Skip to main content
SpringerLink
Log in

Biochemical Modulation of NMDA Receptors: Role in Conditioned Taste Aversion

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Glutamate neurotransmission plays a crucial role in a variety of functions in the central nervous system, including learning and memory. However, little is known about the mechanisms underlying this process in mammals because of the scarceness of experimental models that permit correlation of behavioral and biochemical changes occurring during the different stages of learning and the retrieval of the acquired information. One model that has been useful to study these mechanisms is conditioned taste aversion (CTA), a paradigm in which animals learn to avoid new tastes when they are associated with gastrointestinal malaise. Glutamate receptors of the N-methyl-D-aspartate (NMDA) type appear to be necessary in this process, because blockade of this receptor prevents CTA. Phosphorylation of the main subunits of the NMDA receptor is a well-established biochemical mechanism for the modulation of the receptor response. Such modulation seems to be involved in CTA, because inhibitors of protein kinase C (PKC) block CTA acquisition and because the exposure to an unfamiliar taste results in an increased phosphorylation of tyrosine and serine residues of the NR2B subunit of the receptor in the insular cortex, the cerebral region where gustatory and visceral information converge. In this work we review these mechanisms of NMDA receptor modulation in CTA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Michaelis, E. K. 1998. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 54:369–415.

    Google Scholar 

  2. Nakanishi, S., Nakajima, Y., Masu, M., Ueda, Y., Nakahara, K., Watanabe, D., Yamaguchi, S., Kawabata, S., and Okada, M. 1998. Glutamate receptors: Brain function and signal transduction. Brain Res. Rev. 26:230–235.

    Google Scholar 

  3. Dingledine, R., Borges, K., Bowie, D., and Traynelis, S. F. 1999. The glutamate receptor ion channels. Pharmacol. Rev. 51:7–61.

    Google Scholar 

  4. Bliss, T. V. P. and Collingridge, G. L. 1993. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature 361:31–39.

    Google Scholar 

  5. Sanes, J. R. and Lichtman, J. W. 1999. Can molecules explain long-term potentiation? Nature Neurosci. 2:597–604.

    Google Scholar 

  6. Pláteník, J., Kuramoto, N., and Yoneda, Y. 2000. Molecular mechanisms associated with long-term consolidation of the NMDA signal. Life Sci. 67:335–364.

    Google Scholar 

  7. Meldrum, B. S. 1991. Excitotoxicity and epileptic brain damage. Epilepsy Res. 10:55–61.

    Google Scholar 

  8. Tapia, R., Medina-Ceja, L., and Peña, F. 1999. On the relationship between extracellular glutamate, hyperexcitation and neurodegeneration, in vivo. Neurochem. Int. 34:23–31.

    Google Scholar 

  9. Antonov, I., Antonova, I., Kandel, E. R., and Hawkins, R. D. 2001. The contribution of activity-dependent synaptic plasticity to classical conditioning in Aplysia. J. Neurosci. 21:6413–6422.

    Google Scholar 

  10. Malenka, R. C., and Nicoll, R. A. 1999. Long-term potentiation: A decade of progress? Science 285:1870–1874.

    Google Scholar 

  11. Song, I., and Huganir, R. L. 2002. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25:578–588.

    Google Scholar 

  12. Bailey, C. H., Bartsch, D., and Kandel, E. R. 1996. Toward a molecular definition of long-term memory storage. Proc. Natl. Acad. Sci. USA 93:13445–13452.

    Google Scholar 

  13. Gallo, M., Roldan, G., and Bures, J. 1992. Differential involvement of gustatory insular cortex and amygdala in the acquisition and retrieval of conditioned taste aversion in rats. Behav. Brain Res. 52:91–97.

    Google Scholar 

  14. Bures, J., Bermúdez-Rattoni, F., and Yamamoto, T., 1998. Conditioned taste aversion: Memory of a special kind. Oxford, UK: Oxford University Press.

    Google Scholar 

  15. Welzl, H., D'Adamo, P., and Lipp, H.-P. 2001. Conditioned taste aversion as a learning and memory paradigm. Behav. Brain Res. 125:205–213.

    Google Scholar 

  16. Monyer, H., Burnashev, N., Laurie, D. J., Sakmann, B., and Seeburg, P. H. 1994. Developmental and regional expression in rat brain and functional properties of four NMDA receptors. Neuron 12:529–540.

    Google Scholar 

  17. Laube, B., Hirai, H., Sturgess, M., Betz, H., and Kuhse, J. 1997. Molecular determinants of agonist discrimination by NMDA receptor subunits: Analysis of the glutamate binding site on the NR2B subunit. Neuron 18:493–503.

    Google Scholar 

  18. Pérez-Otaño, I., Schulteis, C. T., Contractor, A., Lipton, S. A., Trimmer, J. S., Sucher, N. J., and Heinemann, S. F. 2001. Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J. Neurosci. 21:1228–1237.

    Google Scholar 

  19. Matsuda, K., Kamiya, Y., Matsuda, S., and Yusaki, M. 2002. Cloning and characterization of a novel NMDA receptor subunit NR3B: A dominant subunit that reduces calcium permeability. Mol. Brain Res. 100:43–52.

    Google Scholar 

  20. Ben-Ari, Y., Aniksztejn, L., and Bregestovski, P. 1992. Protein kinase C modulation of NMDA currents: an important link for LTP induction. Trends Neurosci. 15:333–339.

    Google Scholar 

  21. Raymond, L. A., Blackstone, C. D., and Huganir, R. L. 1993. Phosphorylation of amino acid neurotransmitter receptors in synaptic plasticity. Trends Neurosci. 16:147–153.

    Google Scholar 

  22. Tapia, R., Peña, F., and Arias, C. 1999. Neurotoxic and synaptic effects of okadaic acid, an inhibitor of protein phosphatases. Neurochem. Res. 24:1423–1430.

    Google Scholar 

  23. Westphal, R. S., Tavalin, S. J., Lin, J. W., Alto, N. M., Fraser, I. D. C., Langeberg, I. K., Sheng, M., and Scott, J. D. 1999. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science 285:93–96.

    Google Scholar 

  24. Ramírez-Munguía, N., Vera, G., and Tapia, R. 2003. Epilepsy, neurodegeneration and extracellular glutamate in the hippocampus of awake and anesthetized rats treated with okadaic acid. Neurochem. Res. 28:1517–1524.

    Google Scholar 

  25. Hall, R. A. and Soderling, T. R. 1997. Differential surface expression and phosphorylation of the N-methyl-D-aspartate receptor subunits NR1 and NR2 in cultured hippocampal neurons. J. Biol. Chem. 272:4135–4140.

    Google Scholar 

  26. Leonard, A. S. and Hell, J. W. 1997. Cyclic AMP-dependent protein kinase and protein kinase C phosphorylate N-methyl-D-aspartate receptors at different sites. J. Biol. Chem. 272:12107–12115.

    Google Scholar 

  27. Liao, G.-Y., Wagner, D. A., Hsu, M. H., and Leonard, J. P. 2001. Evidence for direct protein kinase-C mediated modulation of N-methyl-D-aspartate receptor current. Mol. Pharmacol. 59:960–964.

    Google Scholar 

  28. Greengard, P., Jen, J., Narin, A. C., and Stevens, C. F. 1991. Enhancement of the glutamate response by cAMP-dependent protein kinase in hippocampal neurons. Science 253:1135–1138.

    Google Scholar 

  29. Wang, L.-Y., Orser, B. A., and MacDonald, J. F. 1991. Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 253:1132–1135.

    Google Scholar 

  30. Kelso, S. R., Nelson, T. E., and Leonard, J. P. 1992. Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes. J. Physiol. 449:705–718.

    Google Scholar 

  31. Cerne, R., Rudin, K. I., and Randic, M. 1993. Enhancement of the N-methyl-D-aspartate response in spinal dorsal horn neurons by cAMP-dependent protein kinase. Neurosci. Lett. 161:124–128.

    Google Scholar 

  32. Snyder, G. L., Fienberg, A. A., Hunganir, R. L., and Greengard, P. 1998. A dopamine/D1 receptor/protein kinase A/dopamine-and cAMP-regulated phosphoprotein (Mr 32 kDa)/protein phosphatase-1 pathway regulates dephosphorylation of the NMDA receptor. J. Neurosci. 18:10297–10303.

    Google Scholar 

  33. Lieberman, D. N. and Mody, I. 1994. Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 369:235–239.

    Google Scholar 

  34. Wang, L.-Y., Orser, B. A., Brautigan, D. L., and MacDonald, J. F. 1994. Regulation of the NMDA receptors in cultured hippocampal neurons by protein phosphatases 1 and 2A. Nature 369:230–232.

    Google Scholar 

  35. Arias, C., Becerra-García, F., Arrieta, I., and Tapia, R. 1998. The protein phosphatase inhibitor okadaic acid induces heat-shock protein expression and neurodegeneration in rat hippocampus in vivo. Exp. Neurol. 153:242–254.

    Google Scholar 

  36. Arias, C., Montiel, T., Peña, F., Ferrera, P., and Tapia, R. 2002. Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of NMDA receptor in rat hippocampus in vivo. Exp. Neurol. 177:284–291.

    Google Scholar 

  37. Omkumar, R. V., Kiely, M. J., Rosenstein, A. J., Min, K-T. and Kennedy, M. B. 1996. Identification of a phosphorylation site for calcium/calmodulin-dependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J. Biol. Chem. 49: 31670–31678.

    Google Scholar 

  38. Leonard, A. S., Bayer, K. U., Merrill, M. A., Lim, I. A., Shea, M. A., Schulman, H., and Hell, J. W. 2002. Regulation of calcium/ calmodulin-dependent protein kinase II docking to N-methyl-D-aspartate receptors by calcium/calmodulin and α-actinin. J. Biol. Chem. 277:48441–48448.

    Google Scholar 

  39. Mayadevi, M., Praseeda, M., Kumar, K. S., and Omkumar, R. V. 2002. Sequence determinants on the NR2A and NR2B subunits of NMDA receptor responsible for specificity of phosphorylation by CaMKII. Biochim. Biophyis. Acta 1598:40–45.

    Google Scholar 

  40. Lau, L. F. and Huganir, R. L. 1995. Differential tyrosine phosphorylation of N-methyl-D-aspartate receptor subunits. J. Biol. Chem. 270:20036–20041.

    Google Scholar 

  41. Cheung, H. H. and Gurd, J. W. 2001. Tyrosine phosphorylation of N-methyl-D-aspartate receptor by exogenous and postsynaptic density-associated Src-family kinases. J. Neurochem. 78:524–534.

    Google Scholar 

  42. Nakazawa, T., Komai, S., Hisatsune, C., Umemori, H., Semba, K., Misina, M., Manabe, T., and Yamamoto, T. 2001. Characterization of Fyn-mediated tyrosine phosphorylation sites on GluRepsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J. Biol. Chem. 276:693–699.

    Google Scholar 

  43. Wang, Y. T. and Salter, M. W. 1994. Regulation of NMDA receptors by tyrosine kinases and phosphatases. Nature 369:233–235.

    Google Scholar 

  44. Wang, Y. T., Yu, X.-M., and Salter, M. W. 1996. Ca2+-independent reduction of N-methyl-D-aspartate channel activity by protein tyrosine phosphatase. Proc. Natl. Acad. Sci. USA 93:1721–1725.

    Google Scholar 

  45. Salter, M. W. 1998. Src, N-methyl-D-aspartate (NMDA) receptors, and synaptic plasticity. Biochem. Pharmacol. 56:789–798.

    Google Scholar 

  46. Rosenblum, K., Berman, D. E., Hazvi, S., and Dudai, Y. 1996. Carbachol mimics effects of sensory input on tyrosine phosphorylation in cortex. Neuroreport 7:1401–1404.

    Google Scholar 

  47. Aramakis, V. B., Bandrowski, A. E., and Ashe, J. H. 1997. Activation of muscarinic receptors modulates NMDA receptor-mediated responses in auditory cortex. Exp. Brain Res. 113:484–496.

    Google Scholar 

  48. Cepeda, C., Buchwald, N. A., and Levine, M. S. 1993. Neuromodulatory actions of dopamine in the neostriatum are dependent upon the excitatory amino acid receptor subtypes activated. Proc. Natl. Acad. Sci. USA 90:9576–9580.

    Google Scholar 

  49. Raman, I. M., Tong, G., and Jahr, C. E. 1996. β-Adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16:415–421.

    Google Scholar 

  50. Blank, T., Nijholt, I., Teichert, U., Kügler, H., Behrsig, H., Fienberg, A., Greengard, P., and Spiess, J. 1997. The phosphoprotein DARPP-32 mediates cAMP-dependent potentiation of striatal N-methyl-D-aspartate responses. Proc. Natl. Acad. Sci. USA 94:14859–14864.

    Google Scholar 

  51. Fiore, R. S., Murphy, T. H., Sanghera, J. S., Pelech, S. L., and Baraban, J. M. 1993. Activation of p42 mitogen-activated protein kinase by glutamate receptor stimulation in rat primary cortical cultures. J. Neurochem. 61:1626–1633.

    Google Scholar 

  52. Kurino, M., Fukunaga, K., Ushio, Y., and Miyamoto, E. 1995. Activation of mitogen-activated protein kinase in cultured rat hippocampal neurons by stimulation of glutamate receptors. J. Neurochem. 65:1282–1289.

    Google Scholar 

  53. English, J. D. and Sweatt, J. D. 1996. Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. J. Biol. Chem. 271:24329–24332.

    Google Scholar 

  54. Impey, S., Obrietan, K., Wong, S. T., Poser, S., Yano, S., Wayman, G., Deloulme, J. C., Chan, G., and Storm, D. R. 1998. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869–883.

    Google Scholar 

  55. Vanhoutte, P., Barnier, J.-V., Guibert, B., Pagès, C., Besson, M-J., Hipskind, R. A., and Caboche, J. 1999. Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Mol. Cell. Biol. 19:136–146.

    Google Scholar 

  56. Sweatt, J. D. 2001. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J. Neurochem. 76:1–10.

    Google Scholar 

  57. Bures, J. 1998. The CTA paradigm: Terminology, methods, and conventions. Pages 14–25, in Bures, J., Bermúdez-Rattoni, F., and Yamamoto, T., Conditioned taste aversion: Memory of a special kind. Oxford, UK: Oxford University Press.

    Google Scholar 

  58. Bermúdez-Rattoni, F. and Yamamoto, T. 1998. Neuroanatomy of CTA: Lesions studies. Pages 26–45, in Bures, J., Bermúdez-Rattoni, F., and Yamamoto, T., Conditioned taste aversion: Memory of a special kind. Oxford, UK: Oxford University Press.

    Google Scholar 

  59. Nerad, L., Ramírez-Amaya, V., Ormsby, C., and Bermúdez-Rattoni, F. 1996. Differential effects of anterior and posterior insular cortex lesions on the acquisition of conditioned taste aversion and spatial learning. Neurobiol. Learn. Mem. 66:44–50.

    Google Scholar 

  60. Berman, D. E., Hazvi, S., Neduva, V., and Dudai, Y. 2000. The role of identified neurotransmitter systems in the response of insular cortex to unfamiliar taste: Activation of ERK1-2 and formation of a memory trace. J. Neurosci. 20:7017–7023.

    Google Scholar 

  61. Miranda, M. I., Ferreira, M. G., Ramírez-Lugo, L., and Bermúdez-Rattoni, F. 2002. Glutamatergic activity in the amygdala signals visceral input during taste memory formation. Proc. Natl. Acad. Sci. USA 99:11417–11422.

    Google Scholar 

  62. Saper, C. B. 1982. Convergence of autonomic and limbic connections in the insular cortex of the rat. J. Comp. Neurol. 210:163–173.

    Google Scholar 

  63. López-García, J. C., Bermúdez-Rattoni, F., and Tapia, R. 1990. Release of acetylcholine, γ-aminobutyrate, dopamine and glutamate, and activity of some related enzymes, in rat gustatory neocortex. Brain Res. 253:100–104.

    Google Scholar 

  64. López-García, J. C., Fernández-Ruiz, J., Escobar, M. L., Bermúdez-Rattoni, F., and Tapia, R. 1993. Effects of excitotoxic lesions of the nucleus basalis magnocellularis on conditioned taste aversion and inhibitory avoidance in the rat. Pharmacol. Biochem. Behav. 45:147–152.

    Google Scholar 

  65. Naor, C. and Dudai, Y. 1996. Transient impairment of cholinegic function in the rat insular cortex disrupts the encoding of taste in conditioned taste aversion. Behav. Brain Res. 79:61–67.

    Google Scholar 

  66. Gutiérrez, H., Hernández-Echegaray, E., Ramírez-Amaya, V., and Bermúdez-Rattoni, F. 1999. Blockade of N-methyl-D-aspartate receptors in the insular cortex disrupts taste aversion and spatial memory formation. Neuroscience 89:751–758.

    Google Scholar 

  67. Miranda, M. I., Ramírez-Lugo, L., and Bermúdez-Rattoni, F. 2000. Cortical cholinergic activity is related to the novelty of the stimulus. Brain Res. 882:230–235.

    Google Scholar 

  68. Berman, D. E. and Dudai, Y. 2001. Memory extinction, learning anew, and learning the new: Dissociations in the molecular machinery of learning in cortex. Science 291:2417–2419.

    Google Scholar 

  69. Ferreira, G., Gutiérrez, R., De la Cruz, V., and Bermúdez-Rattoni, F. 2002. Differential involvement of cortical muscarinic and NMDA receptors in short-and long-term taste aversion memory. Eur. J. Neurosci. 16:1139–1145.

    Google Scholar 

  70. Inglis, F. M., Day, J. C., and Fibiger, H. C. 1994. Enhanced acetylcholine release in hippocampus and cortex during the anticipating and consumption of palatable meal. Neuroscience 62: 1049–1056.

    Google Scholar 

  71. Inglis, F. M. and Fibiger, H. C. 1995. Increases in hippocampal and frontal cortical acetylcholine release associated with presentation of sensory stimuli. Neuroscience 66:81–86.

    Google Scholar 

  72. Shimura, T., Zuzuki, M., and Yamamoto, T. 1995. Aversive taste stimuli facilitate extracellular acetylcholine release in the insular gustatory cortex of the rat: A microdialysis study. Brain Res. 679:221–226.

    Google Scholar 

  73. Felder, C. C. 1995. Muscarinic acetylcholine receptors: signal transduction through multiple effectors. FASEB J. 9:619–625.

    Google Scholar 

  74. Yashoshima, Y. and Yamamoto, T. 1997. Rat gustatory memory requires protein kinase C activity in the amygdala and cortical gustatory area. Neuroreport 8:1363–1367.

    Google Scholar 

  75. Rosenblum, K., Berman, D. E., Hazvi, S., Lamprecht, R., and Dudai, Y. 1997. NMDA receptor and the tyrosine phosphorylation of its 2B subunit in taste learning in the rat insular cortex. J. Neurosci. 17:5129–5135.

    Google Scholar 

  76. Roberson, E. D., English, J. D., Adams, J. P., Selcher, J. C., Kondratick, C., and Sweatt, J, D. 1999. The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J. Neurosci. 19:4337–4348.

    Google Scholar 

  77. Manabe, T., Aiba, A., Yamada, A., Ichise, T., Sakagami, H., Kondo, H., and Katsuki, M. 2000. Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation. J. Neurosci. 20:2504–2511.

    Google Scholar 

  78. Berman, D. E., Hazvi, S., Rosenblum, K., Seger, R., and Dudai, Y. 1998. Specific and differential activation of mitogen-activated protein kinase cascades by unfamiliar taste in the insular cortex of the behaving rat. J. Neurosci. 18:10037–10044.

    Google Scholar 

  79. Berman, D. E. 2003. Modulation of taste-induced Elk-1 activation by identified neurotransmitter systems in the insular cortex of the behaving rat. Neurobiol. Learn. Mem. 79:122–126.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, D.F., México

    Beatriz Jiménez & Ricardo Tapia

Authors
  1. Beatriz Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ricardo Tapia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ricardo Tapia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiménez, B., Tapia, R. Biochemical Modulation of NMDA Receptors: Role in Conditioned Taste Aversion. Neurochem Res 29, 161–168 (2004). https://doi.org/10.1023/B:NERE.0000010445.27905.aa

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NERE.0000010445.27905.aa

Search

Navigation