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Fortschr Neurol Psychiatr 2010; 78(6): 332-342
DOI: 10.1055/s-0029-1245250
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Serotonin Kompakt – Teil 2[*]

Verhaltensgenetik und PsychopathologieSerotonin Now: Part 2Behavioral Genetics and PsychopathologyC. Kriegebaum1 , L. Gutknecht1 , A. Schmitt1 , K.-P. Lesch1 , A. Reif1
  • 1Klinik für Psychiatrie, Psychosomatik und Psychotherapie, Universität Würzburg (Leiter: Prof. Jürgen Deckert)
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Publication History

Publication Date:
09 March 2010 (online)

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Zusammenfassung

Ein dysfunktionales Serotonin-(5-HT-)System ist sowohl an einer veränderten emotionalen Reaktion als auch einer veränderten Stress-Antwort und damit an der Ätiologie und Pathogenese verschiedener neuropsychiatrischer Erkrankungen beteiligt. Dies wird sowohl durch verhaltenspharmakologische Experimente als auch genetische Studien belegt, wobei jedoch die Einflüsse unterschiedlicher Varianten in Genen, die dem serotonergen System zuzurechnen sind, kontrovers diskutiert werden. Die Untersuchung von Knockout-Mäusen, bei denen ganz gezielt gewebs- und entwicklungsspezifisch Gene des serotonergen Systems ausgeschaltet werden, unterstreicht die wichtige Bedeutung von 5-HT während der Entwicklung und insbesondere hinsichtlich der Entstehung emotionaler Verhaltensweisen. In diesem zweiten Teil des Übersichtsartikels werden neben den tierexperimentellen Studien genetische und pharmakologische Untersuchungen, gepaart mit klinischen Studien, zusammengefasst und kritisch diskutiert. Die Datenlage belegt die komplexen Funktionen von 5-HT, das im Zentrum zahlreicher neurobiologischer Vorgänge steht und weitreichende Implikationen für menschliches Verhalten aufweist. Epigenetische Regulationsmechanismen werden in den kommenden Jahren zunehmend erforscht werden und tragen zur Komplexität des serotonergen Systems bei. Nach wie vor steht daher das 5-HT-System im Mittelpunkt aktueller Hypothesen zur Pathogenese von Erkrankungen mit dem Kernsymptom emotionaler Dysregulation.

Abstract

Several lines of evidence implicate a dysregulation of the serotonin (5-HT) system in emotional behavior and stress, and point to its relevance for the etiology and pathogenesis of various neuropsychiatric disorders. This is evidenced by behavioral pharmacology as well as genetic studies, yet the impact of genetic variation within the 5-HT system on human disorders remains controversial. The generation of tissue-specific and inducible knockout mice lacking genes belonging to the 5-HT system further established the importance of the 5-HT system for neuronal development and the regulation of emotions. This part of the review provides a summary and critical discussion of genetic, neurobiological and pharmacological studies along with recent clinical research. Together, these data underscore the complex effects of 5-HT on human behavior and psychiatric disorders. Epigenetic mechanisms add to the complexity of the 5-HT system and will be increasingly studied in the coming years. Thus, the serotonergic system still remains in the centre of current hypotheses regarding the pathogenesis of disorders with the shared feature of emotional dysregulation.

Schlüsselwörter

Verhalten - Genetik - psychiatrische Erkrankungen - Depression - Tiermodelle

Keywords

behavior - genetic - psychiatric disorders - depression - animal models

1 Die dieser Arbeit zugrundeliegenden Untersuchungen wurden durch die DFG (GK-1156, an CK und KPL, RE1632/1-5 an AR, KFO 125 an AR und KPL; SFB 581 an AS und KPL, SFB TRR 58 an AR und KPL), das BMBF (IZKF Würzburg, 01KS9603, an KPL; IZKF N-27-N, an AR) und die EU (NEWMOOD LSHM-CT-2003-503474, an KPL) gefördert.

Literatur

  • 1 Heisler L K, Chu H M, Brennan T J. et al . Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.  Proc Natl Acad Sci USA. 1998;  95 15049-15054
    Google Scholar
  • 2 Parks C L, Robinson P S, Sibille E. et al . Increased anxiety of mice lacking the serotonin1A receptor.  Proc Natl Acad Sci USA. 1998;  95 10734-10739
    Google Scholar
  • 3 Ramboz S, Oosting R, Amara D A. et al . Serotonin receptor 1A knockout: an animal model of anxiety-related disorder.  Proc Natl Acad Sci USA. 1998;  95 14476-14481
    Google Scholar
  • 4 Brunner D, Buhot M C, Hen R. et al . Anxiety, motor activation, and maternal-infant interactions in 5 HT1B knockout mice.  Behav Neurosci. 1999;  113 587-601
    Google Scholar
  • 5 Malleret G, Hen R, Guillou J L. et al . 5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze.  J Neurosci. 1999;  19 6157-6168
    Google Scholar
  • 6 Ramboz S, Saudou F, Amara D A. et al . 5-HT1B receptor knock out – behavioral consequences.  Behav Brain Res. 1996;  73 305-312
    Google Scholar
  • 7 Saudou F, Amara D A, Dierich A. et al . Enhanced aggressive behavior in mice lacking 5-HT1B receptor.  Science. 1994;  265 1875-1878
    Google Scholar
  • 8 Gaspar P, Cases O, Maroteaux L. The developmental role of serotonin: news from mouse molecular genetics.  Nat Rev Neurosci. 2003;  4 1002-1012
    Google Scholar
  • 9 Ding Y Q, Marklund U, Yuan W. et al . Lmx1b is essential for the development of serotonergic neurons.  Nat Neurosci. 2003;  6 933-938
    Google Scholar
  • 10 Ding Y Q, Yin J, Kania A. et al . Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord.  Development. 2004;  131 3693-3703
    Google Scholar
  • 11 Zhao Z Q, Scott M, Chiechio S. et al . Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity.  J Neurosci. 2006;  26 12781-12788
    Google Scholar
  • 12 Gutknecht L, Waider J, Kraft S. et al . Deficiency of brain 5-HT synthesis but serotonergic neuron formation in Tph2 knockout mice.  J Neural Transm. 2008;  115 1127-1132
    Google Scholar
  • 13 Cannon W A. Absorption of Oxygen by Roots When the Shoot Is in Darkness or in Light.  Plant Physiol. 1932;  7 673-684
    Google Scholar
  • 14 Cannon W B. Important Request.  Cal State J Med. 1914;  12 302
    Google Scholar
  • 15 Strohle A. The neuroendocrinology of stress and the pathophysiology and therapy of depression and anxiety.  Nervenarzt. 2003;  74 279-291; quiz 292
    Google Scholar
  • 16 Dagnino-Subiabre A, Orellana J A, Carmona-Fontaine C. et al . Chronic stress decreases the expression of sympathetic markers in the pineal gland and increases plasma melatonin concentration in rats.  J Neurochem. 2006;  97 1279-1287
    Google Scholar
  • 17 Nieuwenhuizen A G, Rutters F. The hypothalamic-pituitary-adrenal-axis in the regulation of energy balance.  Physiol Behav. 2008;  94 169-177
    Google Scholar
  • 18 Diaz-Marsa M, Carrasco J L, Basurte E. et al . Enhanced cortisol suppression in eating disorders with impulsive personality features.  Psychiatry Res. 2008;  158 93-97
    Google Scholar
  • 19 Junghanns K, Horbach R, Ehrenthal D. et al . Cortisol awakening response in abstinent alcohol-dependent patients as a marker of HPA-axis dysfunction.  Psychoneuroendocrinology. 2007;  32 1133-1137
    Google Scholar
  • 20 Wolfert A, Mehler P S. Osteoporosis: prevention and treatment in anorexia nervosa.  Eat Weight Disord. 2002;  7 72-81
    Google Scholar
  • 21 Deuschle M, Schweiger U, Weber B. et al . Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls.  J Clin Endocrinol Metab. 1997;  82 234-238
    Google Scholar
  • 22 Heuser I, Bissette G, Dettling M. et al . Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment.  Depress Anxiety. 1998;  8 71-79
    Google Scholar
  • 23 Nemeroff C B, Bissette G, Akil H. et al . Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin.  Br J Psychiatry. 1991;  158 59-63
    Google Scholar
  • 24 Lesch K P, Lerer B. The 5-HT receptor – G-protein – effector system complex in depression. I. Effect of glucocorticoids.  J Neural Transm Gen Sect. 1991;  84 3-18
    Google Scholar
  • 25 Lesch K P, Mayer S, Disselkamp-Tietze J. et al . 5-HT1A receptor responsivity in unipolar depression. Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls.  Biol Psychiatry. 1990;  28 620-628
    Google Scholar
  • 26 Lesch K P. 5-HT1A receptor responsivity in anxiety disorders and depression.  Prog Neuropsychopharmacol Biol Psychiatry. 1991;  15 723-733
    Google Scholar
  • 27 Lesch K P, Merschdorf U. Impulsivity, aggression, and serotonin: a molecular psychobiological perspective.  Behav Sci Law. 2000;  18 581-604
    Google Scholar
  • 28 Staner L, Mendlewicz J. [Heredity and role of serotonin in aggressive impulsive behavior].  Encephale. 1998;  24 355-364
    Google Scholar
  • 29 Bunney W E Jr, Davis J M. Norepinephrine in depressive reactions. A review.  Arch Gen Psychiatry. 1965;  13 483-494
    Google Scholar
  • 30 Schildkraut J J. The catecholamine hypothesis of affective disorders: a review of supporting evidence.  Am J Psychiatry. 1965;  122 509-522
    Google Scholar
  • 31 Coppen A. The biochemistry of affective disorders.  Br J Psychiatry. 1967;  113 1237-1264
    Google Scholar
  • 32 Scherman D, Henry J P. Reserpine binding to bovine chromaffin granule membranes. Characterization and comparison with dihydrotetrabenazine binding.  Mol Pharmacol. 1984;  25 113-122
    Google Scholar
  • 33 Maas J W. Biogenic amines and depression. Biochemical and pharmacological separation of two types of depression.  Arch Gen Psychiatry. 1975;  32 1357-1361
    Google Scholar
  • 34 Parker G. Through a glass darkly: the disutility of the DSM nosology of depressive disorders.  Can J Psychiatry. 2006;  51 879-886
    Google Scholar
  • 35 Delgado P L, Charney D S, Price L H. et al . Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan.  Arch Gen Psychiatry. 1990;  47 411-418
    Google Scholar
  • 36 Meltzer H Y. Role of serotonin in depression.  Ann N Y Acad Sci. 1990;  600 486-499; discussion 499 – 500
    Google Scholar
  • 37 Arranz B, Blennow K, Eriksson A. et al . Serotonergic, noradrenergic, and dopaminergic measures in suicide brains.  Biol Psychiatry. 1997;  41 1000-1009
    Google Scholar
  • 38 Stanley M, Mann J J, Cohen L S. Role of the serotonergic system in the postmortem analysis of suicide.  Psychopharmacol Bull. 1986;  22 735-740
    Google Scholar
  • 39 Mendels J, Frazer A. Reduced central serotonergic activity in mania: implications for the relationship between depression and mania.  Br J Psychiatry. 1975;  126 241-248
    Google Scholar
  • 40 Sambeth A, Riedel W J, Tillie D E. et al . Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink.  J Psychopharmacol. 2009;  23 56-64
    Google Scholar
  • 41 Van der Does A J. The effects of tryptophan depletion on mood and psychiatric symptoms.  J Affect Disord. 2001;  64 107-119
    Google Scholar
  • 42 Young S N, Smith S E, Pihl R O. et al . Tryptophan depletion causes a rapid lowering of mood in normal males.  Psychopharmacology (Berl). 1985;  87 173-177
    Google Scholar
  • 43 Bach-Mizrachi H, Underwood M D, Kassir S A. et al . Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide.  Neuropsychopharmacology. 2006;  31 814-824
    Google Scholar
  • 44 De Luca V, Likhodi O, Van Tol H H. et al . Gene expression of tryptophan hydroxylase 2 in post-mortem brain of suicide subjects.  Int J Neuropsychopharmacol. 2006;  9 21-25
    Google Scholar
  • 45 Lesch K P, Schmitt A. Antidepressants and gene expression profiling: how to SNARE novel drug targets.  Pharmacogenomics J. 2002;  2 346-348
    Google Scholar
  • 46 Li Q, Wichems C, Heils A. et al . Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice.  J Pharmacol Exp Ther. 1999;  291 999-1007
    Google Scholar
  • 47 Lesch K P, Aulakh C S, Wolozin B L. et al . Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants.  Brain Res Mol Brain Res. 1993;  17 31-35
    Google Scholar
  • 48 Benmansour S, Owens W A, Cecchi M. et al . Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter.  J Neurosci. 2002;  22 6766-6772
    Google Scholar
  • 49 Calcagno E, Canetta A, Guzzetti S. et al . Strain differences in basal and post-citalopram extracellular 5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity.  J Neurochem. 2007;  103 1111-1120
    Google Scholar
  • 50 Cervo L, Canetta A, Calcagno E. et al . Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression.  J Neurosci. 2005;  25 8165-8172
    Google Scholar
  • 51 Invernizzi R W. Role of TPH-2 in brain function: news from behavioral and pharmacologic studies.  J Neurosci Res. 2007;  85 3030-3035
    Google Scholar
  • 52 Mongeau R, Blier P, Montigny de C. The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments.  Brain Res Brain Res Rev. 1997;  23 145-195
    Google Scholar
  • 53 Wagner G J, Rabkin J G, Rabkin R. Dextroamphetamine as a treatment for depression and low energy in AIDS patients: a pilot study.  J Psychosom Res. 1997;  42 407-411
    Google Scholar
  • 54 Wagner G J, Rabkin R. Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial.  J Clin Psychiatry. 2000;  61 436-440
    Google Scholar
  • 55 Freitag C M, Domschke K, Rothe C. et al . Interaction of serotonergic and noradrenergic gene variants in panic disorder.  Psychiatr Genet. 2006;  16 59-65
    Google Scholar
  • 56 Szabo S T, Blier P. Serotonin (1A) receptor ligands act on norepinephrine neuron firing through excitatory amino acid and GABA(A) receptors: a microiontophoretic study in the rat locus coeruleus.  Synapse. 2001;  42 203-212
    Google Scholar
  • 57 Bradley C C, Blakely R D. Alternative splicing of the human serotonin transporter gene.  J Neurochem. 1997;  69 1356-1367
    Google Scholar
  • 58 Lesch K P, Balling U, Gross J. et al . Organization of the human serotonin transporter gene.  J Neural Transm Gen Sect. 1994;  95 157-162
    Google Scholar
  • 59 Battersby S, Ogilvie A D, Blackwood D H. et al . Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3’ untranslated region of the human serotonin transporter gene.  J Neurochem. 1999;  72 1384-1388
    Google Scholar
  • 60 Lesch K P, Bengel D, Heils A. et al . Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.  Science. 1996;  274 1527-1531
    Google Scholar
  • 61 Lesch K P, Heils A. Serotonergic gene transcriptional control regions: targets for antidepressant drug development?.  Int J Neuropsychopharmacol. 2000;  3 67-79
    Google Scholar
  • 62 Reif A, Rosler M, Freitag C M. et al . Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment.  Neuropsychopharmacology. 2007;  32 2375-2383
    Google Scholar
  • 63 Canli T, Lesch K P. Long story short: the serotonin transporter in emotion regulation and social cognition.  Nat Neurosci. 2007;  10 1103-1109
    Google Scholar
  • 64 Caspi A, McClay J, Moffitt T E. et al . Role of genotype in the cycle of violence in maltreated children.  Science. 2002;  297 851-854
    Google Scholar
  • 65 Munafo M R, Brown S M, Hariri A R. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis.  Biol Psychiatry. 2008;  63 852-857
    Google Scholar
  • 66 Risch N, Herrell R, Lehner T. et al . Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.  JAMA. 2009;  301 2462-2471
    Google Scholar
  • 67 Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis.  Mol Psychiatry. 2008;  13 131-146
    Google Scholar
  • 68 Hettema J M, Neale M C, Kendler K S. A review and meta-analysis of the genetic epidemiology of anxiety disorders.  Am J Psychiatry. 2001;  158 1568-1578
    Google Scholar
  • 69 Bremner J D, Krystal J H, Southwick S M. et al . Noradrenergic mechanisms in stress and anxiety: II. Clinical studies.  Synapse. 1996;  23 39-51
    Google Scholar
  • 70 Deckert J, Catalano M, Syagailo Y V. et al . Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder.  Hum Mol Genet. 1999;  8 621-624
    Google Scholar
  • 71 Domschke K, Deckert J, O’Donovan M C. et al . Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity.  Am J Med Genet B Neuropsychiatr Genet. 2007;  144B 667-673
    Google Scholar
  • 72 Lesch K P, Wiesmann M, Hoh A. et al . 5-HT1A receptor-effector system responsivity in panic disorder.  Psychopharmacology (Berl). 1992;  106 111-117
    Google Scholar
  • 73 Neumeister A, Bain E, Nugent A C. et al . Reduced serotonin type 1A receptor binding in panic disorder.  J Neurosci. 2004;  24 589-591
    Google Scholar
  • 74 Stahl S M. Antidepressants: the blue-chip psychotropic for the modern treatment of anxiety disorders.  J Clin Psychiatry. 1999;  60 356-357
    Google Scholar
  • 75 Lesch K P, Mossner R. Knockout Corner: 5-HT(1A) receptor inactivation: anxiety or depression as a murine experience.  Int J Neuropsychopharmacol. 1999;  2 327-331
    Google Scholar
  • 76 He M, Sibille E, Benjamin D. et al . Differential effects of 5-HT1A receptor deletion upon basal and fluoxetine-evoked 5-HT concentrations as revealed by in vivo microdialysis.  Brain Res. 2001;  902 11-17
    Google Scholar
  • 77 Richer M, Hen R, Blier P. Modification of serotonin neuron properties in mice lacking 5-HT1A receptors.  Eur J Pharmacol. 2002;  435 195-203
    Google Scholar
  • 78 Gross C, Zhuang X, Stark K. et al . Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.  Nature. 2002;  416 396-400
    Google Scholar
  • 79 Zohar J, Chopra M, Sasson Y. et al . Obsessive compulsive disorder: serotonin and beyond.  World J Biol Psychiatry. 2000;  1 92-100
    Google Scholar
  • 80 Delorme R, Betancur C, Callebert J. et al . Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder.  Neuropsychopharmacology. 2005;  30 1539-1547
    Google Scholar
  • 81 Hasselbalch S G, Hansen E S, Jakobsen T B. et al . Reduced midbrain-pons serotonin transporter binding in patients with obsessive-compulsive disorder.  Acta Psychiatr Scand. 2007;  115 388-394
    Google Scholar
  • 82 Mossner R, Walitza S, Geller F. et al . Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder.  Int J Neuropsychopharmacol. 2006;  9 437-442
    Google Scholar
  • 83 Evenden J L. Varieties of impulsivity.  Psychopharmacology (Berl). 1999;  146 348-361
    Google Scholar
  • 84 Vitiello B, Stoff D M. Subtypes of aggression and their relevance to child psychiatry.  J Am Acad Child Adolesc Psychiatry. 1997;  36 307-315
    Google Scholar
  • 85 Baumgarten H G, Grozdanovic Z. Psychopharmacology of central serotonergic systems.  Pharmacopsychiatry. 1995;  28 Suppl 2 73-79
    Google Scholar
  • 86 Baumgarten H G, Grozdanovic Z. [The role of serotonin in behavior modulation].  Fortschr Neurol Psychiatr. 1995;  63 Suppl 1 3-8
    Google Scholar
  • 87 Kulikov A V, Osipova D V, Naumenko V S. et al . Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains.  Genes Brain Behav. 2005;  4 482-485
    Google Scholar
  • 88 Popova N K, Voitenko N N, Kulikov A V. et al . Evidence for the involvement of central serotonin in mechanism of domestication of silver foxes.  Pharmacol Biochem Behav. 1991;  40 751-756
    Google Scholar
  • 89 Evrard A, Malagie I, Laporte A M. et al . Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice.  Eur J Neurosci. 2002;  15 841-851
    Google Scholar
  • 90 Brunner H G, Nelen M, Breakefield X O. et al . Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.  Science. 1993;  262 578-580
    Google Scholar
  • 91 Nilsson K W, Sjoberg R L, Wargelius H L. et al . The monoamine oxidase A (MAO-A) gene, family function and maltreatment as predictors of destructive behaviour during male adolescent alcohol consumption.  Addiction. 2007;  102 389-398
    Google Scholar
  • 92 Lappalainen J, Long J C, Eggert M. et al . Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations.  Arch Gen Psychiatry. 1998;  55 989-994
    Google Scholar
  • 93 Miczek K A, Fish E W, De Bold J F. et al . Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems.  Psychopharmacology (Berl). 2002;  163 434-458
    Google Scholar
  • 94 Spivak B, Vered Y, Yoran-Hegesh R. et al . Circulatory levels of catecholamines, serotonin and lipids in attention deficit hyperactivity disorder.  Acta Psychiatr Scand. 1999;  99 300-304
    Google Scholar
  • 95 Walitza S, Renner T J, Dempfle A. et al . Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.  Mol Psychiatry. 2005;  10 1126-1132
    Google Scholar
  • 96 Winstanley C A, Theobald D E, Dalley J W. et al . 5-HT2A and 5-HT2C receptor antagonists have opposing effects on a measure of impulsivity: interactions with global 5-HT depletion.  Psychopharmacology (Berl). 2004;  176 376-385
    Google Scholar
  • 97 Cleare A J, Bond A J. Ipsapirone challenge in aggressive men shows an inverse correlation between 5-HT1A receptor function and aggression.  Psychopharmacology (Berl). 2000;  148 344-349
    Google Scholar
  • 98 Popova N K. From genes to aggressive behavior: the role of serotonergic system.  Bioessays. 2006;  28 495-503
    Google Scholar
  • 99 Crean J, Richards J B, Wit de H. Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism.  Behav Brain Res. 2002;  136 349-357
    Google Scholar
  • 100 Walderhaug E, Landro N I, Magnusson A. A synergic effect between lowered serotonin and novel situations on impulsivity measured by CPT.  J Clin Exp Neuropsychol. 2008;  30 204-211
    Google Scholar
  • 101 Moeller F G, Dougherty D M, Swann A C. et al . Tryptophan depletion and aggressive responding in healthy males.  Psychopharmacology (Berl). 1996;  126 97-103
    Google Scholar
  • 102 Constantino J N, Morris J A, Murphy D L. CSF 5-HIAA and family history of antisocial personality disorder in newborns.  Am J Psychiatry. 1997;  154 1771-1773
    Google Scholar
  • 103 Goodman D W. The consequences of attention-deficit/hyperactivity disorder in adults.  J Psychiatr Pract. 2007;  13 318-327
    Google Scholar
  • 104 Lesch K P. Alcohol dependence and gene × environment interaction in emotion regulation: Is serotonin the link?.  Eur J Pharmacol. 2005;  526 113-124
    Google Scholar
  • 105 Piazza P V, Rouge-Pont F, Deminiere J M. et al . Dopaminergic activity is reduced in the prefrontal cortex and increased in the nucleus accumbens of rats predisposed to develop amphetamine self-administration.  Brain Res. 1991;  567 169-174
    Google Scholar
  • 106 Murphy D L, Uhl G R, Holmes A. et al . Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.  Genes Brain Behav. 2003;  2 350-364
    Google Scholar
  • 107 Sora I, Hall F S, Andrews A M. et al . Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference.  Proc Natl Acad Sci USA. 2001;  98 5300-5305
    Google Scholar
  • 108 Miller G M, Yatin S M, De La Garza R. et al . Cloning of dopamine, norepinephrine and serotonin transporters from monkey brain: relevance to cocaine sensitivity.  Brain Res Mol Brain Res. 2001;  87 124-143
    Google Scholar
  • 109 Nichols D E. Hallucinogens.  Pharmacol Ther. 2004;  101 131-181
    Google Scholar
  • 110 Belleville R E, Fraser H F, Isbell H. et al . Studies on lysergic acid diethylamide (LSD-25). I. Effects in former morphine addicts and development of tolerance during chronic intoxication.  AMA Arch Neurol Psychiatry. 1956;  76 468-478
    Google Scholar
  • 111 Cholden L S, Kurland A, Savage C. Clinical reactions and tolerance to LSD in chronic schizophrenia.  J Nerv Ment Dis. 1955;  122 211-221
    Google Scholar
  • 112 Buckholtz N S, Zhou D F, Freedman D X. et al . Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain.  Neuropsychopharmacology. 1990;  3 137-148
    Google Scholar
  • 113 Kennett G A, Wood M D, Glen A. et al . In vivo properties of SB 200646A, a 5-HT2C/ 2B receptor antagonist.  Br J Pharmacol. 1994;  111 797-802
    Google Scholar
  • 114 Heinz A, Knable M B, Weinberger D R. Dopamine D 2 receptor imaging and neuroleptic drug response.  J Clin Psychiatry. 1996;  57 (Suppl 11) 84-88; discussion 89 – 93
    Google Scholar
  • 115 Barnes N M, Sharp T. A review of central 5-HT receptors and their function.  Neuropharmacology. 1999;  38 1083-1152
    Google Scholar
  • 116 Huether G, Zhou D, Ruther E. Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ”ecstasy”) and its congeners.  J Neural Transm. 1997;  104 771-794
    Google Scholar
  • 117 Thomasius R, Zapletalova P, Petersen K. et al . Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users: the longitudinal perspective.  J Psychopharmacol. 2006;  20 211-225
    Google Scholar
  • 118 Buchert R, Thomasius R, Wilke F. et al . A voxel-based PET investigation of the long-term effects of ”Ecstasy” consumption on brain serotonin transporters.  Am J Psychiatry. 2004;  161 1181-1189
    Google Scholar
  • 119 Callahan B T, Cord B J, Ricaurte G A. Long-term impairment of anterograde axonal transport along fiber projections originating in the rostral raphe nuclei after treatment with fenfluramine or methylenedioxymethamphetamine.  Synapse. 2001;  40 113-121
    Google Scholar
  • 120 Molliver M E, Berger U V, Mamounas L A. et al . Neurotoxicity of MDMA and related compounds: anatomic studies.  Ann N Y Acad Sci. 1990;  600 649-661
    Google Scholar
  • 121 Montgomery C, Fisk J E. Ecstasy-related deficits in the updating component of executive processes.  Hum Psychopharmacol. 2008;  23 495-511
    Google Scholar
  • 122 Morgan M J. Memory deficits associated with recreational use of „ecstasy” (MDMA).  Psychopharmacology (Berl). 1999;  141 30-36
    Google Scholar
  • 123 Verdejo-Garcia A J, Lopez-Torrecillas F, Aguilar de Arcos F. et al . Differential effects of MDMA, cocaine, and cannabis use severity on distinctive components of the executive functions in polysubstance users: a multiple regression analysis.  Addict Behav. 2005;  30 89-101
    Google Scholar
  • 124 Skelton M R, Williams M T, Vorhees C V. Developmental effects of 3,4-methylenedioxymethamphetamine: a review.  Behav Pharmacol. 2008;  19 91-111
    Google Scholar

1 Die dieser Arbeit zugrundeliegenden Untersuchungen wurden durch die DFG (GK-1156, an CK und KPL, RE1632/1-5 an AR, KFO 125 an AR und KPL; SFB 581 an AS und KPL, SFB TRR 58 an AR und KPL), das BMBF (IZKF Würzburg, 01KS9603, an KPL; IZKF N-27-N, an AR) und die EU (NEWMOOD LSHM-CT-2003-503474, an KPL) gefördert.

Claudia Kriegebaum

Klinik für Psychiatrie, Psychosomatik und Psychotherapie Universität Würzburg

Füchsleinstr. 15

97080 Würzburg

Email: claudia.kriegebaum@web.de

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