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.
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References
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 S40:68–75
Berger AJ, Dieudonne S, Ascher P (1998) Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Physiol 80:3336–3340
Betz H, Laube B (2006) Glycine receptors: recent insights into their structural organization and functional diversity. J Neurochem 97:1600–1610
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 46:131–143
Breustedt J, Schmitz D, Heinemann U, Schmieden V (2004) Characterization of the inhibitory glycine receptor on entorhinal cortex neurons. Eur J Neurosci 19:1987–1991
Buchsbaum MS, Pfefferbaum A (1971) Individual differences in stimulus intensity response. Psychophysiology 8:600–612
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 110:924–932
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 89:691–703
Connolly JF (1987) ERPs suggest the importance of subcortical mechanisms in activities typically associated with cortical functions. Electroencephalogr Clin Neurophysiol Suppl 40:635–644
Coyle JT, Tsai G (2004) The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology 174:32–38
Croft RJ, Barry RJ (2000) EOG correction of blinks with saccade coeffecients: a test and revision of the aligned-artefact average solution. J Neurophysiol 111:444–451
Croft RJ, Klugman A, Baldeweg T, Gruzelier JH (2001) Electrophysiological evidence of serotonergic impairment in long-term MDMA (“Ecstasy”) users. Am J Psychiatr 158:1687–1692
Danysz W, Parsons CG (1998) Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 50:597–664
D’Souza CD, Charney DS, Krystal JH (1995) Glycine Site agonists of the NMDA receptor: a review. CNS Drug Rev 1:227–260
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 47:450–462
Frick A, Zieglgansberger W, Dodt H (2001) Glutamate receptors form hot spots on apical dendrites of neocortical pyramidal neurons. J Neurophysiol 86:1412–1421
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 148:404–411
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 28:530–532
Gannon MC, Nuttall JA, Nuttall FQ (2002) The metabolic response to ingested glycine. Am J Clin Nutr 76:1302–1307
Grossberg S, Gutowski WE (1987) Neural dynamics of decision making under risk: affective balance and cognitive-emotional interactions. Psychol Rev 94:300–318
Hegerl U, Juckel G (1993) Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 33:173–187
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 248:96–103
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 62:93–100
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 31:2047–2054
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 56:29–36
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 4:385–391
Javitt DC, Hashim A, Sershen H (2005) Modulation of striatal dopamine release by glycine transport inhibitors. Neuropsychopharmacology 30:649–656
Jonas P, Bischofberger J, Sandkuhler J (1998) Corelease of two fast neurotransmitters at a central synapse. Science 281:419–424
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 41:1181–1195
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 21:710–716
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 64:115–124
Kirsch J (2006) Glycinergic transmission. Cell Tissue Res 326:535–540
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 23:519–527
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 30:202–205
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 39:213–215
Lewis DA, Moghaddam B (2006) Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 63:1372–1376
Lewis DA, Campell MJ, Foote SL, Morrison JH (1986) The monoaminergic innervation of primate neocortex. Hum Neurobiol 5:181–188
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 557:489–500
Millan MJ (2005) N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives. Psychopharmacology 179:30–53
Naas E, Zilles K, Gnahn H, Betz H, Becker CM, Schroder H (1991) Glycine receptor immunoreactivity in rat and human cerebral cortex. Brain Res 561:139–146
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 30:1584–1585
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 21:47–52
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 188:92–99
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)
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 14:207–216
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 29:1910–1917
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 75:737–755
Roux MJ, Supplisson S (2000) Neuronal and glial glycine transporters have different stoichiometries. Neuron 25:373–383
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 71:515–528
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 53:304–314
Simpson GV, Knight RT (1993) Multiple brain systems generating the rat auditory evoked potential. I. Characterization of the auditory cortex response. Brain Res 602:240–250
Smith KE, Borden LA, Hartig PR, Branchek T, Weinshank RL (1992) Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8:927–935
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:41–47
Taber MT, Baker GB, Fibiger HC (1996) Glutamate receptor agonists decrease extracellular dopamine in the rat nucleus accumbens in vivo. Synapse 24:165–172
Truong DD, Fahn S (1988) Therapeutic trial with glycine in myoclonus. Mov Disord 3:222–232
Tsai GE, Falk WE, Gunther J, Coyle JT (1999) Improved cognition in Alzheimers disease with short-term D-Cycloserine treatment. Am J Psychiatr 156:467–469
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 22:608–617
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 21:463–471
von Knorring L, Perris C (1981) Biochemistry of the augmenting/reducing response in visual evoked potentials. Neuropsychobiology 7:1–8
Waldvogel HJ, Baer K, Snell RG, During MJ, Faull RL, Rees MI (2003) Distribution of gephyrin in the human brain: an immunohistochemical analysis. Neuroscience 116:145–156
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 391–416
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 21:161–194
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 287–295
Acknowledgments
Authors would like to thank Dr Susan Illic for performing medical examinations. The study was supported by a research grant to PJN from Blackmore’s, Australia. Fellowship support for PJN was provided by the National Health and Medical Research Council (NHMRC) of Australia (Grant 345709).
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O’Neill, B.V., Croft, R.J., Leung, S. et al. High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans. Psychopharmacology 195, 85–93 (2007). https://doi.org/10.1007/s00213-007-0870-4
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DOI: https://doi.org/10.1007/s00213-007-0870-4