Advertisement

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.

      Key Words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Barker E.L.
        • Blakely R.D.
        Norepinephrine and serotonin transporters.
        in: Bloom F.E. Kupfer D.J. Psychopharmacology the Fourth Generation of Progress. Raven Press, New York1995: 321-333
        • Benkelfat C.
        • Ellenbogen M.A.
        • Dean P.
        • Palmour R.M.
        • Young S.N.
        Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders.
        Arch Gen Psychiatry. 1994; 51: 687-697
        • Biggio G.
        • Fadda F.
        • Fanni P.
        • Tagliamonte A.
        • Gessa G.L.
        Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet.
        Life Sci. 1974; 14: 1321-1329
        • Blakely R.D.
        • Ramamoorthy S.
        • Schroeter S.
        • Quian Y.
        • Apparsundaram S.
        • Galli A.
        • et al.
        Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins.
        Biol Psychiatry. 1998; 44: 169-178
        • Bremner J.D.
        • Innis R.B.
        • Salomon R.M.
        • Staib L.H.
        • Ng C.K.
        • Miller H.L.
        • et al.
        Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced relapse.
        Arch Gen Psychiatry. 1997; 54: 364-374
        • Brown C.M.
        • Fletcher P.J.
        • Coscina D.V.
        Acute amino acid loads that deplete brain serotonin fail to alter behavior.
        Pharmacol Biochem Behav. 1998; 59: 115-121
        • Burger C.
        • Buck A.
        Requirements and implementation of a flexible kinetic modelling tool.
        J Nucl Med. 1997; 38: 1818-1823
        • Carpenter L.L.
        • Anderson G.M.
        • Pelton G.H.
        • Gudin J.A.
        • Kirwin P.D.S.
        • Price L.H.
        • et al.
        Tryptophan depletion during continuous CSF sampling in healthy human subjects.
        Neuropsychopharmacology. 1998; 19: 26-35
        • Celada P.
        • Artigas F.
        Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat.
        Naunyn Schmiedebergs Arch Pharmacol. 1993; 347: 583-590
        • Delgado P.L.
        • Miller H.L.
        • Salomon R.M.
        • Licinio J.
        • Krystal J.H.
        • Moreno F.A.
        • et al.
        Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine.
        Biol Psychiatry. 1999; 46: 212-220
        • Delgado P.L.
        • Price L.H.
        • Miller H.L.
        • Salomon R.M.
        • Licinio J.
        • Krystal J.H.
        • et al.
        Rapid serotonin depletion as a provocative challenge test for patients with major depression.
        Psychopharmacol Bull. 1991; 27: 321-330
        • Ferrer A.
        • Artigas F.
        Effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain.
        Eur J Pharmacol. 1994; 263: 227-234
        • First M.B.
        • Gibbon M.
        • Spitzer R.L.
        • Williams J.B.W.
        Structured Clinical Interview for DSM-IV, Nonpatient Version. Biometrics Department, New York State Psychiatric Institute, New York1996
        • Gessa G.L.
        • Biggio G.
        • Fadda F.
        • Corsini G.U.
        • Tagliamonte A.
        Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism.
        J Neurochem. 1974; 22: 869-870
        • Ginovart N.
        • Wilson A.A.
        • Meyer J.H.
        • Hussey D.
        • Houle S.
        Positron emission tomography quantification of [11C] DASB binding to the human serotonin transporter.
        J Cereb Blood Flow Metab. 2001; 21: 1342-1353
        • Ginovart N.
        • Wilson A.A.
        • Meyer J.H.
        • Hussey D.
        • Houle S.
        [11C] DASB, a tool for in vivo measurement of SSRI-induced occupancy of the serotonin transporter.
        Synapse. 2003; 47: 123-133
        • Hamilton M.
        Development of a rating scale for primary depressive illness.
        Br J Soc Clin Psychol. 1967; 6: 278-296
        • Heninger G.R.
        • Charney D.S.
        • Sternberg D.E.
        Serotonergic function in depression. Prolactin response to intravenous tryptophan in depressed patients and healthy subjects.
        Arch Gen Psychiatry. 1984; 41: 398-402
        • Houle S.
        • Ginovart N.
        • Hussey D.
        • Meyer J.H.
        • Wilson A.A.
        Imaging the serotonin transporter with positron emission tomography.
        Eur J Nucl Med. 2000; 27: 1719-1722
        • Hummerich R.
        • Reischl G.
        • Ehrlichmann W.
        • Machulla H.J.
        • Heinz A.
        • Schloss P.
        DASB-in vitro binding characteristics on human recombinant monoamine transporters with regard to its potential as positron emission tomography (PET) tracer.
        J Neurochem. 2004; 90: 1218-1226
        • Ichise M.
        • Liow J.S.
        • Lu J.Q.
        • Takano A.
        • Model K.
        • Toyama H.
        • et al.
        Linearized reference tissue parametric imaging methods.
        J Cereb Blood Flow Metab. 2003; 23: 1096-1112
        • Ichise M.
        • Meyer J.H.
        • Yonekura Y.
        An introduction to PET and SPECT neuroreceptor quantification models.
        J Nucl Med. 2001; 42: 755-763
        • Kish S.J.
        • Furukawa Y.
        • Chang L.J.
        • Tong J.
        • Ginovart N.
        • Wilson A.
        • et al.
        Regional distribution of serotonin transporter protein in postmortem human brain.
        Nucl Med Biol. 2005; 32: 123-128
        • Klaassen T.
        • Riedel W.J.
        • van Someren A.
        • Deutz N.E.
        • Honig A.
        • van Praag H.M.
        Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders.
        Biol Psychiatry. 1999; 46: 489-497
        • Knott V.J.
        • Howson A.L.
        • Perugini M.
        • Ravindran A.V.
        • Young S.N.
        The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects.
        Biol Psychiatry. 1999; 46: 229-238
        • Koed K.
        • Linnet K.
        Opposing changes in serotonin and norepinephrine transporter mRNA levels after serotonin depletion.
        Eur Neuropsychopharmacol. 2000; 10: 501-509
        • Leyton M.
        • Ghadirian A.M.
        • Young S.N.
        • Palmour R.M.
        • Blier P.
        • Helmers K.
        • et al.
        Depressive relapse following acute tryptophan depletion in patients with major depressive disorder.
        J Psychopharmacol. 2000; 14: 284-287
        • Linnet K.
        • Koed K.
        • Wiborg O.
        • Gregersen N.
        Serotonin depletion decreases serotonin transporter mRNA levels in rat brain.
        Brain Res. 1995; 697: 251-253
        • Logan J.
        • Fowler J.S.
        • Volkow N.D.
        • Wang G.J.
        • Ding Y.S.
        • Alexoff D.L.
        Distribution volume ratios without blood sampling from graphical analysis of PET data.
        J Cereb Blood Flow Metab. 1996; 16: 834-840
        • Malyszko J.
        • Urano T.
        • Serizawa K.
        • Yan D.
        • Kozima Y.
        • Takada Y.
        • et al.
        Serotonergic measures in blood and brain and their correlations in rats treated with tranylcypromine, a monoamine oxidase inhibitor.
        Jpn J Physiol. 1993; 43: 613-626
        • Mann J.J.
        • Huang Y.Y.
        • Underwood M.D.
        • Kassir S.A.
        • Oppenheim S.
        • Kelly T.M.
        • et al.
        A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide.
        Arch Gen Psychiatry. 2000; 57: 729-738
        • Meyer J.H.
        • Houle S.
        • Sagrati S.
        • Carella A.
        • Hussey D.F.
        • Ginovart N.
        • et al.
        Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography.
        Arch Gen Psychiatry. 2004; 61: 1271-1279
        • Meyer J.H.
        • Wilson A.A.
        • Ginovart N.
        • Goulding V.
        • Hussey D.
        • Hood K.
        • et al.
        Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression.
        Am J Psychiatry. 2001; 158: 1843-1849
        • Meyer J.H.
        • Wilson A.A.
        • Sagrati S.
        • Hussey D.
        • Carella A.
        • Potter W.Z.
        • et al.
        Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses.
        Am J Psychiatry. 2004; 161: 826-835
        • Mintun M.A.
        • Raichle M.E.
        • Kilbourn M.R.
        • Wooten G.F.
        • Welch M.J.
        A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography.
        Ann Neurol. 1984; 15: 217-227
        • Moja E.A.
        • Cipolla P.
        • Castoldi D.
        • Tofanetti O.
        Dose-response decrease in plasma tryptophan and in brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats.
        Life Sci. 1989; 44: 971-976
        • Moreno F.A.
        • Gelenberg A.J.
        • Heninger G.R.
        • Potter R.L.
        • McKnight K.M.
        • Allen J.
        • et al.
        Tryptophan depletion and depressive vulnerability.
        Biol Psychiatry. 1999; 46: 498-505
        • Murphy F.C.
        • Smith K.A.
        • Cowen P.J.
        • Robbins T.W.
        • Sahakian B.J.
        The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.
        Psychopharmacology (Berl). 2002; 163: 42-53
        • Neumeister A.
        Tryptophan depletion, serotonin, and depression.
        Psychopharmacol Bull. 2003; 37: 99-115
        • Neumeister A.
        • Konstantinidis A.
        • Stastny J.
        • Schwarz M.J.
        • Vitouch O.
        • Willeit M.
        • 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.
        Arch Gen Psychiatry. 2002; 59: 613-620
        • Neumeister A.
        • Nugent A.C.
        • Waldeck T.
        • Geraci M.
        • Schwarz M.
        • Bonne O.
        • et al.
        Neural and behavioral responses to tryptophan depletion in unmedicated remitted patients with major depressive disorder and healthy controls.
        Arch Gen Psychiatry. 2004; 61: 765-773
        • Neumeister A.
        • Yuan P.
        • Young T.A.
        • Bonne O.
        • Luckenbaugh D.A.
        • Charney D.S.
        • et al.
        Effects of tryptophan depletion on serum levels of brain-derived neurotrophic factor in unmedicated patients with remitted depression and healthy subjects.
        Am J Psychiatry. 2005; 162: 805-807
        • Owens M.J.
        • Nemeroff C.B.
        Role of serotonin in the pathophysiology of depression.
        Clin Chem. 1994; 40: 288-295
        • Praschak-Rieder N.
        • Hussey D.
        • Wilson A.A.
        • Carella A.
        • Lee M.
        • Dunn E.
        • et al.
        Tryptophan depletion and serotonin loss in SSRI treated depression.
        Biol Psychiatry. 2004; 56: 587-591
        • Quintin P.
        • Benkelfat C.
        • Launay J.M.
        • Arnulf I.
        • Pointereau-Bellenger A.
        • Barbault S.
        • et al.
        Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder.
        Biol Psychiatry. 2001; 50: 184-190
        • Rabiner E.A.
        • Gunn R.N.
        • Castro M.E.
        • Sargent P.A.
        • Cowen P.J.
        • Koepp M.J.
        • et al.
        β-Blocker binding to human 5-HT1A receptors in vivo and in vitro.
        Neuropsychopharmacology. 2000; 23: 285-293
        • Rattray M.
        • Baldessari S.
        • Gobbi M.
        • Mennini T.
        • Samanin R.
        • Bendotti C.
        p-Chlorophenylalanine changes serotonin transporter mRNA levels and expression of the gene product.
        J Neurochem. 1996; 67: 463-472
        • Salomon R.M.
        • Kennedy J.S.
        • Johnson B.W.
        • Schmidt D.E.
        • Kwentus J.
        • Gwirtsman H.E.
        • et al.
        Association of a critical CSF tryptophan threshold level with depressive relapse.
        Neuropsychopharmacology. 2003; 28: 956-960
        • Schloss P.
        • Henn F.A.
        New insights into the mechanisms of antidepressant therapy.
        Pharmacol Ther. 2004; 102: 47-60
        • Schwarz M.J.
        • Offenbaecher M.
        • Neumeister A.
        • Ewert T.
        • Willeit M.
        • Praschak-Rieder N.
        • et al.
        Evidence for an altered tryptophan metabolism in fibromyalgia.
        Neurobiol Dis. 2002; 11: 434-442
        • Spillmann M.K.
        • Van der Does A.J.W.
        • Rankin M.A.
        • Vuolo R.D.
        • Alpert J.E.
        • Nierenberg A.A.
        • et al.
        Tryptophan depletion in SSRI-recovered depressed outpatients.
        Psychopharmacology. 2001; 155: 123-127
        • Stancampiano R.
        • Cocco S.
        • Melis F.
        • Cugusi C.
        • Sarais L.
        • Fadda F.
        The decrease of serotonin release induced by a tryptophan-free amino acid diet does not affect spatial and passive avoidance learning.
        Brain Res. 1997; 762: 269-274
        • Williams W.A.
        • Shoaf S.E.
        • Hommer D.
        • Rawlings R.
        • Linnoila M.
        Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers.
        J Neurochem. 1999; 72: 1641-1647
        • Wilson A.A.
        • Ginovart N.
        • Hussey D.
        • Meyer J.H.
        • Houle S.
        In vitro and in vivo characterization of [11C]-DASB.
        Nucl Med Biol. 2002; 29: 509-515
        • Wilson A.A.
        • Ginovart N.
        • Schmidt M.
        • Meyer J.H.
        • Threlkeld P.G.
        • Houle S.
        Novel radiotracers for imaging the serotonin transporter by positron emission tomography.
        J Med Chem. 2000; 43: 3103-3110
        • Wu Y.
        • Carson R.E.
        Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging.
        J Cereb Blood Flow Metab. 2002; 22: 1440-1452
        • Young S.N.
        • Leyton M.
        The role of serotonin in human mood and social interaction.
        Pharmacol Biochem Behav. 2002; 71: 857-865
        • Yu A.
        • Yang J.
        • Pawlyk A.C.
        • Tejani-Butt S.M.
        Acute depletion of serotonin down-regulates serotonin transporter mRNA in raphe neurons.
        Brain Res. 1995; 688: 209-212
        • Zhou F.C.
        • Tao-Cheng J.H.
        • Segu L.
        • Patel T.
        • Wang Y.
        Serotonin transporters are located on the axons beyond the synaptic junctions.
        Brain Res. 1998; 805: 241-254