Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder: a multitracer positron emission tomography study


Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BPND) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [11C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [11C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BPND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Altered expression of serotonin and dopamine transporters in social anxiety disorder.
Fig. 2: Altered co-expression of serotonin and dopamine transporters in social anxiety disorder.


  1. 1.

    Stein MB, Stein DJ. Social anxiety disorder. Lancet 2008;371:1115–25.

  2. 2.

    Brühl AB, Delsignore A, Komossa K, Weidt S. Neuroimaging in social anxiety disorder—a meta-analytic review resulting in a new neurofunctional model. Neurosci Biobehav Rev. 2014;47:260–80.

  3. 3.

    Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355–66.

  4. 4.

    Gordon JA, Hen R. The serotonergic system and anxiety. Neuromolecular Med 2004;5:27–40.

  5. 5.

    Mayo-Wilson E, Dias S, Mavranezouli I, Kew KMA, Clark DM, Ades A, et al. Psychological and pharmacological interventions for social anxiety disorder in adults: a systematic review and network meta-analysis. Lancet Psychiatry 2014;1:368–76.

  6. 6.

    Lanzenberger RR, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien LK, et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry. 2007;61:1091–89.

  7. 7.

    Frick A, Åhs F, Engman J, Jonasson M, Alaie I, Björkstrand J. et al. Serotonin synthesis and reuptake in social anxiety disorder a positron emission tomography study. JAMA Psychiatry. 2015;72:794–802.

  8. 8.

    Furmark T, Marteinsdottir I, Frick A, Heurling K, Tillfors M, Appel L, et al. Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder. J Psychopharmacol 2016;30:1028–35.

  9. 9.

    Frick A, Åhs F, Appel L, Jonasson M, Wahlstedt K, Bani M, et al. Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder. Eur Neuropsychopharmacol 2016;26:1775–83.

  10. 10.

    van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG. Increased serotonin and dopamine transporter binding in psychotropic medication-naive patients with generalized social anxiety disorder shown by 123I-beta-(4-iodophenyl)-tropane SPECT. J Nucl Med. 2008;49:757–63.

  11. 11.

    Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA. Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB. Eur J Nucl Med. 2000;27:1719–22.

  12. 12.

    Lammel S, Ion DI, Roeper J, Malenka RC. Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron. 2011;70:855–62.

  13. 13.

    de Jong JW, Afjei SA, Pollak Dorocic I, Peck JR, Liu C, Kim C, et al. A neural circuit mechanism for encoding aversive stimuli in the mesolimbic dopamine system. Neuron. 2019;101:133–51.

  14. 14.

    Smillie LD, Wacker J. Dopaminergic foundations of personality and individual differences. Front Hum Neurosci 2014;8:874.

  15. 15.

    Berridge KC, Kringelbach ML. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology. 2008;199:457–80.

  16. 16.

    Wacker J, Smillie LD. Trait extraversion and dopamine function. Soc Personal Psychol Compass 2015;9:225–38.

  17. 17.

    Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015;86:646–64.

  18. 18.

    Richey JA, Ghane M, Valdespino A, Coffman MC, Strege MV, White SW, et al. Spatiotemporal dissociation of brain activity underlying threat and reward in social anxiety disorder. Soc Cogn Affect Neurosci. 2017;12:81–94.

  19. 19.

    Doruyter A, Dupont P, Stein DJ, Lochner C, Warwick JM. Nuclear neuroimaging in social anxiety disorder: a review. J Nucl Med. 2018;59:1794–800.

  20. 20.

    Schneier FR, Liebowitz MR, Abi-dargham A, Zea-ponce Y, Lin S-H, Laruelle M. Low dopamine D 2 receptor binding potential in social phobia. Am J Psychiatry. 2000;157:457–9.

  21. 21.

    Schneier FR, Martinez D, Abi-Dargham A, Zea-Ponce Yolanda, Simpson HB, Liebowitz MR, et al. Striatal dopamine D2 receptor availability in OCD with and without comorbid social anxiety disorder: preliminary findings. Depress Anxiety. 2008;25:1–7.

  22. 22.

    Schneier FR, Abi-dargham A, Martinez D, Slifstein M, Whang DR, Liebowitz MR, et al. Dopamine transporters, D2 receptors, and dopamine release in generalized social anxiety disorder. Depress Anxiety. 2009;8:1–8.

  23. 23.

    Plavén-Sigray P, Hedman E, Victorsson P, Matheson GJ, Forsberg A, Djurfeldt DR, et al. Extrastriatal dopamine D2-receptor availability in social anxiety disorder. Eur Neuropsychopharmacol. 2017;27:462–9.

  24. 24.

    Tiihonen J, Kuikka J, Bergström K, Lepola U, Koponen H, Leinonen E. Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry. 1997;154:239–42.

  25. 25.

    Warwick JM, Carey PD, Cassimjee N, Lochner S, Hemmings H, Smook-Moolman H, et al. Dopamine transporter binding in social anxiety disorder: the effect of treatment with escitalopram. Metab Brain Dis. 2012;27:151–8.

  26. 26.

    Appel L, Jonasson M, Danfors T, Nyholm D, Askmark H, Lubberink M, et al. Use of 11C-PE2I PET in differential diagnosis of parkinsonian disorders. J Nucl Med. 2015;56:234–42.

  27. 27.

    Gray JA, McNaughton N. The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system. New York: Oxford University Press; 2000.

  28. 28.

    Cloninger RC. A unified diosocial theory of personality and its role in the development of anxiety states. Psychiatr Dev. 1986;4:167–226.

  29. 29.

    Kimbrel NA. A model of the development and maintenance of generalized social phobia. Clin Psychol Rev. 2008;28:592–612.

  30. 30.

    Corr PJ, McNaughton N. Neuroscience and approach/avoidance personality traits: A two stage (valuation-motivation) approach. Neurosci Biobehav Rev. 2012;36:2339–54.

  31. 31.

    Dewey SL, Smith GS, Logan J, Alexoff D, Ding YS, King P, et al. Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in viva microdialysis. J Neurosci. 1995;75:921–9.

  32. 32.

    Smith GS, Ma Y, Dhawan V, Chaly T, Eidelberg D. Selective serotonin reuptake inhibitor (SSRI) modulation of striatal dopamine measured with [11C]-raclopride and positron emission tomography. Synapse. 2009;63:1–6.

  33. 33.

    Daws LC. Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy. Pharm Ther. 2009;121:89–99.

  34. 34.

    Nakamura K. The role of the dorsal raphé nucleus in reward-seeking behavior. Front Integr Neurosci. 2013;7:1–18.

  35. 35.

    Esposito E, Di Matteo V, Di Giovanni G. Serotonin-dopamine interaction: an overview. Prog Brain Res. 2008;172:3–6.

  36. 36.

    Dray A, Gonye TJ, Oakley NR, Tanner T. Evidence for the existence of a raphe projection to the substantia nigra in rat. Brain Res. 1976;113:45–57.

  37. 37.

    Forstner AJ, Rambau S, Friedrich N, Ludwig KU, Böhmer AC, Mangold E, et al. Further evidence for genetic variation at the serotonin transporter gene SLC6A4 contributing toward anxiety. Psychiatr Genet. 2017;27:96–102.

  38. 38.

    Rhodes RA, Murthy NV, Dresner MA, Selvaraj S, Stavrakakis N, Babar S, et al. Human 5-HT transporter availability predicts amygdala reactivity in vivo. J Neurosci. 2007;27:9233–7.

  39. 39.

    Furmark T, Tillfors M, Garpenstrand H, Marteinsdottir I, Långström B, Oreland L, et al. Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neurosci Lett. 2004;362:189–92.

  40. 40.

    Furmark T, Henningsson S, Appel L, Åhs F, Linnman C, Pissiota A, et al. Genotype over diagnosis in amygdala responsiveness: affective processing in social anxiety disorder. J Psychiatry Neurosci. 2009;34:30–40.

  41. 41.

    Bergman O, Åhs F, Furmark T, Appel L, Linnman C, Faria V, et al. Association between amygdala reactivity and a dopamine transporter gene polymorphism. Transl Psychiatry 2014;4:e420.

  42. 42.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Text Revision (DSM-IV-TR). 4th ed. Arlington: American Psychiatric Association; 2000.

  43. 43.

    Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59:22–33.

  44. 44.

    Rytwinski NK, Fresco DM, Heimberg RG, Coles ME, Liebowitz LR, Cissel S, et al. Screening for social anxiety disorder with the self-report version of the Liebowitz Social Anxiety Scale. Depress Anxiety. 2009;26:34–8.

  45. 45.

    Logan J, Fowler JS, Volkow ND, Wang G-J, Ding Y-S, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16:834–40.

  46. 46.

    Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage. 1997;6:279–87.

  47. 47.

    Jonasson M, Appel L, Engman J, Frick A, Nyholm D, Askmark H, et al. Validation of parametric methods for [11C]PE2I positron emission tomography. Neuroimage. 2013;74:172–78.

  48. 48.

    Svarer C, Madsen K, Hasselbalch SG, Pinborg LH, Haugbøl S, Frøkjær VG, et al. MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage. 2005;24:969–79.

  49. 49.

    Frick A, Åhs F, Palmquist ÅM, Pissiota A, Wallenquist U, Fernandez M, et al. Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study. Mol Psychiatry. 2016;21:1400–7.

  50. 50.

    Plavén-Sigray P, Gustavsson P, Farde L, Borg J, Stenkrona P, Nyberg L, et al. Dopamine D1 receptor availability is related to social behavior: a positron emission tomography study. Neuroimage. 2014;102:590–5.

  51. 51.

    Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage. 2003;19:1233–9.

  52. 52.

    Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19:224–47.

  53. 53.

    Öhman A. The role of the amygdala in human fear: automatic detection of threat. Psychoneuroendocrinology. 2005;30:953–8.

  54. 54.

    Adhikari A, Lerner TN, Finkelstein J, Pak S, Jennings JH, Davidson TJ, et al. Basomedial amygdala mediates top-down control of anxiety and fear. Nature. 2015;527:179–85.

  55. 55.

    Hensler JG. Serotonergic modulation of the limbic system. Neurosci Biobehav Rev. 2006;30:203–14.

  56. 56.

    Salgado-Pineda P, Delaveau P, Blin O, Nieoullon A. Dopaminergic contribution to the regulation of emotional perception. Clin Neuropharmacol. 1979;28:228–37.

  57. 57.

    Schultz W. Reward functions of the basal ganglia. J Neural Transm. 2016;123:679–93.

  58. 58.

    Bas-Hoogendam JM, van Steenbergen H, Pannekoek NJ, Fouche JP, Lochner C, Hattingh CJ, et al. Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder. NeuroImage Clin. 2017;16:678–88.

  59. 59.

    Carlezon WA, Thomas MJ. Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacology. 2009;56:122–32.

  60. 60.

    Wager TD, Davidson ML, Hughes BL, Lindquist MA, Ochsner KN. Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron. 2008;59:1037–50.

  61. 61.

    Cardinal RN, Parkinson JA, Hall J, Everitt BJ. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev. 2002;26:321–52.

  62. 62.

    Moran RJ, Kishida KT, Lohrenz T, Saez I, Laxton AW, Witcher MR, et al. The protective action encoding of serotonin transients in the human brain. Neuropsychopharmacology. 2018;43:1425–35.

  63. 63.

    Browne CJ, Abela AR, Chu D, Li Z, Ji X, Lambe EK, et al. Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition. Neuropsychopharmacology. 2018;44:793–804.

  64. 64.

    Shirayama Y, Chaki S. Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. Curr Neuropharmacol. 2006;4:277–91.

  65. 65.

    Stuber GD, Sparta DR, Stamatakis AM, van Leeuwen WA, Hardjoprajitno JE, Cho S, et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature. 2011;475:377–80.

  66. 66.

    Oler JA, Fox AS, Shelton SE, Christian BT, Dhanabalan M, Oakes TR, et al. Serotonin transporter availability in the amygdala and bed nucleus of the stria terminalis predicts anxious temperament and brain glucose metabolic activity. J Neurosci. 2009;29:9961–6.

  67. 67.

    Takano A, Arakawa R, Hayashi M, Takahashi H, Ito H, Suhara T. Relationship between neuroticism personality trait and serotonin transporter binding. Biol Psychiatry. 2007;62:588–92.

  68. 68.

    Moriyama TS, Felicio AC, Chagas MHN, Tardelli VS, Ferraz HB, Tumas V, et al. Increased dopamine transporter density in Parkinson’s disease patients with social anxiety disorder. J Neurol Sci. 2011;310:53–7.

  69. 69.

    Fisher PM, Meltzer CC, Ziolko SK, Price JC, Hariri AR. Capacity for 5-HT1A-mediated autoregulation predicts amygdala reactivity. Nat Neurosci. 2006;9:1362–3.

  70. 70.

    Näslund J, Studer E, Pettersson R, Hagsäter M, Nilsson S, Nissbrandt H, et al. Differences in anxiety-like behaviour within a batch of Wistar rats are associated with differences in serotonergic transmission, enhanced by acute SSRI administration and abolished by serotonin depletion. Int J Neuropsychopharmacol. 2015;18:pyv018.

  71. 71.

    Sossi V, De La Fuente-Fernández R, Schulzer M, Troiano AR, Ruth TJ, Stoessl AJ. Dopamine transporter relation to dopamine turnover in Parkinson’s disease: a positron emission tomography study. Ann Neurol. 2007;62:468–74.

  72. 72.

    Zhuang X, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, et al. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci. 2001;98:1982–87.

  73. 73.

    Carpenter AC, Saborido TP, Stanwood GD. Development of hyperactivity and anxiety responses in dopamine transporter-deficient mice. Dev Neurosci 2012;34:250–7.

  74. 74.

    Richey JA, Rittenberg A, Hughes L, Damiano CR, Sabatino A, Miller S, et al. Common and distinct neural features of social and non-social reward processing in autism and social anxiety disorder. Soc Cogn Affect Neurosci. 2014;9:367–77.

  75. 75.

    Farde L, Plavén-Sigray P, Borg J, Cervenka S. Brain neuroreceptor density and personality traits: towards dimensional biomarkers for psychiatric disorders. Philos Trans R Soc B Biol Sci. 2018;373:20170156.

Download references


Supported by the Swedish Research Council and Riksbankens Jubileumsfond—the Swedish Foundation for Humanities and Social Sciences (TF). AF is supported by The Kjell and Märta Beijer Foundation. We thank Jörgen Rosén, Fredrik Åhs, Johannes Björkstrand, Thomas Ågren, Hanna Wallberg, Henrik Annerstedt, Nimo Farah, Jonas Engman, Per Carlbring, Gerhard Andersson, Margareta Reis, and Elna-Marie Larsson for their assistance.

Author information

Correspondence to Olof R. Hjorth.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hjorth, O.R., Frick, A., Gingnell, M. et al. Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder: a multitracer positron emission tomography study. Mol Psychiatry (2019).

Download citation