Psychopharmacology

, Volume 195, Issue 1, pp 85–93 | Cite as

High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans

Original Investigation

Abstract

Rationale

The loudness dependence of the auditory evoked Potential (LDAEP) has been suggested to be a putative marker of central serotonin function, with reported abnormalities in clinical disorders presumed to reflect serotonin dysfunction. Despite considerable research, very little is known about the LDAEP’s sensitivity to other neurotransmitter systems.

Objectives

Given the role of N-methyl-d-aspartate (NMDA) receptors in modulating pyramidal cell activity in cortico-cortico and thalamo-cortical loops, we examined the effect of targeting the glycine modulatory site of the NMDA receptor with high-dose glycine on the LDAEP in healthy subjects.

Materials and methods

The study was a double-blind, placebo-controlled repeated-measures design in which 14 healthy participants were tested under two acute treatment conditions, placebo and oral glycine (0.8 g/kg). Changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at CZ.

Results

Compared to placebo, high-dose glycine induced a weaker LDAEP (a pronounced decrease in the slope of the N1/P2 with increasing tone loudness; p < 0.02).

Conclusion

While the exact mechanism responsible for the effects of glycine on the LDAEP are not known, the findings suggest an inhibitory effect in the cortex, possibly via activation of NMDA receptors on GABA interneurons or inhibitory glycine receptors. The findings add to the growing literature exhibiting modulation of the LDAEP by multiple neurochemical systems in addition to the serotonergic system.

Keywords

Glycine NMDA receptor Glutamate Glycine receptor Loudness dependence auditory-evoked potentials LDAEP Electrophysiology Biological marker Serotonin 

References

  1. Baribeau JC, Laurent JP (1987) The effect of selective attention on augmenting/intensity function of the early negative waves of AEP’s. Electroencephalogr Clin Neurophysiol S40:68–75Google Scholar
  2. Berger AJ, Dieudonne S, Ascher P (1998) Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Physiol 80:3336–3340Google Scholar
  3. Betz H, Laube B (2006) Glycine receptors: recent insights into their structural organization and functional diversity. J Neurochem 97:1600–1610PubMedCrossRefGoogle Scholar
  4. Bowen DM, Francis PT, Pangalos MN, Chessell IP (1993) Neurotransmitter receptors of rat cortical pyramidal neurones: implications for in vivo imaging and therapy. J Reprod Fertil Suppl 46:131–143PubMedGoogle Scholar
  5. Breustedt J, Schmitz D, Heinemann U, Schmieden V (2004) Characterization of the inhibitory glycine receptor on entorhinal cortex neurons. Eur J Neurosci 19:1987–1991PubMedCrossRefGoogle Scholar
  6. Buchsbaum MS, Pfefferbaum A (1971) Individual differences in stimulus intensity response. Psychophysiology 8:600–612PubMedCrossRefGoogle Scholar
  7. Carrillo-de-la-Pena MT (1999) Effects of intensity and order of stimuli presentation on AEPs: an analysis of the consistency of EP augmenting/reducing in the auditory modality. Clin Neurophysiol 110:924–932PubMedCrossRefGoogle Scholar
  8. Chen L, Muhlhauser M, Yang CR (2003) Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 89:691–703PubMedCrossRefGoogle Scholar
  9. Connolly JF (1987) ERPs suggest the importance of subcortical mechanisms in activities typically associated with cortical functions. Electroencephalogr Clin Neurophysiol Suppl 40:635–644PubMedGoogle Scholar
  10. Coyle JT, Tsai G (2004) The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology 174:32–38PubMedCrossRefGoogle Scholar
  11. Croft RJ, Barry RJ (2000) EOG correction of blinks with saccade coeffecients: a test and revision of the aligned-artefact average solution. J Neurophysiol 111:444–451CrossRefGoogle Scholar
  12. Croft RJ, Klugman A, Baldeweg T, Gruzelier JH (2001) Electrophysiological evidence of serotonergic impairment in long-term MDMA (“Ecstasy”) users. Am J Psychiatr 158:1687–1692PubMedCrossRefGoogle Scholar
  13. Danysz W, Parsons CG (1998) Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 50:597–664PubMedGoogle Scholar
  14. D’Souza CD, Charney DS, Krystal JH (1995) Glycine Site agonists of the NMDA receptor: a review. CNS Drug Rev 1:227–260CrossRefGoogle Scholar
  15. D’Souza CD, Gil R, Cassello K, Morrissey K, Abi-saab D, White J, Sturwold R, Bennett A, Karper LP, Zuzarte E, Charney DS, Krystal JH (2000) IV Glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans. Biol Psychiatry 47:450–462PubMedCrossRefGoogle Scholar
  16. Frick A, Zieglgansberger W, Dodt H (2001) Glutamate receptors form hot spots on apical dendrites of neocortical pyramidal neurons. J Neurophysiol 86:1412–1421PubMedGoogle Scholar
  17. Gallinat J, Bottlender R, Juckel G, Munke-Puchner A, Stotz G, Kuss HJ (2000) The loudness dependence of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression. Psychopharmacology 148:404–411PubMedCrossRefGoogle Scholar
  18. Gallinat J, Senkowski D, Wernicke C, Juckel G, Becker I, Sander T, Smolka M, Hegerl U, Rommelspacher H, Winterer G, Herrmann WM (2003) Allelic variants of the functional promoter polymorphism of the human serotonin transporter gene is associated with auditory cortical stimulus processing. Neuropsychopharmacology 28:530–532PubMedCrossRefGoogle Scholar
  19. Gannon MC, Nuttall JA, Nuttall FQ (2002) The metabolic response to ingested glycine. Am J Clin Nutr 76:1302–1307PubMedGoogle Scholar
  20. Grossberg S, Gutowski WE (1987) Neural dynamics of decision making under risk: affective balance and cognitive-emotional interactions. Psychol Rev 94:300–318PubMedCrossRefGoogle Scholar
  21. Hegerl U, Juckel G (1993) Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 33:173–187PubMedCrossRefGoogle Scholar
  22. Hegerl U, Bottlender R, Gallinat J, Kuss HJ, Ackenheil M, Moller HJ (1998) The serotonin syndrome scale: first results on validity. Eur Arch Psychiatry Clin Neurosci 248:96–103PubMedCrossRefGoogle Scholar
  23. Hegerl U, Gallinat J, Juckel G (2001) Event-related potentials. Do they reflect central serotonergic neurotransmission and do they predict clinical response to serotonin agonists? J Affect Disord 62:93–100PubMedCrossRefGoogle Scholar
  24. Hensch T, Wargelius HL, Herold U, Lesch KP, Oreland L, Brocke B (2006) Further evidence for an association of 5-HTTLPR with intensity dependence of auditory-evoked potentials. Neuropsychopharmacology 31:2047–2054PubMedCrossRefGoogle Scholar
  25. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56:29–36PubMedCrossRefGoogle Scholar
  26. Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, Lindenmayer JP, Suckow R, Zukin SR (2001) Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol 4:385–391PubMedGoogle Scholar
  27. Javitt DC, Hashim A, Sershen H (2005) Modulation of striatal dopamine release by glycine transport inhibitors. Neuropsychopharmacology 30:649–656PubMedCrossRefGoogle Scholar
  28. Jonas P, Bischofberger J, Sandkuhler J (1998) Corelease of two fast neurotransmitters at a central synapse. Science 281:419–424PubMedCrossRefGoogle Scholar
  29. Juckel G, Molnar M, Hegerl U, Csepe V, Karmos G (1997) Auditory evoked potentials as indicator of brain serotonergic activity—first evidence in behaving cats. Biol Psychiatry 41:1181–1195PubMedCrossRefGoogle Scholar
  30. Juckel G, Hegerl U, Molnar M, Csepe V, Karmos G (1999) Auditory evoked potentials reflect serotonergic neuronal activity—a study in behaving cats administered drugs acting on 5-HT1A autoreceptors acting in the dorsal raphe nucleus. Neuropsychopharmacology 21:710–716PubMedCrossRefGoogle Scholar
  31. Juckel G, Gallinat J, Riedel M, Sokullu S, Schulz C, Hans-Jurgen M, Muller R, Hegerl U (2003) Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity. Schizophr Res 64:115–124PubMedCrossRefGoogle Scholar
  32. Kirsch J (2006) Glycinergic transmission. Cell Tissue Res 326:535–540PubMedCrossRefGoogle Scholar
  33. Laube B, Maksay G, Schemm R, Betz H (2002) Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses? Trends Pharmacol Sci 23:519–527PubMedCrossRefGoogle Scholar
  34. Lee TW, Yu YW, Chen TJ, Tsai SJ (2005) Loudness dependence of the auditory evoked potential and response to antidepressants in Chinese patients with major depression. J Psychiatry Neurosci 30:202–205PubMedGoogle Scholar
  35. Leiderman E, Zylberman I, Zukin SR, Cooper TB, Javitt DC (1996) Preliminary investigation of high-dose oral glycine on serum levels and negative symptoms in schizophrenia: an open-label trial. Biol Psychiatry 39:213–215PubMedCrossRefGoogle Scholar
  36. Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376PubMedCrossRefGoogle Scholar
  37. Lewis DA, Campell MJ, Foote SL, Morrison JH (1986) The monoaminergic innervation of primate neocortex. Hum Neurobiol 5:181–188PubMedGoogle Scholar
  38. Martina M, Gorfinkel Y, Halman S, Lowe JA, Periyalwar P, Schmidt CJ, Bergeron R (2004) Glycine transporter type 1 blockade changes NMDA receptor-mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels. J Physiol 557:489–500PubMedCrossRefGoogle Scholar
  39. Millan MJ (2005) N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179:30–53PubMedCrossRefGoogle Scholar
  40. Naas E, Zilles K, Gnahn H, Betz H, Becker CM, Schroder H (1991) Glycine receptor immunoreactivity in rat and human cerebral cortex. Brain Res 561:139–146PubMedCrossRefGoogle Scholar
  41. Nathan PJ, O’Neill B, Croft RJ (2005) Is the loudness dependence of the auditory evoked potential a sensitive and selective in vivo marker of central serotonergic function? Neuropsychopharmacology 30:1584–1585PubMedCrossRefGoogle Scholar
  42. Nathan PJ, Segrave R, Phan KL, O’Neill B, Croft RJ (2006) Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function. Hum Psychopharmacol 21:47–52PubMedCrossRefGoogle Scholar
  43. O’Neill BV, Croft RJ, Leung S, Guille V, Galloway M, Phan KL, Nathan PJ (2006) Dopamine receptor stimulation does not modulate the loudness dependence of the auditory evoked potential in humans. Psychopharmacology 188:92–99PubMedCrossRefGoogle Scholar
  44. Palmer C, Ellis KA, O’Neill BV, Croft RJ, Leung S, Oliver C, Wesnes KA, Nathan PJ (2007) The cognitive effects of modulating the glycine site of the NMDA receptor with high-dose glycine. Hum Psychopharmacol (in press)Google Scholar
  45. Parsons CG, Danysz W, Hesselink M, Hartmann S, Lorenz B, Wollenburg C, Quack G (1998) Modulation of NMDA receptors by glycine–introduction to some basic aspects and recent developments. Amino Acids 14:207–216PubMedCrossRefGoogle Scholar
  46. Pogarell O, Tatsch K, Juckel G, Hamann C, Mulert C, Popperl G, Folkerts M, Chouker M, Riedel M, Zaudig M, Moller HJ, Hegerl U (2004) Serotonin and dopamine transporter availabilities correlate with the loudness dependence of auditory evoked potentials in patients with obsessive–compulsive disorder. Neuropsychopharmacology 29:1910–1917PubMedCrossRefGoogle Scholar
  47. Rampon C, Luppi P-H, Fort P, Peyron C, Jouvet M (1996) Distribution of glycine-immunoreactive cell bodies and fibers in the rat brain. Neuroscience 75:737–755PubMedCrossRefGoogle Scholar
  48. Roux MJ, Supplisson S (2000) Neuronal and glial glycine transporters have different stoichiometries. Neuron 25:373–383PubMedCrossRefGoogle Scholar
  49. Sawaguchi T, Goldman-Rakic PS (1994) The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 71:515–528PubMedGoogle Scholar
  50. Senkowski D, Linden M, Zubragel D, Bar T, Gallinat J (2003) Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder. Biol Psychiatry 53:304–314PubMedCrossRefGoogle Scholar
  51. Simpson GV, Knight RT (1993) Multiple brain systems generating the rat auditory evoked potential. I. Characterization of the auditory cortex response. Brain Res 602:240–250PubMedCrossRefGoogle Scholar
  52. Smith KE, Borden LA, Hartig PR, Branchek T, Weinshank RL (1992) Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8:927–935PubMedCrossRefGoogle Scholar
  53. Strobel A, Debener S, Schmidt D, Hunnerkopf R, Lesch KP, Brocke B (2003) Allelic variation in serotonin transporter function associated with the intensity dependence of the auditory evoked potential. Am J Med Genet B Neuropsychiatr Genet 118B:41–47CrossRefPubMedGoogle Scholar
  54. Taber MT, Baker GB, Fibiger HC (1996) Glutamate receptor agonists decrease extracellular dopamine in the rat nucleus accumbens in vivo. Synapse 24:165–172PubMedCrossRefGoogle Scholar
  55. Truong DD, Fahn S (1988) Therapeutic trial with glycine in myoclonus. Mov Disord 3:222–232PubMedCrossRefGoogle Scholar
  56. Tsai GE, Falk WE, Gunther J, Coyle JT (1999) Improved cognition in Alzheimers disease with short-term D-Cycloserine treatment. Am J Psychiatr 156:467–469PubMedGoogle Scholar
  57. Tuchtenhagen F, Daumann J, Norra C, Gobbele R, Becker S, Pelz S, Sass H, Buchner H, Gouzoulis-Mayfrank E (2000) High intensity dependence of auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users. Neuropsychopharmacology 22:608–617PubMedCrossRefGoogle Scholar
  58. Uhl I, Gorynia I, Gallinat J, Mulert C, Wutzler A, Heinz A, Juckel G (2006) Is the loudness dependence of auditory evoked potentials modulated by the selective serotonin reuptake inhibitor citalopram in healthy subjects? Hum Psychopharmacol 21:463–471PubMedCrossRefGoogle Scholar
  59. von Knorring L, Perris C (1981) Biochemistry of the augmenting/reducing response in visual evoked potentials. Neuropsychobiology 7:1–8CrossRefGoogle Scholar
  60. Waldvogel HJ, Baer K, Snell RG, During MJ, Faull RL, Rees MI (2003) Distribution of gephyrin in the human brain: an immunohistochemical analysis. Neuroscience 116:145–156PubMedCrossRefGoogle Scholar
  61. Wenthold RJ, Hunter C (1990) Immunocytochemistry of glycine and glycvine receptors in the central auditory system. In: Ottersen OP, Storm-Mathisen J (eds) Glycine neurotransmission. Wiley, New York, pp 391–416Google Scholar
  62. Yang CR, Seamans JK, Gorelova N (1999) Developing a neuronal model for the pathophysiology of schizophrenia based on the nature of electrophysiological actions of dopamine in the prefrontal cortex. Neuropsychopharmacology 21:161–194PubMedCrossRefGoogle Scholar
  63. Zemon V, Kaplan E, Ratliff F (1986) The role of GABA-mediated intracortical inhibition in the generation of visual evoked potentials. In: Cracco RQ, Bodis-Wollner I (eds) Evoked potentials. Liss, New York, pp 287–295Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Barry V. O’Neill
    • 1
    • 2
  • Rodney J. Croft
    • 1
    • 2
  • Sumie Leung
    • 1
  • Chris Oliver
    • 3
  • K. Luan Phan
    • 2
    • 4
  • Pradeep J. Nathan
    • 2
  1. 1.Biological Psychiatry Research Unit, Brain Sciences InstituteSwinburne University of TechnologyMelbourneAustralia
  2. 2.Behavioural Neuroscience Laboratory, School of Psychology, Psychiatry, Psychological MedicineMonash UniversityClaytonAustralia
  3. 3.School of Natural and Complementary MedicineSouthern Cross UniversityLismoreAustralia
  4. 4.Brain Imaging and Emotions Lab (BIEL) Department of PsychiatryThe University of ChicagoChicagoUSA

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