Effects of Tryptophan Depletion on the Serotonin Transporter in Healthy Humans

BACKGROUND Lowering of brain serotonin by acute tryptophan depletion (TD) frequently leads to transient symptoms of depression in vulnerable individuals but not in euthymic healthy subjects with a negative family history of depression. The effects of TD on regional serotonin transporter binding potential (5-HTT BP), an index of 5-HTT density and affinity, were studied in healthy individuals using 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ([11C]DASB) positron emission tomography (PET). Adaptive decreases in 5-HTT density and/or affinity during TD would be a possible compensatory mechanism to maintain sufficient extracellular serotonin levels during TD, thereby preventing a depressive relapse. METHODS Regional noninvasive 5-HTT BP was found in 25 healthy subjects using [11C]DASB PET. Fourteen subjects were scanned twice, once after TD and once after sham depletion, and 11 other healthy subjects were scanned twice to measure test-retest reliability of the method. RESULTS None of the healthy subjects experienced depressive symptoms during TD and there was no difference in regional 5-HTT BP during TD as compared with sham depletion. CONCLUSIONS Acute changes in 5-HTT density or affinity are unlikely to play a role in protecting healthy subjects against mood symptoms during TD. Other mechanisms that may be associated with greater resilience against acute lowering of extracellular serotonin should be explored to gain further insight into the neurochemical basis of different vulnerabilities to short-term depressive relapse.

[1]  M. Hamilton,et al.  Development of a rating scale for primary depressive illness. , 1967, The British journal of social and clinical psychology.

[2]  Sylvain Houle,et al.  Regional distribution of serotonin transporter protein in postmortem human brain: is the cerebellum a SERT-free brain region? , 2005, Nuclear medicine and biology.

[3]  C. Benkelfat,et al.  Depressive relapse following acute tryptophan depletion in patients with major depressive disorder , 2000, Journal of psychopharmacology.

[4]  C. Benkelfat,et al.  Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. , 1994, Archives of general psychiatry.

[5]  G. Biggio,et al.  Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. , 1974, Life sciences.

[6]  Sylvain Houle,et al.  In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography. , 2002, Nuclear medicine and biology.

[7]  C. Nemeroff,et al.  Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. , 1994, Clinical chemistry.

[8]  Jeih-San Liow,et al.  Linearized Reference Tissue Parametric Imaging Methods: Application to [11C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  Sylvain Houle,et al.  [11C]‐DASB, a tool for in vivo measurement of SSRI‐induced occupancy of the serotonin transporter: PET characterization and evaluation in cats , 2003, Synapse.

[10]  S. Kasper,et al.  Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. , 2002, Archives of general psychiatry.

[11]  R. Salomon,et al.  Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. , 1991, Psychopharmacology bulletin.

[12]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  P. Celada,et al.  Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat , 1993, Naunyn-Schmiedeberg's Archives of Pharmacology.

[14]  C Burger,et al.  Requirements and implementation of a flexible kinetic modeling tool. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[15]  W. Riedel,et al.  Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders , 1999, Biological Psychiatry.

[16]  T. Robbins,et al.  The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers , 2002, Psychopharmacology.

[17]  Alan A. Wilson,et al.  Tryptophan depletion and serotonin loss in selective serotonin reuptake inhibitor–treated depression: An [18F] MPPF positron emission tomography study , 2004, Biological Psychiatry.

[18]  Husseini Manji,et al.  Effects of tryptophan depletion on serum levels of brain-derived neurotrophic factor in unmedicated patients with remitted depression and healthy subjects. , 2005, The American journal of psychiatry.

[19]  Alan A. Wilson,et al.  Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. , 2001, The American journal of psychiatry.

[20]  V. Knott,et al.  The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects , 1999, Biological Psychiatry.

[21]  J. Małyszko,et al.  Serotonergic measures in blood and brain and their correlations in rats treated with tranylcypromine, a monoamine oxidase inhibitor. , 1993, The Japanese journal of physiology.

[22]  R. Blakely,et al.  Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins , 1998, Biological Psychiatry.

[23]  M. Mintun,et al.  A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography , 1984, Annals of neurology.

[24]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[25]  Paul J. Harrison,et al.  β-blocker Binding to Human 5-HT1A Receptors in vivo and in vitro: Implications for Antidepressant Therapy , 2000, Neuropsychopharmacology.

[26]  Alan A. Wilson,et al.  Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB , 2000, European Journal of Nuclear Medicine.

[27]  Sylvain Houle,et al.  Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. , 2004, The American journal of psychiatry.

[28]  M. Leboyer,et al.  Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder , 2001, Biological Psychiatry.

[29]  R. Salomon,et al.  Association of a Critical CSF Tryptophan Threshold Level with Depressive Relapse , 2003, Neuropsychopharmacology.

[30]  John J. B. Allen,et al.  Tryptophan depletion and depressive vulnerability , 1999, Biological Psychiatry.

[31]  Alan A. Wilson,et al.  Positron Emission Tomography Quantification of [11C]-DASB Binding to the Human Serotonin Transporter: Modeling Strategies , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[32]  S. Houle,et al.  Novel Radiotracers for Imaging the Serotonin Transporter by Positron Emission Tomography: Synthesis, Radiosynthesis, and in Vitro and ex Vivo Evaluation of (11)C-Labeled 2-(Phenylthio)araalkylamines. , 2000, Journal of medicinal chemistry.

[33]  A. Heinz,et al.  DASB –in vitro binding characteristics on human recombinant monoamine transporters with regard to its potential as positron emission tomography (PET) tracer , 2004, Journal of neurochemistry.

[34]  H L Miller,et al.  Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. , 1997, Archives of general psychiatry.

[35]  G. Biggio,et al.  Effect of the oral administration of tryptophan‐free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism , 1974, Journal of neurochemistry.

[36]  F. Fadda,et al.  The decrease of serotonin release induced by a tryptophan-free amino acid diet does not affect spatial and passive avoidance learning , 1997, Brain Research.

[37]  A. Neumeister.  Tryptophan depletion, serotonin, and depression: where do we stand? , 2003, Psychopharmacology bulletin.

[38]  V. Arango,et al.  A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. , 2000, Archives of general psychiatry.

[39]  E. Moja,et al.  Dose-response decrease in plasma tryptophan and in brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats. , 1989, Life sciences.

[40]  Peter Herscovitch,et al.  Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. , 2004, Archives of general psychiatry.

[41]  R. Salomon,et al.  Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action , 1999, Biological Psychiatry.

[42]  Y Yonekura,et al.  An introduction to PET and SPECT neuroreceptor quantification models. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[43]  N. Praschak-Rieder,et al.  Evidence for an Altered Tryptophan Metabolism in Fibromyalgia , 2002, Neurobiology of Disease.

[44]  Ove Wiborg,et al.  Serotonin depletion decreases serotonin transporter mRNA levels in rat brain , 1995, Brain Research.

[45]  F. Henn,et al.  New insights into the mechanisms of antidepressant therapy. , 2004, Pharmacology & therapeutics.

[46]  D. Charney,et al.  Serotonergic function in depression. Prolactin response to intravenous tryptophan in depressed patients and healthy subjects. , 1984, Archives of general psychiatry.

[47]  Sylvain Houle,et al.  Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. , 2004, Archives of general psychiatry.

[48]  M. Gobbi,et al.  p‐Chlorophenylalanine Changes Serotonin Transporter mRNA Levels and Expression of the Gene Product , 1996, Journal of neurochemistry.

[49]  Richard E Carson,et al.  Noise Reduction in the Simplified Reference Tissue Model for Neuroreceptor Functional Imaging , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[50]  M. Fava,et al.  Tryptophan depletion in SSRI-recovered depressed outpatients , 2001, Psychopharmacology.

[51]  Marco Leyton,et al.  The role of serotonin in human mood and social interaction Insight from altered tryptophan levels , 2002, Pharmacology Biochemistry and Behavior.

[52]  F. Artigas,et al.  Effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain. , 1994, European journal of pharmacology.

[53]  F. Zhou,et al.  Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence , 1998, Brain Research.

[54]  D Hommer,et al.  Effects of Acute Tryptophan Depletion on Plasma and Cerebrospinal Fluid Tryptophan and 5‐Hydroxyindoleacetic Acid in Normal Volunteers , 1999, Journal of neurochemistry.

[55]  K. Koed,et al.  Opposing changes in serotonin and norepinephrine transporter mRNA levels after serotonin depletion , 2000, European Neuropsychopharmacology.

[56]  C. McDougle,et al.  Tryptophan Depletion During Continuous CSF Sampling in Healthy Human Subjects , 1998, Neuropsychopharmacology.

[57]  Acute depletion of serotonin down-regulates serotonin transporter mRNA in raphe neurons , 1995, Brain Research.

[58]  P. Fletcher,et al.  Acute Amino Acid Loads That Deplete Brain Serotonin Fail to Alter Behavior , 1998, Pharmacology Biochemistry and Behavior.