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Licensed Unlicensed Requires Authentication Published online by De Gruyter May 16, 2022

Boosted dopamine and blunted serotonin in Tourette syndrome – evidence from in vivo imaging studies

Susanne Nikolaus ORCID logo, Eduards Mamlins, Christina Antke, Mardjan Dabir, Hans-Wilhelm Müller and Frederik L. Giesel


The precise cortical and subcortical mechanisms of Tourette syndrome (TS) are still not fully understood. In the present retrospective analysis, adolescent and adult medication-naïve patients showed increased DA transporter (DAT) binding in nucleus caudate (CAUD), putamen (PUT) and/or whole neostriatum (NSTR). D2 receptor (R) binding and DA release were not different from controls throughout the nigrostriatal and mesolimbocortical system. When patients were medication-free (either medication-naïve or under withdrawal), DAT was still increased in PUT, but not different from controls in CAUD, NSTR and ventral striatum (VSTR). SERT was unaltered in midbrain/pons (MP), but decreased in PUT, thalamus (THAL) and hypothalamus. D2R was unaltered throughout the nigrostriatal and mesolimbocortical system, while DA release was not different from controls in PUT, CAUD and NSTR, but elevated in VSTR. 5-HT2AR binding was unaltered in neocortex and cingulate. In acutely medicated adults, DAT was unaltered in PUT, but still increased in CAUD, whereas DA release remained unaltered throughout the nigrostriatal and mesolimbocortical system. When part of the patients was acutely medicated, vesicular monoamine transporter (VMAT2), DAT, SERT and DA synthesis were not different from controls in striatal regions, whereas D2R was decreased in NSTR, THAL, frontal cortex and limbic regions. Conversely, 5-HT2AR binding was unaltered in striatal regions and THAL, but increased in neocortical and limbic areas. It may be hypothesized that both the DA surplus and the 5-HT shortage in key regions of the nigrostriatal and mesolimbic system are relevant for the bouts of motor activity and the deficiencies in inpulse control.

Corresponding author: Susanne Nikolaus, Department of Nuclear Medicine, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany, E-mail:
H. W. Müller and F. L. Giesel share senior author status.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.


American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. 5th ed., Washington DC, 2013.10.1176/appi.books.9780890425596Search in Google Scholar

Adamczyk, A., Gause, C.D., Sattler, R., Vidensky, S., Rothstein, J.D., Singer, H., and Wang, T. (2011). Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome. Psychiatr. Genet. 21: 90–97. in Google Scholar

Alexander, G.E., DeLong, M.R., and Strick, P.L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9: 357–381. in Google Scholar

Bacqué-Cazenave, J., Bharatiya, R., Barrière, G., Delbecque, J.P., Bouguiyoud, N., Di Giovanni, G., Cattaert, D., and De Deurwaerdère, P. (2020). Serotonin in animal cognition and behavior. Int. J. Mol. Sci. 21: 1649.10.3390/ijms21051649Search in Google Scholar

Barr, C.L., Wigg, K.G., Zovko, E., Sandor, P., and Tsui, L.C. (1996). No evidence for a major gene effect of the dopamine D4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families. Am. J. Med. Genet. 67: 301–305.<301::aid-ajmg6>;2-p.10.1002/(SICI)1096-8628(19960531)67:3<301::AID-AJMG6>3.0.CO;2-PSearch in Google Scholar

Bhikram, T., Elmaghraby, R., Abi-Jaoude, E., and Sandor, P. (2021). An international survey of health care services available to patients with tourette syndrome. Front. Psychiatr. 12: 621874. in Google Scholar

Bloch, M.H., Peterson, B.S., Scahill, L., Otka, J., Katsovich, L., Zhang, H., and Leckman, J.F. (2006). Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome. Arch. Pediatr. Adolesc. Med. 160: 65–69. in Google Scholar

Buse, J., Enghardt, S., Kirschbaum, C., Ehrlich, S., and Roessner, V. (2016). Tic frequency decreases during short-term psychosocial stress – an experimental study on children with tic disorders. Front. Psychiatr. 7: 84. in Google Scholar

Bortolozzi, A., Díaz-Mataix, L., Scorza, M.C., Celada, P., and Artigas, F. (2005). The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J. Neurochem. 95: 1597–1607. in Google Scholar

Bouthenet, M.L., Martres, M.P., Sales, N., and Schwartz, J.C. (1987). A detailed mapping of dopamine D-2 receptors in rat central nervous system by autoradiography with [125I]iodosulpride. Neuroscience 20: 117–155. in Google Scholar

Butcher, S.P., Liptrot, J., and Aburthnott, G.W. (1991). Characterisation of methylphenidate and nomifensine induced dopamine release in rat striatum using in vivo brain microdialysis. Neurosci. Lett. 122: 245–248. in Google Scholar

Cath, D.C., Hedderly, T., Ludolph, A.G., Stern, J.S., Murphy, T., Hartmann, A., Czernecki, V., Robertson, M.M., Martino, D., Munchau, A., et al.. (2011). ESSTS Guidelines Group. European clinical guidelines for Tourette syndrome and other tic disorders. Part I: assessment. Eur. Child Adolesc. Psychiatr. 20: 155–171. in Google Scholar

Cavallini, M.C., Di Bella, D., Catalano, M., and Bellodi, L. (2000). An association study between 5-HTTLPRpolymorphism, COMT polymorphism, and Tourette’s syndrome. Psychiatr. Res. 97: 93–100. in Google Scholar

Chappell, P.B., Leckman, J.F., Scahill, L.D., Hardin, M.T., Anderson, G., and Cohen, D.J. (1993). Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette’s syndrome: a pilot study. Psychiatr. Res. 47: 267–380. in Google Scholar

Díaz-Anzaldúa, A., Joober, R., Rivière, J.B., Dion, Y., Lespérance, P., Richer, F., Chouinard, S., and Rouleau, G.A. (2004). Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadianfounder population. Mol. Psychiatr. 9: 272–277.10.1038/ in Google Scholar PubMed

Erdmann, J., Shimron-Abarbanell, D., Cichon, S., Albus, M., Maier, W., Lichtermann, D., Minges, J., Reuner, U., Franzek, E., Ertl, M.A., et al.. (1995). Systematic screening for mutations in the promoter and thecoding region of the 5-HT1A gene. Am. J. Med. Genet. 60: 393–399. in Google Scholar

Floresco, S.B. (2015). The nucleus accumbens: an interface between cognition, emotion, and action. Annu. Rev. Psychol. 66: 25–52. in Google Scholar

Gade, R., Muhleman, D., Blake, H., MacMurray, J., Johnson, P., Verde, R., Saucier, G., and Comings, D.E. (1998). Correlation of length of VNTR alleles at the X-linked MAOA gene and phenotype effect in Tourette syndrome and drug abuse. Mol. Psychiatr. 3: 50–60. in Google Scholar

Gelernter, J., Kennedy, J.L., Grandy, D.K., Zhou, Q.Y., Civelli, O., Pauls, D.L., Pakstis, A., Kurlan, R., Sunahara, R.K., and Niznik, H.B. (1993). Exclusion of close linkage of Tourette’s syndrome to D1 dopamine receptor. Am. J. Psychiatr. 150: 449–453. in Google Scholar

Geradin, E., Pochon, J.B., Poline, J.B., Tremblay, L., Van de Moortele, P.F., Levy, R., Dubois, B., Le Bihan, D., and Lehericy, S. (2004). Distinct striatal regions support movement selection, preparation and execution. Neuroreport 15: 2327–2331. in Google Scholar

Gilles de la Tourette, G. (1885). Étude sur une affection nerveuse caractérisée par de l’incoordination motrice accompagnée d’écholalie et de coprolalie [French]. Arch. Neurol. 9:158–200.Search in Google Scholar

Girault, J.A., Spampinato, U., Glowinski, J., and Besson, M.J. (1986). In vivo release of /3H/ gamma-aminobutyric acid in the rat neostriatum∼II. Opposing effects of Dl and D2 dopamine receptor stimulation dorsal caudate putamen. Neuroscience 19: 1109–1115. in Google Scholar

Grigoriadis, N., Simeonidou, C., Parashos, S.A., Alban, M., and Guiba-Tziampiri, O. (1996). Ontogenetic development of the locomotor response to levodopa in the rat. Pediatr. Neurol. 14: 41–45. in Google Scholar

Gobert, A. and Millan, J.M. (1999). Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology 38: 315–317. in Google Scholar

Gonce, M. and Barbeau, A. (1977). Seven cases of Gilles de la tourette’s syndrome: partial relief with clonazepam: a pilot study. Can. J. Neurol. Sci. 4: 279–283. in Google Scholar

Grillner, S. and Robertson, B. (2015). The basal ganglia downstream control of brainstem motor centres-an evolutionarily conserved strategy. Curr. Opin. Neurobiol. 33: 47–52. in Google Scholar

Haber, S.N. (2003). The primate basal ganglia: parallel and integrative networks. J. Chem. Neuroanat. 26: 317–330. in Google Scholar

Haber, S.N. (2016). Corticostriatal circuitry. Dialogues Clin. Neurosci. 18: 7–21. in Google Scholar

Han, D.D. and Gu, H.H. (2006). Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol. 6: 6. in Google Scholar

Harrison, A.A., Everitt, B.J., and Robbins, T.W. (1997). Doubly dissociable effects of median- and dorsal-raphe lesions on the performance of the five-choice serial reaction time test of attention in rats. Behav. Brain Res. 89: 135–149.10.1016/S0166-4328(97)00053-3Search in Google Scholar

Hirschtritt, M.E., Dy, M.E., Yang, K.G., and Scharf, J.M. (2016). Child neurology: diagnosis and treatment of tourette syndrome. Neurology 87: e65–67. in Google Scholar

Hemming, M. and Yellowlees, P.M. (1993). Effective treatment of Tourette’s syndrome with marijuana. J. Psychopharmacol. 7: 389–391. in Google Scholar

Hoekstra, P.J., Dietrich, A., Edwards, M.J., Elamin, I., and Martino, D. (2013). Environmental factors in Tourette syndrome. Neurosci. Biobehav. Rev. 37: 1040–1049. in Google Scholar

Hornung, J.P. (2003). The human raphe nuclei and the serotonergic system. J. Chem. Neuroanat. 26: 331–243. in Google Scholar

Huang, Y., Liu, X., Li, T., Guo, L., Sun, X., Xiao, X., Ma, X., Wang, Y., and Collier, D.A. (2001). Cases-control association study and transmission disequilibrium test of T102C polymorphism in 5HT2A and Tourette syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18: 11–13.Search in Google Scholar

Ishizu, K., Smith, D.F., Bender, D., Danielsen, E., Hansen, S.B., Wong, D.F., Cumming, P., and Gjedde, A. (2000). Positron emission tomography of radioligand binding in porcine striatum in vivo: haloperidol inhibition linked to endogenous ligand release. Synapse 38: 87–101.<87::aid-syn10>;2-c.10.1002/1098-2396(200010)38:1<87::AID-SYN10>3.0.CO;2-CSearch in Google Scholar

Jacob, S.N. and Nienborg, H. (2018). Monoaminergic neuromodulation of sensory processing. Front. Neural Circ. 12: 51. in Google Scholar

Kawashima, T. (2018). The role of the serotonergic system in motor control. Neurosci. Res. 129: 32–39. in Google Scholar

Kim, D.D., Warburton, D.E.R., Wu, N., Barr, A.M., Honer, W.G., and Procyshyn, R.M. (2018). Effects of physical activity on the symptoms of Tourette syndrome: a systematic review. Eur. Psychiatr. 48: 13–19. in Google Scholar

Knight, T., Steeves, T., Day, L., Lowerison, M., Jette, N., and Pringsheim, T. (2012). Prevalence of tic disorders: a systematic review and meta-analysis. Pediatr. Neurol. 47: 77–90. in Google Scholar

Leckman, J.F., Walker, D.E., and Cohen, D.J. (1993). Premonitory urges in Tourette’s syndrome. Am. J. Psychiatr. 150: 98–102. in Google Scholar

Leckman, J.F., Zhang, H.P., Vitale, A., Lahnin, F., Lynch, K., Bondi, C., Kim, Y.S., and Peterson, B.S. (1998). Course of tic severity in Tourette syndrome: the first two decades. Pediatrics 102: 14–19. in Google Scholar

Leckman, J.F. (2002). Tourette’s syndrome. Lancet 360: 1577–1586. in Google Scholar

Lerner, A., Bagic, A., Simmons, J.M., Mari, Z., Bonne, O., Xu, B., Kazuba, D., Herscovitch, P., Carson, R.E., Murphy, D.L., et al.. (2012). Widespread abnormality of the γ-aminobutyric acid-ergic system in Tourette syndrome. Brain 135: 1926–1936. in Google Scholar

Lucas, G. and Spampinato, U. (2000). Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum J. Neurochem. 74: 693–701. in Google Scholar

Mahone, E.M., Puts, N.A., Edden, R.A.E., Ryan, M., and Singer, H.S. (2018). GABA and glutamate in children with Tourette syndrome: a 1H MR spectroscopy study at 7T. Psychiatry Res. Neuroimaging 273: 46–53. in Google Scholar

Matsuda, N., Nonaka, M., Kono, T., Fujio, M., Nobuyoshi, M., and Kano, Y. (2020). Premonitory awareness facilitates tic suppression: subscales of the premonitory urge for tics scale and a new self-report questionnaire for tic-associated sensations. Front. Psychiatr. 11: 592. in Google Scholar

Micheli, F., Gatto, M., Lekhuniec, E., Mangone, C., Fernandez Pardal, M., Pikielny, R., and Casas Parera, I. (1990). Treatment of Tourette’s syndrome with calcium antagonists. Clin. Neuropharmacol. 13: 77–83. in Google Scholar

Moghaddam, B. and Bunney, B.S. (1990). Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J. Neurochem. 54: 1755–1760. in Google Scholar

Niesler, B., Frank, B., Hebebrand, J., and Rappold, G. (2005). Serotonin receptor genes HTR3A and HTR3B are notinvolved in Gilles de la Tourette syndrome. Psychiatr. Genet. 15: 303–304. in Google Scholar

Nikolaus, S., Antke, C., and Müller, H.W. (2009). In vivo imaging of synaptic function in the central nervous system. II. Mental and affective disorders. Behav. Brain Res. 204: 32–66. in Google Scholar

Nikolaus, S., Beu, M., Antke, C., and Müller, H.W. (2010). Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders – results from in vivo imaging studies. Rev. Neurosci. 21: 119–139. in Google Scholar

Nikolaus, S., de Souza Silva, M.A., Hautzel, H., and Müller, H.W. (2013). The neurotachykinin NK1 receptor – a novel target for diagnostics and therapy. Curr. Mol. Imag. 3: 130–147. in Google Scholar

Nikolaus, S., Mamlins, E., Giesel, F.L., Schmitt, D., and Müller, H.W. (2021). Monoaminergic hypo- or hyperfunction inadolescent and adult attention-deficit hyperactivity disorder? Rev. Neurosci. (Epub ahead of print).Search in Google Scholar

Nordstrom, E.J., Bittner, K.C., McGrath, M.J., Parks3rdC.R., and Burton, F.H. (2015). “Hyperglutamatergic cortico-striato-thalamo-cortical circuit” breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome. Brain Res. 1629: 38–53. in Google Scholar

Parent, A. and Hazrati, L.N. (1995). Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res. Rev. 20: 91–127. in Google Scholar

Pauls, D.L., Fernandez, T.V., Mathews, C.A., State, M.W., and Scharf, J.M. (2014). The inheritance of tourette disorder: a review. J. Obsessive Compuls. Relat. Disord. 3: 380–385. in Google Scholar

Pehek, E.A. and Yamamoto, B.K. (1994). Differential effects of locally administered clozapine and haloperidol on dopamine efflux in the rat prefrontal cortex and caudateputamen. J. Neurochem. 63: 2118–2124. in Google Scholar

Pehek, E.A. (1999). Comparison of effects of haloperidol administration on amphetaminestimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum. J. Pharmacol. Exp. Therapeut. 289: 14–23.Search in Google Scholar

Perlmutter, J.S., Garvey, M.A., Castellanos, X., Mittleman, B.B., Giedd, J., Rapoport, J.L., and Swedo, S.E. (1998). A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Am. J. Psychiatr. 155: 1592–1598. in Google Scholar

Qi, Y., Zheng, Y., Li, Z., and Xiong, L. (2017). Progress in genetic studies of tourette’s syndrome. Brain Sci. 7: 134. in Google Scholar

Scahill, L., Erenberg, G., BerlinJrC.M., Budman, C., Coffey, B.J., Jankovic, J., Kiessling, L., King, R.A., Kurlan, R., Lang, A., et al.. (2006). Contemporary assessment and pharmacotherapy of tourette syndrome. Tourette syndrome association medical advisory board: practice committee. NeuroRx. 3:192–206. in Google Scholar

Seideman, M.S. and Seideman, T.A. (2020). A review of the current treatment of tourette syndrome. J. Pediatr. Pharmacol. Therapeut. 25: 401–412. in Google Scholar

Shapiro, A.K., Baron, M., Shapiro, E., and Levitt, M. (1984). Enzyme activity in Tourette’s syndrome. Arch. Neurol. 41: 382–385. in Google Scholar

Stein, D.J. and Stahl, S. (2000). Serotonin and anxiety: current models. Int. Clin. Psychopharmacol. 15 (Suppl. 2): S1–S6. in Google Scholar

Tanner, C.M., Goetz, C.G., Klawans, H.L. (1982). Cholinergic mechanisms in Tourette syndrome. Neurology 32: 1315–1317. in Google Scholar

Varrone, A., Dickson, J.C., Tossici-Bolt, L., Sera, T., Asenbaum, S., Booij, J., Kapucu, O.L., Kluge, A., Knudsen, G.M., Koulibaly, P.M., et al.. (2013). European multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis. Eur. J. Nucl. Med. Mol. Imaging 40: 213–227.10.1007/s00259-012-2276-8Search in Google Scholar

Wu, Q., Reith, M.E., Walker, Q.D., Kuhn, C.M., Carroll, F.I., and Garris, P.A. (2002). Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study. J. Neurosci. 22: 6272–6281. in Google Scholar

Yagishita, S. (2020). Transient and sustained effects of dopamine and serotonin signaling in motivation-related behavior. Psychiatr. Clin. Neurosci. 74: 91–98. in Google Scholar

Yan, Q., Reith, M.E., and Yan, S. (2000). Enhanced accumbal dopamine release following 5-HT(2A) receptor stimulation in rats pretreated with intermittent cocaine. Brain Res. 863: 254–258. in Google Scholar

Received: 2022-04-04
Accepted: 2022-04-12
Published Online: 2022-05-16

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