Download PDF
Nervenheilkunde 2007; 26(03): 141-149
DOI: 10.1055/s-0038-1626841
Original Article
Schattauer GmbH

Rolle des zentralen dopaminergen Systems bei psychiatrischen Erkrankungen

Schizophrenie, Depression, Manie und ADHSNew insights concerning the role of the central dopaminergic system in psychiatric disordersschizophrenia, depression, mania and ADHD
B. Abler
1   Universitätsklinikum Ulm, Abteilung Psychiatrie III (Ärztlicher Direktor: Prof. Dr. Dr. M. Spitzer)
,
N. Vasic
1   Universitätsklinikum Ulm, Abteilung Psychiatrie III (Ärztlicher Direktor: Prof. Dr. Dr. M. Spitzer)
› Author Affiliations
Further Information

Publication History

Eingegangen am: 14 November 2006

angenommen am: 15 November 2006

Publication Date:
19 January 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

In verschiedenen Untersuchungen konnte bislang gezeigt werden, dass eine Dysfunktion des zentralen dopaminergen Systems bei vielen psychiatrischen Erkrankungen eine wichtige Rolle spielt, unter anderen Schizophrenie, Depression, bipolare Erkrankung und ADHS. Die daraus resultierenden neurokognitiven und psychopathologischen Funktionsveränderungen– auf motivationaler, psychomotorischer sowie exekutiver Ebene – können mittlerweile mit ihren neuroanatomischen und neurofunktionellen Korrelaten in eine direkte Verbindung gebracht werden. Im Fokus des Forschungsinteresses liegen insbesondere das ventrale und dorsale Striatum, aber auch Teile des limbischen Systems und der präfrontale Kortex. In diesem Beitrag werden aktuelle genetische, molekularbiologische und bildgebende Befunde präsentiert, die die Rolle der dopaminergen Transmission sowie der Interaktion von Dopamin mit anderen Transmittersystemen in der Pathogenese wichtiger psychiatrischer Störungen näher spezifizieren. Schwerpunktmäßig diskutiert werden solche Erkenntnisse, die für neue Therapierichtungen ausschlaggebend sein könnten.

Summary

Various previous studies show that a dysfunction of the central dopaminergic neurotransmission is involved ina series of neuropsychiatric disorders, including schizophrenia, depression, bipolar disorder and ADHD. The neurocognitive and psychopathological manifestations of central dopaminergic dysfunction – ona motivational, psychomotoric and executive level– have lately been put into a relationship with neuroanatomical and neurofunctional sites. The dorsal and ventral striatum, as well as cortical regions such as the limbic and prefrontal cortex, among other locations are in the focus of current research interests. This article presents current genetic, molecular-biologic and imaging findings, specifying the prominent role of dopaminergic transmission as well as the interaction of dopamine with other transmitters in the pathogenesis of some of the most important psychiatric disorders. We emphasize insights which might be crucial for the development of new therapeutic approaches.

Schlüsselwörter

Dopamin - Belohnungssystem - Striatum - Serotonin - psychiatrische Erkrankungen

Keywords

Dopamine - reward-system - striatum - serotonine - psychiatric disorders
 

  • Literatur

  • 1 Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002; 22: 3708-19.
    CrossrefPubMedGoogle Scholar
  • 2 Abler B, Erk S, Walter H. Das menschliche Belohnungssystem – Erkenntnisse der funktionellen Bildgebung und klinische Implikationen. Nervenheilkunde 2005; 24: 167-76.
    Article in Thieme ConnectGoogle Scholar
  • 3 Abler B, Walter H, Erk S. Neural correlates of frustration. Neuroreport 2005; 16: 669-72.
    CrossrefPubMedGoogle Scholar
  • 4 Abler B, Walter H, Erk S, Kammerer H, Spitzer M. Prediction error as a linear function of reward probability is coded in human nucleus accumbens. Neuroimage 2006; 31: 790-5.
    CrossrefPubMedGoogle Scholar
  • 5 Almasy L, Blangero J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet 2001; 105: 42-4.
    CrossrefPubMedGoogle Scholar
  • 6 Ayd F, Zohar J. Psychostimulant therapy for chronic and treatment-resistant depression. In: Zohar B. (Hrsg). Treating resistant depression. NewYork: PMA 1987.;
    Google Scholar
  • 7 Belmaker RH, Wald D. Haloperidol in normals. Br J Psychiatry 1977; 131: 222-3.
    PubMedGoogle Scholar
  • 8 Bertolino A. et al. Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. J Neurosci 2006; 26: 3918-22.
    CrossrefPubMedGoogle Scholar
  • 9 Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 2005; 57: 1215-20.
    CrossrefPubMedGoogle Scholar
  • 10 Bush G. et al. Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry 1999; 45: 1542-52.
    CrossrefPubMedGoogle Scholar
  • 11 Cardinal RN. et al. Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 2001; 292: 2499-501.
    CrossrefPubMedGoogle Scholar
  • 12 Castellanos FX, Tannock R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 2002; 03: 617-28.
    CrossrefPubMedGoogle Scholar
  • 13 Castner SA, Williams GV, Goldman-Rakic PS. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 2000; 287: 2020-2.
    CrossrefPubMedGoogle Scholar
  • 14 Chou YH, Halldin C, Farde L. Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study. Psychopharmacology (Berl) 2006; 185: 29-35.
    CrossrefPubMedGoogle Scholar
  • 15 Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481-3.
    CrossrefPubMedGoogle Scholar
  • 16 Cropley VL, Fujita M, Innis RB, Nathan PJ. Molecular imaging of the dopaminergic system and its association with human cognitive function. Biol Psychiatry 2006; 59: 898-907.
    CrossrefPubMedGoogle Scholar
  • 17 Delay J, Deniker P, Harl Grasset A. N-dimethylamino-prophylchlorophenothiazine (4560 RP) therapy of confusional states. Ann Med Psychol (Paris) 1952; 110: 398-403.
    PubMedGoogle Scholar
  • 18 Delgado MR, Stenger VA, Fiez JA. Motivationdependent responses in the human caudate nucleus. Cereb Cortex 2004; 14: 1022-30.
    CrossrefPubMedGoogle Scholar
  • 19 Dinn WM, Robbins NC, Harris CL. Adult attention-deficit/hyperactivity disorder: neuropsychological correlates and clinical presentation. Brain Cogn 2001; 46: 114-21.
    CrossrefPubMedGoogle Scholar
  • 20 Dremencov E. et al. The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 141-7.
    CrossrefPubMedGoogle Scholar
  • 21 Dremencov E. et al. Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment. Neuropharmacology 2005; 48: 34-42.
    CrossrefPubMedGoogle Scholar
  • 22 Ebert D, Lammers CH. [The central dopaminergic system and depression]. Nervenarzt 1997; 68: 545-55.
    CrossrefPubMedGoogle Scholar
  • 23 Egan MF. et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917-22.
    CrossrefPubMedGoogle Scholar
  • 24 Elliott R, Friston KJ, Dolan RJ. Dissociable neural responses in human reward systems. J Neurosci 2000; 20: 6159-65.
    CrossrefPubMedGoogle Scholar
  • 25 Ernst M. et al. High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder. Am J Psychiatry 1999; 156: 1209-15.
    PubMedGoogle Scholar
  • 26 Esposito E. Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets 2006; 07: 177-85.
    CrossrefPubMedGoogle Scholar
  • 27 Faraone SV, Doyle AE. Genetic influences on attention deficit hyperactivity disorder. Curr Psychiatry Rep 2000; 02: 143-6.
    CrossrefPubMedGoogle Scholar
  • 28 Giedd JN, Blumenthal J, Molloy E, Castellanos FX. Brain imaging of attention deficit/hyperactivity disorder. Ann NY Acad Sci 2001; 931: 33-49.
    PubMedGoogle Scholar
  • 29 Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001; 158: 1367-77.
    CrossrefPubMedGoogle Scholar
  • 30 Goldman-Rakic PS, Muly 3rd EC, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev 2000; 31: 295-301.
    CrossrefPubMedGoogle Scholar
  • 31 Greenhill LL, Halperin JM, Abikoff H. Stimulant medications. JAmAcad Child Adolesc Psychiatry 1999; 38: 503-12.
    Google Scholar
  • 32 Honey GD, Bullmore ET, Soni W, Varatheesan M, Williams SC, Sharma T. Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci USA 1999; 96: 13432-7.
    CrossrefPubMedGoogle Scholar
  • 33 Hough CJ, Ursano RJ. A guide to the genetics of psychiatric disease. Psychiatry 2006; 69: 1-20.
    CrossrefPubMedGoogle Scholar
  • 34 Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001; 76: 1521-31.
    CrossrefPubMedGoogle Scholar
  • 35 Iyer RN, Bradberry CW. Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. J Pharmacol Exp Ther 1996; 277: 40-7.
    PubMedGoogle Scholar
  • 36 Juckel G. et al. Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics. Psychopharmacology (Berl) 2006; 187: 222-8.
    CrossrefPubMedGoogle Scholar
  • 37 Juckel G. et al. Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 2006; 29: 409-16.
    CrossrefPubMedGoogle Scholar
  • 38 Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003; 160: 13-23.
    CrossrefPubMedGoogle Scholar
  • 39 Kapur S, Mann JJ. Role of the dopaminergic system in depression. Biol Psychiatry 1992; 32: 1-17.
    CrossrefPubMedGoogle Scholar
  • 40 Karl T, Duffy L, O’Brien E, Matsumoto I, Dedova I. Behavioural effects of chronic haloperidol and risperidone treatment in rats. Behav Brain Res 2006; 171: 286-94.
    CrossrefPubMedGoogle Scholar
  • 41 Kienast T, Heinz A. Dopamine and the diseased brain. CNS Neurol Disord Drug Targets 2006; 05: 109-31.
    CrossrefPubMedGoogle Scholar
  • 42 Kirsch P, Schienle A, Stark R, Sammer G, Blecker C, Walter B, Ott U, Burkart J, Vaitl D. Anticipation of reward in a non-aversive differential conditioning paradigm and the brain reward system: an event-related fMRI study. Neuroimage 2003; 20: 1086-95.
    CrossrefPubMedGoogle Scholar
  • 43 Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport 2001; 12: 3683-7.
    CrossrefPubMedGoogle Scholar
  • 44 Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K. Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography. Neurosci Lett 2000; 285: 107-10.
    CrossrefPubMedGoogle Scholar
  • 45 Krystal JH. et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199-214.
    PubMedGoogle Scholar
  • 46 Lammers CH, Diaz J, Schwartz JC, Sokoloff P. Dopamine D3 receptor gene expression in the shell of nucleus accumbens is increased by chronic antidepressant treatment. Mol Psychiatry 2000; 05: 229.
    CrossrefPubMedGoogle Scholar
  • 47 Martinot M. et al. Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry 2001; 158: 314-6.
    CrossrefPubMedGoogle Scholar
  • 48 Mayeux R. Depression in the patient with Parkinson’s disease. J Clin Psychiatry 1990; 51 Suppl: 20-3 discussion 24–5..
    PubMedGoogle Scholar
  • 49 McClure SM, Berns GS, Montague PR. Temporal prediction errors in a passive learning task activate human striatum. Neuron 2003; 38: 339-46.
    CrossrefPubMedGoogle Scholar
  • 50 Mehta MA, Riedel WJ. Dopaminergic enhancement of cognitive function. Curr Pharm Des 2006; 12: 2487-500.
    CrossrefPubMedGoogle Scholar
  • 51 Mehta MA, Sahakian BJ, McKenna PJ, Robbins TW. Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease. Psychopharmacology (Berl) 1999; 146: 162-74.
    CrossrefPubMedGoogle Scholar
  • 52 Narendran R. et al. Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry 2005; 162: 2352-9.
    CrossrefPubMedGoogle Scholar
  • 53 Nestler EJ, Carlezon Jr. WA. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006; 59: 1151-9.
    CrossrefPubMedGoogle Scholar
  • 54 Nolen WA. Dopamine and mania. The effects of trans- and cis-clopenthixol in a double-blind pilot study.J Affect Disord 1983; 05: 91-6.
    Google Scholar
  • 55 Olijslagers JE, Werkman TR, McCreary AC, Siarey R, Kruse CG, Wadman WJ. 5-HT2 receptors differentially modulate dopamine-mediated autoinhibition in A9 and A10 midbrain areas of the rat. Neuropharmacology 2004; 46: 504-10.
    CrossrefPubMedGoogle Scholar
  • 56 Papp M, Klimek V, Willner P. Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine. Psychopharmacology 1994; 112: 110-14.
    Google Scholar
  • 57 Perlis RH, Welge JA, Vornik LA, Hirschfeld RM, Keck Jr. PE. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2006; 67: 509-16.
    CrossrefPubMedGoogle Scholar
  • 58 Sesack SR, Carr DB. Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 2002; 77: 513-7.
    CrossrefPubMedGoogle Scholar
  • 59 Sonuga-Barke EJ. Psychological heterogeneity in AD/HD –a dual pathway model of behaviour and cognition. Behav Brain Res 2002; 130: 29-36.
    CrossrefPubMedGoogle Scholar
  • 60 Spitzer M. A cognitive neuroscience view of schizophrenic thought disorder. Schizophrenia Bulletin 1997; 23: 29-50.
    CrossrefPubMedGoogle Scholar
  • 61 Swanson JM. et al. Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD):a family-based approach. Mol Psychiatry 1998; 03: 38-41.
    CrossrefPubMedGoogle Scholar
  • 62 Teicher MH, Anderson CM, Polcari A, Glod CA, Maas LC, Renshaw PF. Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry. Nat Med 2000; 06: 470-3.
    CrossrefPubMedGoogle Scholar
  • 63 Tremblay LK, Naranjo CA, Cardenas L, Herrmann N, Busto UE. Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine. Arch Gen Psychiatry 2002; 59: 409-16.
    CrossrefPubMedGoogle Scholar
  • 64 Tremblay LK. et al. Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry 2005; 62: 1228-36.
    CrossrefPubMedGoogle Scholar
  • 65 Volkow ND, Wang GJ, Fowler JS, Ding YS. Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1410-5.
    CrossrefPubMedGoogle Scholar
  • 66 Volkow ND. et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998; 155: 1325-31.
    CrossrefPubMedGoogle Scholar
  • 67 Volkow ND. et al. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry 2004; 161: 1173-80.
    CrossrefPubMedGoogle Scholar
  • 68 Waldman ID. et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 1998; 63: 1767-76.
    CrossrefPubMedGoogle Scholar
  • 69 Weinberger DR. et al. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001; 50: 825-44.
    CrossrefPubMedGoogle Scholar
  • 70 Wells BG, Marken PA. Bromocriptine in treatment of depression. Dicp 1989; 23: 600-2.
    CrossrefPubMedGoogle Scholar
  • 71 Werkman TR, Glennon JC, Wadman WJ, McCreary AC. Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol Disord Drug Targets 2006; 05: 3-23.
    Google Scholar
  • 72 Willner P, Muscat R, Papp M. Chronic mild stressinduced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 1992; 16: 525-34.
    CrossrefPubMedGoogle Scholar
  • 73 Winstanley CA. et al. Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology (Berl) 2003; 167: 304-14.
    CrossrefPubMedGoogle Scholar
  • 74 Yatham LN. et al. PET study of the effects of valproate on dopamine D(2) receptors in neuroleptic- and mood-stabilizer-naive patients with nonpsychotic mania. Am J Psychiatry 2002; 159: 1718-23.
    CrossrefPubMedGoogle Scholar
  • 75 Yatham LN. et al. PET study of [(18)F]6-fluoro- L-dopa uptake in neurolepticand mood-stabilizer-naive first-episode nonpsychotic mania: effects of treatment with divalproex sodium. Am J Psychiatry 2002; 159: 768-74.
    CrossrefPubMedGoogle Scholar
  • 76 Zink CF. et al. Human striatal responses to monetary reward depend on saliency. Neuron 2004; 42: 509-17.
    CrossrefPubMedGoogle Scholar
  • 77 Zink CF. et al. Human striatal response to salient nonrewarding stimuli. J Neurosci 2003; 23: 8092-7.
    CrossrefPubMedGoogle Scholar