetam on the GABAA receptorchannel complex in dorsal root ganglion neurons,” Neuropharmacology, 35, Nos. 9/10, 1251-1261 (1996)PubMedCrossRefGoogle Scholar
  16. 16.
    N. M. Porter, R. E. Twyman, M. D. Uhler, et al., “Cyclic AMP-dependent protein kinase decreases GABAA receptor current in mouse spinal neurons,” Neuron, 5, No. 6, 789-796 (1990)PubMedCrossRefGoogle Scholar
  17. 17.
    N. Gonçalves, A. T. Simões, R. A. Cunha, et al., “Caffeine and adenosine A(2A) receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease,” Ann. Neurol., 73, No. 5, 655-666 (2013).PubMedCrossRefGoogle Scholar
  18. 18.
    N. Vanattou-Saïfoudine, B. Behan, and A. Harkin, “Dopamine D1 receptor-mediated intracellular responses in the hypothalamus after co-administration of caffeine with MDMA,” Basic Clin. Pharmacol. Toxicol., 110, No. 3, 283-289 (2012).PubMedCrossRefGoogle Scholar
  19. 19.
    K. M. Capiotti, F. P. Menezes, L. R. Nazario, et al., “Early exposure to caffeine affects gene expression of adenosine receptors, DARPP-32 and BDNF without affecting sensibility and morphology of developing zebrafish (Danio rerio),” Neurotoxicol. Teratol., 33 No. 6, 680-685 (2011).PubMedCrossRefGoogle Scholar
  20. 20.
    S. Sharmin, H. Guan, A. S. Williams, et al., “Caffeine reduces 11β-hydroxysteroid dehydrogenase type 2 expression in human trophoblast cells through the adenosine A(2B) receptor,” PLoS One, No. 6, e3808 (2012).Google Scholar
  21. 21.
    R. L. Weir and R. E. Hruska,“ Interaction between methylxanthines and the benzodiazepine receptor,” Arch. Int. Pharmacodyn. Ther., 265, No. 1, 42-48 (1983).PubMedGoogle Scholar
  22. 22.
    F. R. da Silva , R. Lazzarini, L. C. de Sá-Rocha, et al., “Effects of acute and long-term diazepam administrations on neutrophil activity: a flow cytometric study,” Eur. J. Pharmacol., 478, Nos. 2/3, 97-104 (2003)PubMedCrossRefGoogle Scholar
  23. 23.
    H. Z. Hu and Z. W. Li,“Modulation by adenosine of GABA-activated current in rat dorsal root ganglion neurons,” J. Physiol., 501, 67-75 (1997).PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    M. Inoue, Y. Oomura, T. Yakushiji, et al., “Intracellular calcium ions decrease the affinity of the GABA receptor,” Nature, 324, No. 6093, 156-158 (1986)PubMedCrossRefGoogle Scholar
  25. 25.
    Y. C. Yu, L. H. Cao, X. L. Yang, et al.,“ Modulation by brain natriuretic peptide of GABA receptors on rat retinal ON-type bipolar cells,” J. Neurosci., 26, No. 2, 696-707 (2006).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of UrologyDalian Friendship HospitalDalianChina
  2. 2.Department of PhysiologyDalianChina
  3. 3.Department of Clinical Medicine, Anesthesiology MajorDalian Medical UniversityDalianChina
  4. 4.Department of AnesthesiologyJinan Central HospitalJinanChina

Personalised recommendations