Abstract
Disturbances of serotonergic neurotransmission in the brain have been implicated in the pathogenesis and maintenance of several psychiatric disorders. According to recent preclinical and clinical studies, the loudness dependence of auditory evoked potentials (LD) is related to the central serotonergic neurotransmission in humans. As the serotonergic phenotype has been reported to be associated with brain-derived neurotrophic factor (BDNF), we studied whether BDNF serum concentrations are related to LD in 109 healthy human volunteers (62 male, 47 female, age: 42.5±13.1 years). Pearson correlation showed a significant negative correlation between the BDNF serum concentrations and the LD measured at Fz (r=−0.259, p=0.007) and a trend for the Cz electrode (r=−0.185, p=0.055). Although this association needs to be replicated, the results are in line with the assumption that low serum BDNF levels reflect low central serotonergic neurotransmission as indicated by a strong LD.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Altar CA (1999). Neurotrophins and depression. Trends Pharmacol Sci 20: 59–61.
Altar CA, Boylan C, Fritsche M, Jackson C, Hyman C, Lindsay RM (1994). The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra. Exp Neurol 130: 31–40.
Biver F, Wikler D, Lotstra F, Dambaut P, Goldman S, Mendlewicz J (1997). Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 171: 444–448.
Brocke B, Beauducel A, John R, Debener S, Heilemann H (2000). Sensation seeking and affective disorders: characteristics in the intensity dependence of acoustic evoked potentials. Neuropsychobiology 41: 24–30.
Chaouloff F (1994). Influence of physical exercise on 5-HT1A receptor- and anxiety-related behaviours. Neurosci Lett 176: 226–230.
Chaouloff F, Laude D, Guezennec Y, Elghozi JL (1986). Motor activity increases tryptophan, 5-hydroxyindoleacetic acid, and homovanillic acid in ventricular cerebrospinal fluid of the conscious rat. J Neurochem 46: 1313–1316.
Cheetham SC, Katona CLE, Horton RW (1991). Post-mortem studies of neurotransmitter biochemistry in depression and suicide. In: Horton RW, Katona CLE (eds). Biological Aspects of Affective Disorders. Academic Press: London, UK. pp 192–221.
Costa PT, McCrae RR (1992). Revised NEO Personality Inventory and NEO Five-Factor Inventory, Professional Manual. Psychological Assessment Resources: Odessa, Fl.
Dey S, Singh RH, Dey PK (1992). Exercise training: significance of regional alterations in serotonin metabolism of rat brain in relation to antidepressant effect of exercise. Physiol Behav 52: 1095–1099.
D'Sa C, Duman RS (2002). Antidepressants and neuroplasticity. Bipolar Disord 4: 183–194.
Duman RS, Heninger GR, Nestler EJ (1997). A molecular and cellular theory of depression. Arch Gen Psychiatry 54: 597–606.
Eaton MJ, Staley JK, Globus MYT, Whittemore SR (1995). Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization. Dev Biol 170: 169–182.
Friedman J, Meares R (1979). The effect of placebo and tricyclic antidepressants on cortical evoked potentials in depressed patients. Biol Psychol 8: 291–302.
Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J et al (2002). Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 87: 728–734.
Gallinat J, Bottlender R, Juckel G, Munke-Puchner A, Stotz G, Kuss HJ et al (2000). The loudness dependency of the auditory evoked N1/P2-component as a predictor of the acute SSRI response in depression. Psychopharmacology 148: 404–411.
Gallinat J, Mulert C, Bajbouj M, Herrmann WM, Schunter J, Senkowski D et al (2002). Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia. Neuroimage 17: 110–127.
Gallinat J, Senkowski D, Wernicke C, Juckel G, Becker I, Sander T et al (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.
Garza AA, Ha TG, Garcia C, Chen MJ, Russo-Neustadt AA (2004). Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain. Pharmacol Biochem Behav 77: 209–220.
Gjerris A (1988). Baseline studies on transmitter substances in cerebrospinal fluid in depression. Acta Psychiatr Scand Suppl 346: 1–35.
Gur E, Dremencov E, Garcia F, Van de Kar LD, Lerer B, Newman ME (2002). Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus. Brain Res 952: 52–60.
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, 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, Juckel G, Rao ML, Müller-Oerlinghausen B (1991). Blood serotonin and auditory evoked potentials under fluvoxamine challenge and phototherapy. In: Cassano GB, Akiskal HS (eds). Serotonin-Related Psychiatric Syndromes: Clinical and Therapeutic Links. Royal Society of Medicine Services Limited: New York. pp 163–170.
Heinz A, Mann K, Weinberger DR, Goldman D (2001). Serotonergic dysfunction, negative mood states, and response to alcohol. Alcohol Clin Exp Res 25: 487–495.
Hellweg R, Hock C, Hartung HD (1989). An improved rapid and highly sensitive enzyme immunoassay for nerve growth factor. J Methods Cell Mol Biol 1: 43–49.
Hellweg R, von Armin CAF, Büchner M, Huber R, Riepe MW (2003). Neuroprotection and neuronal dysfunction upon repetitive disinhibition of oxidative phosphorylation. Exp Neurol 183: 346–354.
Herrmann MJ, Sonnek G, Weijers HG, Wiesbeck GA, Boning J, Fallgatter AJ (2002). Electrophysiological indication for a link between serotonergic neurotransmission and personality in alcoholism. Prog Neuropsychopharmacol Biol Psychiatry 26: 157–161.
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 in the dorsal raphe nucleus. Neuropsychopharmacology 21: 710–716.
Juckel G, Molnár M, Hegerl U, Csépe V, Karmos G (1997). Auditory evoked potentials as indicators of brain serotonergic activity—first evidence in cats. Biol Psychiatry 41: 1181–1195.
Karege F, Schwald M, Cisse M (2002). Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett 328: 261–264.
Lang UE, Hellweg R, Gallinat J (2004). BDNF serum concentrations in healthy humans are associated with depression-related personality traits. Neuropsychopharmacology 29: 795–798.
Lesch KP, Wolozin BL, Murphy DL, Riederer P (1993). Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 60: 2319–2322.
Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L et al (1998). Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3-beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 44: 1090–1098.
Mamounas LA, Altar CA, Blue ME, Kaplan DR, Tessarollo L, Lyons WE (2000). BDNF promotes the regenerative sprouting, but not survival, of injured serotoninergic axons in the adult rat brain. J Neurosci 20: 771–782.
Mamounas LA, Blue ME, Siuciak JA, Altar CA (1995). Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15: 7929–7939.
Manjarrez GG, Hernandez ZE, Robles OA, Gonzalez RM, Hernandez RJ (2001). Developmental impairment of auditory evoked N1/P2 component in rats undernourished in utero: its relation to brain serotonin activity. Brain Res Dev Brain Res 127: 149–155.
Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff KA, Gray N et al (2003). Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 53: 707–742.
Meeusen R, Thorre K, Chaouloff F, Sarre S, De Meirleir K, Ebinger G et al (1996). Effects of tryptophan and/or acute running on extracellular 5-HT and 5-HIAA levels in the hippocampus of food-deprived rats. Brain Res 740: 245–252.
Mössner R, Daniel S, Albert D, Heils A, Okladnova O, Schmitt A et al (2000). Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem Int 36: 197–202.
Nibuya M, Morinobu S, Duman RS (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15: 7539–7547.
Owens MJ, Nemeroff CB (1994). Role of serotonin in the pathophysiology of depression: focus on the serotonin receptor. Clin Chem 40: 288–295.
Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ (1998). Transport of brain-derived neurotrophic factor across the blood–brain barrier. Neuropsychopharmacol 37: 1553–1561.
Pardridge WM (2002). Neurotrophins, neuroprotection and the blood–brain barrier. Curr Opin Investig Drugs 3: 1753–1757.
Pearse AG (1980). The common peptides and the cytochemistry of their cells of origin. Basic Appl Histochem 24: 63–73.
Petty F, Davis LL, Kabel D, Kramer GL (1996). Serotonin dysfunction disorders: a behavioral neurochemistry perspective. J Clin Psychiatry 57 (Suppl 8): 11–16.
Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S et al (2004). Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 61: 556–563.
Rumajogee P, Madeira A, Vergé D, Hamon M, Miquel MC (2002). Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share TrkB-dependent mechanisms. J Neurochem 83: 1525–1528.
Russo-Neustadt A (2003). Brain-derived neurotrophic factor, behavior, and new directions for the treatment of mental disorders. Semin Clin Neuropsychiatry 8: 109–118.
Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW (2000). Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101: 305–312.
Schildkraut JJ (1965). The catecholamine hypothesis of affective disorders: a review of the supporting evidence. Am J Psychiatry 122: 509–521.
Sen S, Nesse RM, Stoltenberg SF, Li S, Gleiberman L, Chakravarti A et al (2003). A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28: 397–401.
Sen S, Villafuerte S, Nesse R, Stoltenberg SF, Hopcian J, Gleiberman L et al (2004). Serotonin transporter and GABAA alpha 6 receptor variants are associated with neuroticism. Biol Psychiatry 55: 244–249.
Senkowski D, Linden M, Zubrägel D, Bär T, Gallinat J (2003). Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder. Biol Psychiatry 53: 304–314.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59: 22–33.
Shen H, Numachi Y, Yoshida S, Toda S, Awata S, Matsuoka H et al (2001). Electroconvulsive shock regulates serotonin transporter mRNA expression in rat raphe nucleus. Psychiatry Clin Neurosci 55: 75–77.
Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS (2002). Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22: 3251–3261.
Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM (1996). BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res 710: 11–20.
Siuciak JA, Clark MS, Rind HB, Whettemore SR, Russo AF (1998). BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J Neurosci Res 52: 149–158.
Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM (1997). Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56: 131–137.
Stanley M, Mann JJ (1983). Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1: 214–216.
Tuchtenhagen F, Daumann J, Norra C, Gobbele R, Becker S, Pelz S et al (2000). High intensity dependence of auditory evoked dipole source activity indicates decreased serotonergic activity in abstinent ecstasy (MDMA) users. Neuropsychopharmacology 22: 608–617.
von Knorring L, Perris C (1981). Biochemistry of the augmenting-reducing response in visual evoked potentials. Neuropsychobiology 7: 1–8.
Yamamoto H, Gurney ME (1990). Human platelets contain brain-derived neurotrophic factor. J Neurosci 10: 3469–3478.
Yates M, Leake A, Candy JM, Fairbaim AF, McKeith IG, Ferrier IN (1990). 5HT2 receptor changes in major depression. Biol Psychiatry 27: 489–496.
Acknowledgements
We gratefully acknowledge the excellent technical assistance of Mrs Bunge.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lang, U., Hellweg, R. & Gallinat, J. Association of BDNF Serum Concentrations with Central Serotonergic Activity: Evidence from Auditory Signal Processing. Neuropsychopharmacol 30, 1148–1153 (2005). https://doi.org/10.1038/sj.npp.1300666
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1300666
Keywords
This article is cited by
-
Serum brain-derived neurotrophic factor level and exercise tolerance complement each other in predicting the prognosis of patients with heart failure
Heart and Vessels (2018)
-
Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants
Psychopharmacology (2011)
-
Loudness dependence of auditory evoked potentials (LDAEP) correlates with the availability of dopamine transporters and serotonin transporters in healthy volunteers—a two isotopes SPECT study
Psychopharmacology (2011)
-
Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking
Psychopharmacology (2007)
-
Further Evidence for an Association of 5-HTTLPR with Intensity Dependence of Auditory-Evoked Potentials
Neuropsychopharmacology (2006)