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. 1996 Mar;117(6):1133–1138. doi: 10.1111/j.1476-5381.1996.tb16707.x

Desensitization of AMPA receptors and AMPA-NMDA receptor interaction: an in vivo cyclic GMP microdialysis study in rat cerebellum.

E Fedele 1, M Raiteri 1
PMCID: PMC1909803  PMID: 8882607

Abstract

1. Desensitization is an important characteristic of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type. 2. Stimulation of N-methyl-D-aspartate (NMDA) or AMPA receptors in cerebellum results in increased production of cyclic GMP. We have investigated AMPA receptor desensitization in vivo by monitoring extracellular cyclic GMP during intracerebellar microdialysis in conscious unrestrained adult rats. 3. Local infusion of AMPA (10 to 100 microM) caused dose-related elevations of cyclic GMP levels. The effect of AMPA was prevented by the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NOARG). 4. In the absence of AMPA, DNQX lowered the basal levels of cyclic GMP whereas the NMDA receptor channel antagonist dizocilpine (MK-801) was ineffective. 5. Cyclothiazide, a blocker of AMPA receptor desensitization, potentiated the cyclic GMP response to exogenous AMPA. Moreover, cyclothiazide (100-300 microM) produced on its own dose-dependent elevations of extracellular cyclic GMP. The cyclothiazide-induced response was prevented not only by DNQX but also by MK-801. 6. While the cyclic GMP response elicited by AMPA was totally insensitive to MK-801, the response produced by AMPA (10 microM) plus cyclothiazide (30 microM) was strongly attenuated by the NMDA receptor antagonist (30 microM). 7. The results suggest that (a) AMPA receptors linked to the NO-cyclic GMP pathway in the cerebellum can undergo desensitization in vivo during exposure to exogenous AMPA; cyclothiazide inhibits such desensitization; (b) AMPA receptors (but not NMDA receptors) are 'tonically' activated and kept in a partly desensitized state by endogenous glutamate; (c) if cyclothiazide is present, activation of AMPA receptors may permit endogenous activation of NMDA receptors.

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Selected References

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  1. Barnes J. M., Dev K. K., Henley J. M. Cyclothiazide unmasks AMPA-evoked stimulation of [3H]-L-glutamate release from rat hippocampal synaptosomes. Br J Pharmacol. 1994 Oct;113(2):339–341. doi: 10.1111/j.1476-5381.1994.tb16902.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bekkers J. M., Stevens C. F. NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature. 1989 Sep 21;341(6239):230–233. doi: 10.1038/341230a0. [DOI] [PubMed] [Google Scholar]
  3. Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9030–9033. doi: 10.1073/pnas.86.22.9030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Daniel H., Hemart N., Jaillard D., Crepel F. Long-term depression requires nitric oxide and guanosine 3':5' cyclic monophosphate production in rat cerebellar Purkinje cells. Eur J Neurosci. 1993 Aug 1;5(8):1079–1082. doi: 10.1111/j.1460-9568.1993.tb00961.x. [DOI] [PubMed] [Google Scholar]
  5. Desai M. A., Burnett J. P., Schoepp D. D. Cyclothiazide selectively potentiates AMPA- and kainate-induced [3H]norepinephrine release from rat hippocampal slices. J Neurochem. 1994 Jul;63(1):231–237. doi: 10.1046/j.1471-4159.1994.63010231.x. [DOI] [PubMed] [Google Scholar]
  6. Desce J. M., Godeheu G., Galli T., Artaud F., Chéramy A., Glowinski J. L-glutamate-evoked release of dopamine from synaptosomes of the rat striatum: involvement of AMPA and N-methyl-D-aspartate receptors. Neuroscience. 1992;47(2):333–339. doi: 10.1016/0306-4522(92)90249-2. [DOI] [PubMed] [Google Scholar]
  7. Garthwaite J., Garthwaite G., Palmer R. M., Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol. 1989 Oct 17;172(4-5):413–416. doi: 10.1016/0922-4106(89)90023-0. [DOI] [PubMed] [Google Scholar]
  8. Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci. 1991 Feb;14(2):60–67. doi: 10.1016/0166-2236(91)90022-m. [DOI] [PubMed] [Google Scholar]
  9. Ito M. Long-term depression. Annu Rev Neurosci. 1989;12:85–102. doi: 10.1146/annurev.ne.12.030189.000505. [DOI] [PubMed] [Google Scholar]
  10. Lagadic-Gossmann D., Vaughan-Jones R. D., Buckler K. J. Adrenaline and extracellular ATP switch between two modes of acid extrusion in the guinea-pig ventricular myocyte. J Physiol. 1992 Dec;458:385–407. doi: 10.1113/jphysiol.1992.sp019423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Luo D., Leung E., Vincent S. R. Nitric oxide-dependent efflux of cGMP in rat cerebellar cortex: an in vivo microdialysis study. J Neurosci. 1994 Jan;14(1):263–271. doi: 10.1523/JNEUROSCI.14-01-00263.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Marin P., Quignard J. F., Lafon-Cazal M., Bockaert J. Non-classical glutamate receptors, blocked by both NMDA and non-NMDA antagonists, stimulate nitric oxide production in neurons. Neuropharmacology. 1993 Jan;32(1):29–36. doi: 10.1016/0028-3908(93)90126-n. [DOI] [PubMed] [Google Scholar]
  13. May P. C., Robison P. M. Cyclothiazide treatment unmasks AMPA excitotoxicity in rat primary hippocampal cultures. J Neurochem. 1993 Mar;60(3):1171–1174. doi: 10.1111/j.1471-4159.1993.tb03272.x. [DOI] [PubMed] [Google Scholar]
  14. Mayer M. L., Vyklicky L., Jr Concanavalin A selectively reduces desensitization of mammalian neuronal quisqualate receptors. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1411–1415. doi: 10.1073/pnas.86.4.1411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mayer M. L., Westbrook G. L., Guthrie P. B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984 May 17;309(5965):261–263. doi: 10.1038/309261a0. [DOI] [PubMed] [Google Scholar]
  16. Moudy A. M., Yamada K. A., Rothman S. M. Rapid desensitization determines the pharmacology of glutamate neurotoxicity. Neuropharmacology. 1994 Aug;33(8):953–962. doi: 10.1016/0028-3908(94)90153-8. [DOI] [PubMed] [Google Scholar]
  17. Partin K. M., Patneau D. K., Winters C. A., Mayer M. L., Buonanno A. Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron. 1993 Dec;11(6):1069–1082. doi: 10.1016/0896-6273(93)90220-l. [DOI] [PubMed] [Google Scholar]
  18. Patneau D. K., Vyklicky L., Jr, Mayer M. L. Hippocampal neurons exhibit cyclothiazide-sensitive rapidly desensitizing responses to kainate. J Neurosci. 1993 Aug;13(8):3496–3509. doi: 10.1523/JNEUROSCI.13-08-03496.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Raiteri M., Garrone B., Pittaluga A. N-methyl-D-aspartic acid (NMDA) and non-NMDA receptors regulating hippocampal norepinephrine release. II. Evidence for functional cooperation and for coexistence on the same axon terminal. J Pharmacol Exp Ther. 1992 Jan;260(1):238–242. [PubMed] [Google Scholar]
  20. Rammes G., Parsons C., Müller W., Swandulla D. Modulation of fast excitatory synaptic transmission by cyclothiazide and GYKI 52466 in the rat hippocampus. Neurosci Lett. 1994 Jul 4;175(1-2):21–24. doi: 10.1016/0304-3940(94)91068-5. [DOI] [PubMed] [Google Scholar]
  21. Sommer B., Keinänen K., Verdoorn T. A., Wisden W., Burnashev N., Herb A., Köhler M., Takagi T., Sakmann B., Seeburg P. H. Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science. 1990 Sep 28;249(4976):1580–1585. doi: 10.1126/science.1699275. [DOI] [PubMed] [Google Scholar]
  22. Staubli U., Rogers G., Lynch G. Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):777–781. doi: 10.1073/pnas.91.2.777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Trussell L. O., Zhang S., Raman I. M. Desensitization of AMPA receptors upon multiquantal neurotransmitter release. Neuron. 1993 Jun;10(6):1185–1196. doi: 10.1016/0896-6273(93)90066-z. [DOI] [PubMed] [Google Scholar]
  24. Vallebuona F., Raiteri M. Age-related changes in the NMDA receptor/nitric oxide/cGMP pathway in the hippocampus and cerebellum of freely moving rats subjected to transcerebral microdialysis. Eur J Neurosci. 1995 Apr 1;7(4):694–701. doi: 10.1111/j.1460-9568.1995.tb00673.x. [DOI] [PubMed] [Google Scholar]
  25. Vallebuona F., Raiteri M. Extracellular cGMP in the hippocampus of freely moving rats as an index of nitric oxide (NO) synthase activity. J Neurosci. 1994 Jan;14(1):134–139. doi: 10.1523/JNEUROSCI.14-01-00134.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vallebuona F., Raiteri M. Monitoring of cyclic GMP during cerebellar microdialysis in freely-moving rats as an index of nitric oxide synthase activity. Neuroscience. 1993 Dec;57(3):577–585. doi: 10.1016/0306-4522(93)90007-3. [DOI] [PubMed] [Google Scholar]
  27. Whitton P. S., Maione S., Biggs C. S., Fowler L. J. Tonic desensitization of hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors regulates 5-hydroxytryptamine release in vivo. Neuroscience. 1994 Dec;63(4):945–948. doi: 10.1016/0306-4522(94)90562-2. [DOI] [PubMed] [Google Scholar]
  28. Wood P. L., Emmett M. R., Rao T. S., Cler J., Mick S., Iyengar S. Inhibition of nitric oxide synthase blocks N-methyl-D-aspartate-, quisqualate-, kainate-, harmaline-, and pentylenetetrazole-dependent increases in cerebellar cyclic GMP in vivo. J Neurochem. 1990 Jul;55(1):346–348. doi: 10.1111/j.1471-4159.1990.tb08859.x. [DOI] [PubMed] [Google Scholar]
  29. Wood P. L. Pharmacology of the second messenger, cyclic guanosine 3',5'-monophosphate, in the cerebellum. Pharmacol Rev. 1991 Mar;43(1):1–25. [PubMed] [Google Scholar]
  30. Yamada K. A., Tang C. M. Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents. J Neurosci. 1993 Sep;13(9):3904–3915. doi: 10.1523/JNEUROSCI.13-09-03904.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Young A. B., Fagg G. E. Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches. Trends Pharmacol Sci. 1990 Mar;11(3):126–133. doi: 10.1016/0165-6147(90)90199-i. [DOI] [PubMed] [Google Scholar]
  32. Zivkovic I., Thompson D. M., Bertolino M., Uzunov D., DiBella M., Costa E., Guidotti A. 7-Chloro-3-methyl-3-4-dihydro-2H-1,2,4 benzothiadiazine S,S-dioxide (IDRA 21): a benzothiadiazine derivative that enhances cognition by attenuating DL-alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor desensitization. J Pharmacol Exp Ther. 1995 Jan;272(1):300–309. [PubMed] [Google Scholar]

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