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The Impact of Genetic Polymorphisms on Neuroreceptor Binding: Results from PET and SPECT Neuroreceptor Imaging Studies

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PET and SPECT of Neurobiological Systems

Abstract

Major psychiatric disorders are highly heritable. Nevertheless, more than three decades of candidate gene studies and genome-wide association studies have yielded few, if any, unambiguous and replicable results that would be strong enough as to direct research toward new pharmacological targets. This is in part due to the complex non-Mendelian inheritance patterns and difficult-to-define phenotypes of psychiatric disorders. In addition, the relationship between genetic risk and phenotypic expression is blurred by the strong contribution of environmental factors and epigenetic modification. A research strategy that has successfully been pursued over the last years with magnetic resonance-based methods is imaging of endophenotypes. However, these techniques have the drawback that their results are not easily transferable to a molecular level potentially accessible to therapeutic drugs. Neuroreceptor imaging methods such as positron emission tomography (PET) and single photon emission computer tomography (SPECT) make it possible to explore the impact of genetic variation on neuroreceptor binding and function of transporters and other molecules that play a central role in neuropsychiatric disorders, besides certain aspects of molecules that play a central role in our understanding and treatment of psychiatric disorders. This chapter tries to cover the current state of knowledge about the impact of genetic variation on the behavior of PET and SPECT radioligands in the living human brain.

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References

  • Abi-Dargham A, Gil R, Krystal J et al (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155(6):761–767

    CAS  PubMed  Google Scholar 

  • Abi-Dargham A, Rodenhiser J, Printz D et al (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 97(14):8104–8109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M (2009) Baseline and amphetamine-stimulated dopamine activity are related in drug-naive schizophrenic subjects. Biol Psychiatry 65(12):1091–1093

    Article  CAS  PubMed  Google Scholar 

  • Akimova E, Lanzenberger R, Kasper S (2009) The serotonin-1A receptor in anxiety disorders. Biol Psychiatry 66(7):627–635

    Article  CAS  PubMed  Google Scholar 

  • Albert PR, Zhou QY, Van Tol HH, Bunzow JR, Civelli O (1990) Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene. J Biol Chem 265(10):5825–5832

    Article  CAS  PubMed  Google Scholar 

  • Alex KD, Yavanian GJ, McFarlane HG et al (2005) Modulation of dopamine release by striatal 5-HT2C receptors. Synapse 55(4):242–251

    Article  CAS  PubMed  Google Scholar 

  • Alia-Klein N, Goldstein RZ, Kriplani A et al (2008) Brain monoamine oxidase A activity predicts trait aggression. J Neurosci 28(19):5099–5104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anguelova M, Benkelfat C, Turecki G (2003) A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry 8(7):646–653

    Article  CAS  PubMed  Google Scholar 

  • Anholt RR, Pedersen PL, De Souza EB, Snyder SH (1986) The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem 261(2):576–583

    Article  CAS  PubMed  Google Scholar 

  • Bailer UF, Frank GK, Henry SE et al (2005) Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635. Arch Gen Psychiatry 62(9):1032–1041

    Article  CAS  PubMed  Google Scholar 

  • Bailer UF, Frank GK, Henry SE et al (2007) Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa. Biol Psychiatry 61(9):1090–1099

    Article  CAS  PubMed  Google Scholar 

  • Baldinger P, Hahn A, Mitterhauser M et al (2014) Impact of COMT genotype on serotonin-1A receptor binding investigated with PET. Brain Struct Funct 219(6):2017–2028

    Article  CAS  PubMed  Google Scholar 

  • Bel N, Artigas F (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur J Pharmacol 229(1):101–103

    Article  CAS  PubMed  Google Scholar 

  • Bergstrom M, Westerberg G, Langstrom B (1997) 11C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies. Nucl Med Biol 24(4):287–293

    Article  CAS  PubMed  Google Scholar 

  • Bertolino A, Taurisano P, Pisciotta NM et al (2010) Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance. PLoS One 5(2):e9348

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bondy B, Buettner A, Zill P (2006) Genetics of suicide. Mol Psychiatry 11(4):336–351

    Article  CAS  PubMed  Google Scholar 

  • Borg J, Henningsson S, Saijo T et al (2009) Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans. Int J Neuropsychopharmacol 12(6):783–792

    Article  CAS  PubMed  Google Scholar 

  • Bose SK, Turkheimer FE, Howes OD et al (2008) Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging. Schizophr Res 106(2–3):148–155

    Article  PubMed  Google Scholar 

  • Breier A, Su TP, Saunders R et al (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 94(6):2569–2574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brody AL, Mandelkern MA, Olmstead RE et al (2006) Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch Gen Psychiatry 63(7):808–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunner HG, Nelen MR, van Zandvoort P et al (1993) X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet 52(6):1032–1039

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brunoni AR, Lopes M, Fregni F (2008) A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 11(8):1169–1180

    Article  CAS  PubMed  Google Scholar 

  • Buchert R, Schulze O, Wilke F et al (2006) Is correction for age necessary in SPECT or PET of the central serotonin transporter in young, healthy adults? J Nucl Med 47(1):38–42

    CAS  PubMed  Google Scholar 

  • Burghardt PR, Love TM, Stohler CS et al (2012) Leptin regulates dopamine responses to sustained stress in humans. J Neurosci 32(44):15369–15376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cagnin A, Rossor M, Sampson EL, Mackinnon T, Banati RB (2004) In vivo detection of microglial activation in frontotemporal dementia. Ann Neurol 56(6):894–897

    Article  PubMed  Google Scholar 

  • Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE (2010) Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167(5):509–527

    Article  PubMed  PubMed Central  Google Scholar 

  • Caspi A, McClay J, Moffitt TE et al (2002) Role of genotype in the cycle of violence in maltreated children. Science 297(5582):851–854

    Article  CAS  PubMed  Google Scholar 

  • Caspi A, Sugden K, Moffitt TE et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–389

    Article  CAS  PubMed  Google Scholar 

  • Castaneda TR, de Prado BM, Prieto D, Mora F (2004) Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light. J Pineal Res 36(3):177–185

    Article  CAS  PubMed  Google Scholar 

  • Castren E (2004) Neurotrophic effects of antidepressant drugs. Curr Opin Pharmacol 4(1):58–64

    Article  CAS  PubMed  Google Scholar 

  • Ceravolo R, Piccini P, Bailey DL et al (2002) 18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson’s disease. Synapse 43(3):201–207

    Article  CAS  PubMed  Google Scholar 

  • Cheon KA, Ryu YH, Kim JW, Cho DY (2005) The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. Eur Neuropsychopharmacol 15(1):95–101

    Article  CAS  PubMed  Google Scholar 

  • Christian BT, Wooten DW, Hillmer AT et al (2013) Serotonin transporter genotype affects serotonin 5-HT1A binding in primates. J Neurosci 33(6):2512–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciliax BJ, Drash GW, Staley JK et al (1999) Immunocytochemical localization of the dopamine transporter in human brain. J Comp Neurol 409(1):38–56

    Article  CAS  PubMed  Google Scholar 

  • Collier DA, Stober G, Li T et al (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1(6):453–460

    CAS  PubMed  Google Scholar 

  • Costa A, Riedel M, Muller U, Moller HJ, Ettinger U (2011) Relationship between SLC6A3 genotype and striatal dopamine transporter availability: a meta-analysis of human single photon emission computed tomography studies. Synapse 65(10):998–1005

    Article  CAS  PubMed  Google Scholar 

  • Cumming P (2009) Imaging dopamine. Cambridge University Press, New York

    Book  Google Scholar 

  • David SP, Murthy NV, Rabiner EA et al (2005) A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 25(10):2586–2590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Almeida J, Mengod G (2008) Serotonin 1A receptors in human and monkey prefrontal cortex are mainly expressed in pyramidal neurons and in a GABAergic interneuron subpopulation: implications for schizophrenia and its treatment. J Neurochem 107(2):488–496

    Article  PubMed  CAS  Google Scholar 

  • Debruyne JC, Van Laere KJ, Versijpt J et al (2002) Semiquantification of the peripheral-type benzodiazepine ligand [11C]PK11195 in normal human brain and application in multiple sclerosis patients. Acta Neurol Belg 102(3):127–135

    PubMed  Google Scholar 

  • Domino EF, Evans CL, Ni L et al (2010) Tobacco smoking produces greater striatal dopamine release in G-allele carriers with mu opioid receptor A118G polymorphism. Prog Neuro-Psychopharmacol Biol Psychiatry 38(2):236–240

    Article  CAS  Google Scholar 

  • Domino EF, Evans CL, Ni L et al (2012) Tobacco smoking produces greater striatal dopamine release in G-allele carriers with mu opioid receptor A118G polymorphism. Prog Neuro-Psychopharmacol Biol Psychiatry 38(2):236–240

    Article  CAS  Google Scholar 

  • Drago A, Ronchi DD, Serretti A (2008) 5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. Int J Neuropsychopharmacol 11(5):701–721

    Article  CAS  PubMed  Google Scholar 

  • Drevets WC, Frank E, Price JC et al (1999) PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46(10):1375–1387

    Article  CAS  PubMed  Google Scholar 

  • Drevets WC, Frank E, Price JC et al (2000) Serotonin type-1A receptor imaging in depression. Nucl Med Biol 27(5):499–507

    Article  CAS  PubMed  Google Scholar 

  • Drevets WC, Thase ME, Moses-Kolko EL et al (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 34(7):865–877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drgon T, Lin Z, Wang GJ et al (2006) Common human 5′ dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol 26(4–6):875–889

    CAS  PubMed  Google Scholar 

  • Edison P, Archer HA, Gerhard A et al (2008) Microglia, amyloid, and cognition in Alzheimer’s disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis 32(3):412–419

    Article  CAS  PubMed  Google Scholar 

  • Egan MF, Kojima M, Callicott JH et al (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2):257–269

    Article  CAS  PubMed  Google Scholar 

  • Eisenberg DP, Kohn PD, Baller EB et al (2010) Seasonal effects on human striatal presynaptic dopamine synthesis. J Neurosci 30(44):14691–14694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Emamian ES, Hall D, Birnbaum MJ et al (2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36:131–137

    Article  CAS  PubMed  Google Scholar 

  • Fargin A, Raymond JR, Regan JW et al (1989) Effector coupling mechanisms of the cloned 5-HT1A receptor. J Biol Chem 264(25):14848–14852

    Article  CAS  PubMed  Google Scholar 

  • Featherstone RE, Tatard-Leitman VM, Suh JD et al (2013) Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression. Psychopharmacology 227:639–649

    Article  CAS  PubMed  Google Scholar 

  • Fergusson DM, Boden JM, Horwood LJ, Miller AL, Kennedy MA (2011) MAOA, abuse exposure and antisocial behaviour: 30-year longitudinal study. Br J Psychiatry 198(6):457–463

    Article  PubMed  PubMed Central  Google Scholar 

  • Fisher PM, Holst KK, Adamsen D et al (2015) BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels. Hum Brain Mapp 36:313–323

    Article  PubMed  Google Scholar 

  • Fisher PM, Holst KK, Mc Mahon B et al (2012) 5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [(11)C]SB207145 PET in humans. NeuroImage 62(1):130–136

    Article  CAS  PubMed  Google Scholar 

  • Fisher PM, Ozenne B, Svarer C et al (2017) BDNF val66met association with serotonin transporter binding in healthy humans. Transl Psychiatry 7(2):e1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fowler JS, Alia-Klein N, Kriplani A et al (2007) Evidence that brain MAO A activity does not correspond to MAO A genotype in healthy male subjects. Biol Psychiatry 62(4):355–358

    Article  CAS  PubMed  Google Scholar 

  • Frankle WG, Huang Y, Hwang DR et al (2004) Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans. J Nucl Med 45(4):682–694

    CAS  PubMed  Google Scholar 

  • Frankle WG, Lombardo I, Kegeles LS et al (2006) Serotonin 1A receptor availability in patients with schizophrenia and schizo-affective disorder: a positron emission tomography imaging study with [11C]WAY 100635. Psychopharmacology 189(2):155–164

    Article  CAS  PubMed  Google Scholar 

  • Freund TF, Gulyas AI, Acsady L, Gorcs T, Toth K (1990) Serotonergic control of the hippocampus via local inhibitory interneurons. Proc Natl Acad Sci U S A 87(21):8501–8505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujita M, Imaizumi M, Zoghbi SS et al (2008) Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. NeuroImage 40(1):43–52

    Article  PubMed  Google Scholar 

  • Ginovart N, Meyer JH, Boovariwala A et al (2006) Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain. J Cereb Blood Flow Metab 26(3):330–344

    Article  CAS  PubMed  Google Scholar 

  • Gogos JA, Morgan M, Luine V et al (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A 95(17):9991–9996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gratacos M, Gonzalez JR, Mercader JM et al (2007) Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry 61(7):911–922

    Article  CAS  PubMed  Google Scholar 

  • Greenberg BD, Tolliver TJ, Huang SJ et al (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88(1):83–87

    Article  CAS  PubMed  Google Scholar 

  • Grunblatt E, Loffler C, Zehetmayer S et al (2006) Association study of the 5-HTTLPR polymorphism and depression in 75-year-old nondemented subjects from the Vienna transdanube aging (VITA) study. J Clin Psychiatry 67(9):1373–1378

    Article  PubMed  Google Scholar 

  • Guo N, Hwang DR, Lo ES et al (2003) Dopamine depletion and in vivo binding of PET D1 receptor radioligands: implications for imaging studies in schizophrenia. Neuropsychopharmacology 28(9):1703–1711

    Article  CAS  PubMed  Google Scholar 

  • Hariri AR, Goldberg TE, Mattay VS et al (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23(17):6690–6694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hariri AR, Holmes A (2006) Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 10(4):182–191

    Article  PubMed  Google Scholar 

  • Hariri AR, Mattay VS, Tessitore A et al (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297(5580):400–403

    Article  CAS  PubMed  Google Scholar 

  • Heils A, Teufel A, Petri S et al (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66(6):2621–2624

    Article  CAS  PubMed  Google Scholar 

  • Heinz A, Goldman D, Jones DW et al (2000a) Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 22(2):133–139

    Article  CAS  PubMed  Google Scholar 

  • Heinz A, Jones DW, Mazzanti C et al (2000b) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47(7):643–649

    Article  CAS  PubMed  Google Scholar 

  • Henningsson S, Borg J, Lundberg J et al (2009) Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men. Biol Psychiatry 66(5):477–485

    Article  CAS  PubMed  Google Scholar 

  • Hernaus D, Collip D, Lataster J et al (2013) COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge. PLoS One 8(6):e65662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hietala J, Syvalahti E, Vilkman H et al (1999) Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophr Res 35(1):41–50

    Article  CAS  PubMed  Google Scholar 

  • Hietala J, Syvalahti E, Vuorio K et al (1995) Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346(8983):1130–1131

    Article  CAS  PubMed  Google Scholar 

  • Hirvonen J, Karlsson H, Kajander J et al (2008) Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int J Neuropsychopharmacol 11(4):465–476

    Article  CAS  PubMed  Google Scholar 

  • Hirvonen M, Laakso A, Nagren K et al (2004) C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal DRD2 availability in vivo. Mol Psychiatry 9(12):1060–1061

    Article  CAS  PubMed  Google Scholar 

  • Hirvonen MM, Laakso A, Nagren K et al (2009) C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity. Synapse 63(10):907–912

    Article  CAS  PubMed  Google Scholar 

  • Homberg JR, Lesch KP (2010) Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry 69(6):513–519

    Article  PubMed  CAS  Google Scholar 

  • Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA (2000) Imaging the serotonin transporter with positron emission tomography: initial human studies with [C-11]DAPP and [C-11]DASB. Eur J Nucl Med 27(11):1719–1722

    Article  CAS  PubMed  Google Scholar 

  • Howes OD, Kambeitz J, Kim E et al (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69(8):776–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang TY, Hwang DR, Narendran R et al (2002) Comparative evaluation in nonhuman primates of five PET radiotracers for imaging the serotonin transporters: [C-11]McN 5652, [C-11]ADAM, [C-11]DASB, [C-11]DAPA, and [C-11]AFM. J Cereb Blood Flow Metab 22(11):1377–1398

    Article  CAS  PubMed  Google Scholar 

  • Ira E, Zanoni M, Ruggeri M, Dazzan P, Tosato S (2013) COMT, neuropsychological function and brain structure in schizophrenia: a systematic review and neurobiological interpretation. J Psychiatry Neurosci 38(3):120178

    Google Scholar 

  • Ito H, Halldin C, Farde L (1999) Localization of 5-HT1A receptors in the living human brain using [carbonyl-11C]WAY-100635: PET with anatomic standardization technique. J Nucl Med 40(1):102–109

    CAS  PubMed  Google Scholar 

  • Jacobsen LK, Staley JK, Zoghbi S et al (2000) Prediction of dopamine transporter binding availability by genotype: a preliminary report. Am J Psychiatry 157(10):1700–1703

    Article  CAS  PubMed  Google Scholar 

  • Jennings KA, Licht CL, Bruce A et al (2011) Genetic variation in 5-hydroxytryptamine transporter expression causes adaptive changes in 5-HT(4) receptor levels. Int J Neuropsychopharmacol 15(8):1099–1107

    Article  PubMed  CAS  Google Scholar 

  • Jennings KA, Loder MK, Sheward WJ et al (2006) Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission. J Neurosci 26(35):8955–8964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johansson C, Willeit M, Levitan R et al (2003) The serotonin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality. Psychol Med 33(5):785–792

    Article  CAS  PubMed  Google Scholar 

  • Jones KR, Reichardt LF (1990) Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci U S A 87(20):8060–8064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonsson EG, Nothen MM, Grunhage F et al (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4(3):290–296

    Article  CAS  PubMed  Google Scholar 

  • Jönsson EG, Nöthen MM, Grünhage F et al (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4:290–296

    Article  PubMed  Google Scholar 

  • Joutsa J, Hirvonen MM, Arponen E et al (2014) DRD2-related TaqIA genotype is associated with dopamine release during a gambling task. J Addict Med 8(4):294–295

    Article  PubMed  Google Scholar 

  • Kalbitzer J, Erritzoe D, Holst KK et al (2010) Seasonal changes in brain serotonin transporter binding in short serotonin transporter linked polymorphic region-allele carriers but not in long-allele homozygotes. Biol Psychiatry 67(11):1033–1039

    Article  CAS  PubMed  Google Scholar 

  • Kalbitzer J, Frokjaer VG, Erritzoe D et al (2009) The personality trait openness is related to cerebral 5-HTT levels. NeuroImage 45(2):280–285

    Article  PubMed  Google Scholar 

  • Kalgutkar AS, Dalvie DK, Castagnoli N Jr, Taylor TJ (2001) Interactions of nitrogen-containing xenobiotics with monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and inhibitors. Chem Res Toxicol 14(9):1139–1162

    Article  CAS  PubMed  Google Scholar 

  • Kapur S, Phillips AG, Insel TR (2012) Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry 17(12):1174–1179

    Article  CAS  PubMed  Google Scholar 

  • Karg K, Burmeister M, Shedden K, Sen S (2011) The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry 68(5):444–454

    Article  PubMed  PubMed Central  Google Scholar 

  • Kasparbauer AM, Rujescu D, Riedel M et al (2015) Methylphenidate effects on brain activity as a function of SLC6A3 genotype and striatal dopamine transporter availability. Neuropsychopharmacology 40(3):736–745

    Article  CAS  PubMed  Google Scholar 

  • Kauppila E, Vanninen E, Kaurijoki S et al (2013) Influence of serotonin transporter gene polymorphism (5-HTTLPR polymorphism) on the relation between brain 5-HT transporter binding and heart rate corrected cardiac repolarization interval. PLoS One 8(1):e50303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kautzky A, James GM, Phillipe C et al (2017) The influence of the rs6295 gene polymorphism on serotonin-1A receptor distribution investigated with PET in patients with major depression applying machine learning. Transl Psychiatry 7:e1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kautzky A, James GM, Phillipe C et al (2019) Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression. Transl Psychiatry 9(1):5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kegeles LS, Abi-Dargham A, Frankle WG et al (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67(3):231–239

    Article  CAS  PubMed  Google Scholar 

  • Kishi T, Yoshimura R, Fukuo Y et al (2012) The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder. Eur Arch Psychiatry Clin Neurosci 263(2):105–118

    Article  PubMed  Google Scholar 

  • Klein AB, Trajkovska V, Erritzoe D et al (2010) Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels. J Cereb Blood Flow Metab 30(11):e1–e7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kraft JB, Slager SL, McGrath PJ, Hamilton SP (2005) Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry 58(5):374–381

    Article  CAS  PubMed  Google Scholar 

  • Kraus C, Baldinger P, Rami-Mark C et al (2014) Exploring the Impact of BDNF Val66Met Genotype on Serotonin Transporter and Serotonin-1A Receptor Binding. PLoS One 9(9):e106810

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Krause J, Dresel SH, Krause KH et al (2006) Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: No higher DAT availability in patients with homozygosity for the 10-repeat allele. World J Biol Psychiatry 7(3):152–157

    Article  PubMed  Google Scholar 

  • Kreisl WC, Fujita M, Fujimura Y et al (2009) Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage 49(4):2924–2932

    Article  PubMed  CAS  Google Scholar 

  • Kreisl WC, Jenko KJ, Hines CS et al (2012) A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab 33(1):53–58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kumakura Y, Cumming P, Vernaleken I et al (2007) Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study. J Neurosci 27(30):8080–8087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunugi H, Hattori M, Kato T et al (1997) Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 2(6):457–462

    Article  CAS  PubMed  Google Scholar 

  • Laakso A, Pohjalainen T, Bergman J et al (2005) The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects. Pharmacogenet Genomics 15(6):387–391

    Article  CAS  PubMed  Google Scholar 

  • Lachman HM, Morrow B, Shprintzen R et al (1996) Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 67(5):468–472

    Article  CAS  PubMed  Google Scholar 

  • Lafuente A, Bernardo M, Mas S et al (2007) Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr Res 90(1–3):115–122

    Article  PubMed  Google Scholar 

  • Laine TP, Ahonen A, Rasanen P et al (2001) The A1 allele of the D2 dopamine receptor gene is associated with high dopamine transporter density in detoxified alcoholics. Alcohol Alcohol 36(3):262–265

    Article  CAS  PubMed  Google Scholar 

  • Laje G, Cannon DM, Allen AS et al (2010) Genetic variation in HTR2A influences serotonin transporter binding potential as measured using PET and [11C]DASB. Int J Neuropsychopharmacol 13(6):715–724

    Article  CAS  PubMed  Google Scholar 

  • Lanzenberger R, Baldinger P, Hahn A et al (2012a) Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET. Mol Psychiatry 18(1):93–100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lanzenberger R, Mitterhauser M, Hahn A et al (2012b) Molecular imaging genetics of the serotonin-1A receptor investigating the common rs6295 single nucleotide polymorphism. J Cereb Blood Flow Metab 32(Suppl 1):S85

    Google Scholar 

  • Lanzenberger RR, Mitterhauser M, Spindelegger C et al (2007) Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 61(9):1081–1089

    Article  CAS  PubMed  Google Scholar 

  • Laruelle M, Abi-Dargham A, van Dyck CH et al (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93(17):9235–9240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laruelle M, Gelernter J, Innis RB (1998) D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene. Mol Psychiatry 3(3):261–265

    Article  CAS  PubMed  Google Scholar 

  • Le Francois B, Czesak M, Steubl D, Albert PR (2008) Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 55(6):977–985

    Article  PubMed  CAS  Google Scholar 

  • Lee M, Bailer UF, Frank GK et al (2005) Relationship of a 5-HT transporter functional polymorphism to 5-HT1A receptor binding in healthy women. Mol Psychiatry 10(8):715–716

    Article  CAS  PubMed  Google Scholar 

  • Lesch KP, Bengel D, Heils A et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274(5292):1527–1531

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Melchitzky DS, Sesack SR et al (2001) Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 432(1):119–136

    Article  CAS  PubMed  Google Scholar 

  • Li YC, Yang SS, Gao WJ (2016) Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex. Neuropharmacology 108:403–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Licht CL, Marcussen AB, Wegener G et al (2009) The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration. J Neurochem 109(5):1363–1374

    Article  CAS  PubMed  Google Scholar 

  • Lindstrom LH, Gefvert O, Hagberg G et al (1999) Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET. Biol Psychiatry 46(5):681–688

    Article  CAS  PubMed  Google Scholar 

  • Lothe A, Boni C, Costes N et al (2009) Association between triallelic polymorphism of the serotonin transporter and [F-18] MPPF binding potential at 5-HT1A receptors in healthy subjects. NeuroImage 47(2):482–492

    Article  PubMed  Google Scholar 

  • Love TM, Enoch MA, Hodgkinson CA et al (2012) Oxytocin gene polymorphisms influence human dopaminergic function in a sex-dependent manner. Biol Psychiatry 72(3):198–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lynch DR, Mozley PD, Sokol S et al (2003) Lack of effect of polymorphisms in dopamine metabolism related genes on imaging of TRODAT-1 in striatum of asymptomatic volunteers and patients with Parkinson’s disease. Mov Disord 18(7):804–812

    Article  PubMed  Google Scholar 

  • MacGregor RR, Halldin C, Fowler JS et al (1985) Selective, irreversible in vivo binding of [11C]clorgyline and [11C]-L-deprenyl in mice: potential for measurement of functional monoamine oxidase activity in brain using positron emission tomography. Biochem Pharmacol 34(17):3207–3210

    Article  CAS  PubMed  Google Scholar 

  • Maisonpierre PC, Le Beau MM, Espinosa R 3rd et al (1991) Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10(3):558–568

    Article  CAS  PubMed  Google Scholar 

  • Malhotra AK, Goldman D, Mazzanti C et al (1998) A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol Psychiatry 3(4):328–332

    Article  CAS  PubMed  Google Scholar 

  • Malison RT, Price LH, Berman R 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(11):1090–1098

    Article  CAS  PubMed  Google Scholar 

  • Marner L, Gillings N, Comley RA et al (2009) Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo. J Nucl Med 50(6):900–908

    Article  CAS  PubMed  Google Scholar 

  • Marner L, Gillings N, Madsen K et al (2010) Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET. NeuroImage 50(3):855–861

    Article  CAS  PubMed  Google Scholar 

  • Martinez D, Gelernter J, Abi-Dargham A et al (2001) The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 24(5):553–560

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Weickert CS, Akil M et al (2003) Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116(1):127–137

    Article  CAS  PubMed  Google Scholar 

  • Maynard KR, Hill JL, Calcaterra NE et al (2016) Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling. Neuropsychopharmacology 41(8):1943–1955

    Article  CAS  PubMed  Google Scholar 

  • McGowan S, Lawrence AD, Sales T, Quested D, Grasby P (2004) Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. Arch Gen Psychiatry 61(2):134–142

    Article  PubMed  Google Scholar 

  • McMahon FJ, Buervenich S, Charney D et al (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78(5):804–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meltzer CC, Price JC, Mathis CA et al (2004) Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology 29(12):2258–2265

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH (2007) Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 32(2):86–102

    PubMed  PubMed Central  Google Scholar 

  • Meyer JH, Ginovart N, Boovariwala A et al (2006) Elevated monoamine oxidase A levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63(11):1209–1216

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH, Houle S, Sagrati S et al (2004) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography – effects of major depression episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61(12):1271–1279

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Lindenberg A, Kohn PD, Kolachana B et al (2005) Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 8(5):594–596

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Lindenberg A, Miletich RS, Kohn PD et al (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5(3):267–271

    Article  CAS  PubMed  Google Scholar 

  • Mickey BJ, Ducci F, Hodgkinson CA et al (2008) Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo. J Neurosci 28(44):11354–11359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mickey BJ, Sanford BJ, Love TM et al (2012) Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans. J Neurosci 32(27):9344–9350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller JM, Kinnally EL, Ogden RT et al (2009) Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder. Synapse 63(7):565–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizrahi R, Rusjan PM, Kennedy J et al (2012) Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA. J Cereb Blood Flow Metab 32(6):968–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moses-Kolko EL, Price JC, Thase ME et al (2007) Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635. Synapse 61(7):523–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murthy NV, Selvaraj S, Cowen PJ et al (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain. NeuroImage 52(1):50–54

    Article  CAS  PubMed  Google Scholar 

  • Nakamura M, Ueno S, Sano A, Tanabe H (2000) The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 5(1):32–38

    Article  CAS  PubMed  Google Scholar 

  • Narendran R, Tumuluru D, May MA et al (2016) cortical dopamine transmission as measured with the [11C]FLB 457—Amphetamine PET imaging paradigm is not influenced by COMT genotype. PLoS One 11(6):e0157867

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Neumeister A, Bain E, Nugent AC et al (2004) Reduced serotonin type 1A receptor binding in panic disorder. J Neurosci 24(3):589–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neumeister A, Yuan P, Young TA et al (2005) Effects of tryptophan depletion on serum levels of brain-derived neurotrophic factor in unmedicated patients with remitted depression and healthy subjects. Am J Psychiatry 162(4):805–807

    Article  PubMed  Google Scholar 

  • Neumeyer JL, Wang SY, Milius RA et al (1991) [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane: high-affinity SPECT radiotracer of monoamine reuptake sites in brain. J Med Chem 34(10):3144–3146

    Article  CAS  PubMed  Google Scholar 

  • Neves-Pereira M, Mundo E, Muglia P et al (2002) The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 71(3):651–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nobile M, Begni B, Giorda R et al (1999) Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 38(11):1396–1402

    Article  CAS  PubMed  Google Scholar 

  • Nozaki S, Kato M, Takano H et al (2009) Regional dopamine synthesis in patients with schizophrenia using L-[beta-11C]DOPA PET. Schizophr Res 108(1–3):78–84

    Article  PubMed  Google Scholar 

  • Owen DR, Howell OW, Tang SP et al (2010) Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30(9):1608–1618

    Article  PubMed  PubMed Central  Google Scholar 

  • Owen DR, Yeo AJ, Gunn RN et al (2011) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 32(1):1–5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pak K, Nam HY, Shin S et al (2018) Effects of rs591323 on serotonin transporter availability in healthy male subjects. Ann Nucl Med 32:431

    Article  CAS  PubMed  Google Scholar 

  • Palchaudhuri M, Flugge G (2005) 5-HT1A receptor expression in pyramidal neurons of cortical and limbic brain regions. Cell Tissue Res 321(2):159–172

    Article  CAS  PubMed  Google Scholar 

  • Pardini M, Krueger F, Hodgkinson C et al (2011) Prefrontal cortex lesions and MAO-A modulate aggression in penetrating traumatic brain injury. Neurology 76(12):1038–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parsey RV, Hastings RS, Oquendo MA et al (2006a) Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163(1):48–51

    Article  PubMed  Google Scholar 

  • Parsey RV, Olvet DM, Oquendo MA et al (2006b) Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology 31(8):1745–1749

    Article  CAS  PubMed  Google Scholar 

  • Parsey RV, Oquendo MA, Ogden RT et al (2006c) Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 59(2):106–113

    Article  CAS  PubMed  Google Scholar 

  • Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM (2010) Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab 30(10):1682–1706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patkar AA, Berrettini WH, Mannelli P et al (2004) Relationship between serotonin transporter gene polymorphisms and platelet serotonin transporter sites among African-American cocaine-dependent individuals and healthy volunteers. Psychiatr Genet 14(1):25–32

    Article  PubMed  Google Scholar 

  • Peciña M, Martínez-Jauand M, Love T et al (2014) Valence-specific effects of BDNF Val66Met polymorphism on dopaminergic stress and reward processing in humans. J Neurosci 34(17):5874–5881

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Peciña M, Mickey BJ, Love T et al (2012) DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience. Cortex 49(3):877–890

    Article  PubMed  PubMed Central  Google Scholar 

  • Pernhorst K, van Loo KM, von Lehe M et al (2013) Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue. Brain Res 1499:136–144

    Article  CAS  PubMed  Google Scholar 

  • Pezawas L, Meyer-Lindenberg A, Drabant EM et al (2005) 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8(6):828–834

    Article  CAS  PubMed  Google Scholar 

  • Pezawas L, Meyer-Lindenberg A, Goldman LA et al (2008) Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry 13(7):709–716

    Article  CAS  PubMed  Google Scholar 

  • Pezawas L, Verchinski BA, Mattay VS et al (2004) The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 24(45):10099–10102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirker W, Asenbaum S, Hauk M et al (2000) Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding kinetics and effects of normal aging. J Nucl Med 41(1):36–44

    CAS  PubMed  Google Scholar 

  • Pohjalainen T, Nagren K, Syvalahti EK, Hietala J (1999) The dopamine D2 receptor 5′-flanking variant, -141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo. Pharmacogenetics 9(4):505–509

    CAS  PubMed  Google Scholar 

  • Pohjalainen T, Rinne JO, Nagren K et al (1998) The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 3(3):256–260

    Article  CAS  PubMed  Google Scholar 

  • Praschak-Rieder N, Kennedy J, Wilson AA et al (2007) Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [C-11] DASB positron emission tomography study. Biol Psychiatry 62(4):327–331

    Article  CAS  PubMed  Google Scholar 

  • Praschak-Rieder N, Willeit M (2012) Imaging of seasonal affective disorder and seasonality effects on serotonin and dopamine function in the human brain. Curr Top Behav Neurosci 11:149–167

    Article  PubMed  Google Scholar 

  • Praschak-Rieder N, Willeit M, Wilson AA, Houle S, Meyer JH (2008) Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry 65(9):1072–1078

    Article  PubMed  Google Scholar 

  • Premi E, Archetti S, Pilotto A, Seripa D, Paghera B, Padovani A, Borroni B (2015) Functional genetic variation in the serotonin 5-HTTLPR modulates brain damage in frontotemporal dementia. Neurobiol Aging 36(1):446–451

    Article  CAS  PubMed  Google Scholar 

  • Purcell SM, Wray NR, Stone JL et al (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752

    Article  CAS  PubMed  Google Scholar 

  • Reimold M, Smolka MN, Schumann G et al (2007) Midbrain serotonin transporter binding potential measured with [C-11]DASB is affected by serotonin transporter genotype. J Neural Transm 114(5):635–639

    Article  CAS  PubMed  Google Scholar 

  • Reith J, Benkelfat C, Sherwin A et al (1994) Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci U S A 91(24):11651–11654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Risch N, Herrell R, Lehner T et al (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 301(23):2462–2471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenthal NE, Mazzanti CM, Barnett RL et al (1998) Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder. Mol Psychiatry 3(2):175–177

    Article  CAS  PubMed  Google Scholar 

  • Roses AD (2010) An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease. Arch Neurol 67(5):536–541

    Article  PubMed  PubMed Central  Google Scholar 

  • Ruhe HG, Booij J, Reitsma JB, Schene AH (2009) Serotonin transporter binding with [I-123]beta-CIT SPECT in major depressive disorder versus controls: effect of season and gender. Eur J Nucl Med Mol Imaging 36(5):841–849

    Article  CAS  PubMed  Google Scholar 

  • Ruottinen HM, Niinivirta M, Bergman J et al (2001) Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson’s disease requires prolonged imaging. Synapse 40(1):19–26

    Article  CAS  PubMed  Google Scholar 

  • Sabol SZ, Hu S, Hamer D (1998) A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 103(3):273–279

    Article  CAS  PubMed  Google Scholar 

  • Sacher J, Wilson AA, Houle S et al (2010) Elevated brain monoamine oxidase A binding in the early postpartum period. Arch Gen Psychiatry 67(5):468–474

    Article  PubMed  Google Scholar 

  • Saijo T, Takano A, Suhara T et al (2010) Effect of electroconvulsive therapy on 5-HT1A receptor binding in patients with depression: a PET study with [11C]WAY 100635. Int J Neuropsychopharmacol 13(6):785–791

    Article  CAS  PubMed  Google Scholar 

  • Sambataro F, Fazio L, Taurisano P et al (2011) DRD2 Genotype-based variation of default mode network activity and of its relationship with striatal DAT binding. Schizophr Bull 39(1):206–216

    Article  PubMed  PubMed Central  Google Scholar 

  • Savitz J, Hodgkinson CA, Martin-Soelch C et al (2013) The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement. PLoS One 8(1):e54108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savitz J, Lucki I, Drevets WC (2009) 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol 88(1):17–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schosser A, Calati R, Serretti A et al (2011) The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder–a European multicenter study. Eur Neuropsychopharmacol 22(4):259–266

    Article  PubMed  CAS  Google Scholar 

  • Selvaraj S, Murthy NV, Bhagwagar Z et al (2009) Diminished brain 5-HT transporter binding in major depression: a positron emission tomography study with [11C]DASB. Psychopharmacology 213(2–3):555–562

    PubMed  Google Scholar 

  • Seretti A, Cusin C, Lattuada E et al (1999) Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol Psychiatry 4(3):280–283

    Article  CAS  PubMed  Google Scholar 

  • Shen HW, Hagino Y, Kobayashi H et al (2004) Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29(10):1790–1799

    Article  CAS  PubMed  Google Scholar 

  • Shi J, Levinson DF, Duan J et al (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460(7256):753–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shioe K, Ichimya T, Suhara T et al (2003) No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 48(4):184–188

    Article  CAS  PubMed  Google Scholar 

  • Shumay E, Fowler JS, Wang GJ et al (2012a) Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability. Transl Psychiatry 2:e86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shumay E, Logan J, Volkow ND, Fowler JS (2012b) Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men. Epigenetics 7(10):1151–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shumay E, Wiers CE, Shokri-Kojori E et al (2017) New repeat polymorphism in the AKT1 gene predicts striatal dopamine D2/D3 receptor availability and stimulant-induced dopamine release in the healthy human brain. J Neurosci 37(19):4982–4991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siddarth P, Burggren AC, Merrill DA et al (2018) Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding. PLoS One 13(12):e0208358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sklar P, Gabriel SB, McInnis MG et al (2002) Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neurotrophic factor. Mol Psychiatry 7(6):579–593

    Article  CAS  PubMed  Google Scholar 

  • Slifstein M, Kolachana B, Simpson EH et al (2008) COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET. Mol Psychiatry 13(8):821–827

    Article  CAS  PubMed  Google Scholar 

  • Spindelegger C, Lanzenberger R, Wadsak W et al (2009) Influence of escitalopram treatment on 5-HT(1A) receptor binding in limbic regions in patients with anxiety disorders. Mol Psychiatry 14(11):1040–1050

    Article  CAS  PubMed  Google Scholar 

  • Sprouse JS, Aghajanian GK (1988) Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: a comparative study with dorsal raphe neurons. Neuropharmacology 27(7):707–715

    Article  CAS  PubMed  Google Scholar 

  • Stefansson H, Ophoff RA, Steinberg S et al (2009) Common variants conferring risk of schizophrenia. Nature 460(7256):744–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stockmeier CA (2003) Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 37(5):357–373

    Article  PubMed  Google Scholar 

  • Storvik M, Hakkinen M, Tupala E, Tiihonen J (2009) 5-HT(1A) receptors in the frontal cortical brain areas in Cloninger type 1 and 2 alcoholics measured by whole-hemisphere autoradiography. Alcohol Alcohol 44(1):2–7

    Article  CAS  PubMed  Google Scholar 

  • Suehiro M, Scheffel U, Ravert HT, Dannals RF, Wagner HN (1993) [C-11] (+)MCN5652 as a radiotracer for imaging serotonin uptake sites with PET. Life Sci 53(11):883–892

    Article  CAS  PubMed  Google Scholar 

  • Sullivan GM, Ogden RT, Huang YY et al (2013) Higher in vivo serotonin-1a binding in posttraumatic stress disorder: a pet study with [11C]way-100635. Depress Anxiety 30(3):197–206

    Article  CAS  PubMed  Google Scholar 

  • Sullivan PF (2010) The psychiatric GWAS consortium: big science comes to psychiatry. Neuron 68(2):182–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo Z, McCann UD, Wilson AA et al (2002) Comparison of (+)-C-11-McN5652 and C-11-DASB as serotonin transporter radioligands under various experimental conditions. J Nucl Med 43(5):678–692

    CAS  PubMed  Google Scholar 

  • Szobot CM, Roman T, Hutz MH et al (2010) Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity. Synapse 65(2):154–159

    Article  CAS  Google Scholar 

  • Talkowski ME, McCann KL, Chen M et al (2010) Fine-mapping reveals novel alternative splicing of the dopamine transporter. Am J Med Genet B Neuropsychiatr Genet 153B(8):1434–1447

    Article  CAS  PubMed  Google Scholar 

  • Tauscher J, Kapur S, Verhoeff NP et al (2002) Brain serotonin 5-HT(1A) receptor binding in schizophrenia measured by positron emission tomography and [11C]WAY-100635. Arch Gen Psychiatry 59(6):514–520

    Article  CAS  PubMed  Google Scholar 

  • Tsai HY, Chen KC, Yang YK et al (2011) Sunshine-exposure variation of human striatal dopamine D(2)/D(3) receptor availability in healthy volunteers. Prog Neuro-Psychopharmacol Biol Psychiatry 35(1):107–110

    Article  CAS  Google Scholar 

  • Urban NB, Martinez D (2012) Neurobiology of addiction: insight from neurochemical imaging. Psychiatr Clin North Am 35(2):521–541

    Article  PubMed  Google Scholar 

  • van de Giessen E, Nimgaonkar VL, Watson AM et al (2012) Association tests of striatal DAT availability and SNPs that impact a novel splice variant in the DAT gene. J Nucl Med 53(5):839

    PubMed  Google Scholar 

  • van de Giessen EM, de Win MM, Tanck MW et al (2009) Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med 50(1):45–52

    Article  PubMed  CAS  Google Scholar 

  • van Dyck CH, Malison RT, Jacobsen LK et al (2005) Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 46(5):745–751

    PubMed  Google Scholar 

  • Van Dyck CH, Malison RT, Staley JK et al (2004) Central serotonin transporter availability measured with [I-123]beta-CIT SPECT in relation to serotonin transporter genotype. Am J Psychiatry 161(3):525–531

    Article  PubMed  Google Scholar 

  • Vandenbergh DJ, Persico AM, Hawkins AL et al (1992) Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14(4):1104–1106

    Article  CAS  PubMed  Google Scholar 

  • Vandenbergh DJ, Thompson MD, Cook EH et al (2000) Human dopamine transporter gene: coding region conservation among normal, Tourette’s disorder, alcohol dependence and attention-deficit hyperactivity disorder populations. Mol Psychiatry 5(3):283–292

    Article  CAS  PubMed  Google Scholar 

  • Varnas K, Halldin C, Pike VW, Hall H (2003) Distribution of 5–HT4 receptors in the postmortem human brain–an autoradiographic study using [125I]SB 207710. Eur Neuropsychopharmacol 13(4):228–234

    Article  CAS  PubMed  Google Scholar 

  • Vidal R, Valdizan EM, Mostany R, Pazos A, Castro E (2009) Long-term treatment with fluoxetine induces desensitization of 5-HT4 receptor-dependent signalling and functionality in rat brain. J Neurochem 110(3):1120–1127

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F (2009) Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 56(Suppl 1):3–8

    Article  CAS  PubMed  Google Scholar 

  • Waeber C, Sebben M, Bockaert J, Dumuis A (1996) Regional distribution and ontogeny of 5-HT4 binding sites in rat brain. Behav Brain Res 73(1–2):259–262

    CAS  PubMed  Google Scholar 

  • Walther DJ, Peter JU, Bashammakh S et al (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299(5603):76

    Article  CAS  PubMed  Google Scholar 

  • Weidenauer A, Bauer M, Sauerzopf U, Bartova L, Nics L, Pfaff S, Philippe C, Berroterán-Infante N, Pichler V, Meyer BM, Rabl U, Sezen P, Cumming P, Stimpfl T, Sitte HH, Lanzenberger R, Mossaheb N, Zimprich A, Rusjan P, Dorffner G, Mitterhauser M, Hacker M, Pezawas L, Kasper S, Wadsak W, Praschak-Rieder N, Willeit M. (2020) On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study. Transl Psychiatry. 8;10(1):2. https://doi.org/10.1038/s41398-019-0681-5. PMID: 32066718; PMCID: PMC7026156

  • Willeit M, Praschak-Rieder N (2010) Imaging the effects of genetic polymorphisms on radioligand binding in the living human brain: a review on genetic neuroreceptor imaging of monoaminergic systems in psychiatry. NeuroImage 53(3):878–892

    Article  CAS  PubMed  Google Scholar 

  • Willeit M, Praschak-Rieder N, Neumeister A et al (2000) [I-123]-beta-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biol Psychiatry 47(6):482–489

    Article  CAS  PubMed  Google Scholar 

  • Willeit M, Praschak-Rieder N, Neumeister A et al (2003) A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder. Mol Psychiatry 8(11):942–946

    Article  CAS  PubMed  Google Scholar 

  • Willeit M, Sitte HH, Thierry N et al (2008) Enhanced serotonin transporter function during depression in seasonal affective disorder. Neuropsychopharmacology 33(7):1503–1513

    Article  CAS  PubMed  Google Scholar 

  • Willeit M, Stastny J, Pirker W et al (2001) No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 50(1):8–12

    Article  CAS  PubMed  Google Scholar 

  • Wilson AA, Garcia A, Parkes J et al (2008) Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors. Nucl Med Biol 35(3):305–314

    Article  CAS  PubMed  Google Scholar 

  • Wilson AA, Ginovart N, Schmidt M et al (2000) Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of C-11-labeled 2-(phenylthio)araalkylamines. J Med Chem 43(16):3103–3110

    Article  CAS  PubMed  Google Scholar 

  • Wilson AA, Houle S (1999) Radiosynthesis of carbon-11 labelled N-methyl-2-(arylthio)benzylamines: potential radiotracers for the serotonin reuptake receptor. J Label Compd Radiopharm 42(13):1277–1288

    Article  CAS  Google Scholar 

  • Witte AV, Floel A (2011) Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain Res Bull 88(5):418–428

    Article  PubMed  CAS  Google Scholar 

  • Wu K, O’Keeffe D, Politis M et al (2012) The catechol-O-methyltransferase Val(158)Met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson’s disease: a PET study. Brain 135(Pt 8):2449–2457

    Article  PubMed  Google Scholar 

  • Wu S, Comings DE (1999) A common C-1018G polymorphism in the human 5-HT1A receptor gene. Psychiatr Genet 9(2):105–106

    Article  CAS  PubMed  Google Scholar 

  • Zalsman G, Huang YY, Oquendo MA et al (2006) Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. Am J Psychiatry 163(9):1588–1593

    Article  PubMed  Google Scholar 

  • Zheng H, Wang X, Tang Z et al (2013) The PI3K/Akt and ERK1/2 signaling pathways mediate the erythropoietin-modulated calcium influx in kainic acid-induced epilepsy. Neuroreport 24:335–341

    Article  CAS  PubMed  Google Scholar 

  • Zill P, Buttner A, Eisenmenger W, Bondy B, Ackenheil M (2004) Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur Neuropsychopharmacol 14(4):282–284

    Article  CAS  PubMed  Google Scholar 

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Graf, I., Willeit, M., Kasper, S., Praschak-Rieder, N. (2021). The Impact of Genetic Polymorphisms on Neuroreceptor Binding: Results from PET and SPECT Neuroreceptor Imaging Studies. In: Dierckx, R.A., Otte, A., de Vries, E.F., van Waarde, A., Lammertsma, A.A. (eds) PET and SPECT of Neurobiological Systems. Springer, Cham. https://doi.org/10.1007/978-3-030-53176-8_6

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