The effect of citalopram hydrobromide on 5-HT2A receptors in the impulsive–aggressive dog, as measured with 123I-5-I-R91150 SPECT

  • K. Peremans
  • K. Audenaert
  • Y. Hoybergs
  • A. Otte
  • I. Goethals
  • I. Gielen
  • P. Blankaert
  • M. Vervaet
  • C. van Heeringen
  • R. Dierckx
Molecular Imaging



Involvement of the serotonergic system in impulsive aggression has been demonstrated in both human and animal studies. The purpose of the present study was to investigate the effect of citalopram hydrobromide (a selective serotonin re-uptake inhibitor) on the 5-HT2A receptor and brain perfusion in impulsive–aggressive dogs by means of single-photon emission computed tomography.


The binding index of the radioligand 123I-5-I-R91150 was measured before and after treatment with citalopram hydrobromide in nine impulsive–aggressive dogs. Regional perfusion was measured with 99mTc-ethyl cysteinate dimer (ECD). Behaviour was assessed before treatment and again after 6 weeks of treatment.


A correlation was found between decreased binding and behavioural improvement in eight out of nine dogs. The 5-HT2A receptor binding index was significantly reduced after citalopram hydrobromide treatment in all cortical regions but not in the subcortical area. None of the dogs displayed alterations in perfusion on the post-treatment scans.


This study supports previous findings regarding the involvement of the serotonergic system in impulsive aggression in dogs in general. More specifically, the effect of treatment on the 5-HT2A receptor binding index could be demonstrated and the decreased binding index correlated with behavioural improvement.


SPECT 5-HT2A receptor 123I-5-I-R91150 Impulsive aggression Citalopram hydrobromide Dogs 


  1. 1.
    Virkkunen M, Rawlings R, Tokola R, Poland RE, Guidotti A, Nemeroff C, et al. CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers. Arch Gen Psychiatry 1994;51:20–7.Google Scholar
  2. 2.
    Cremniter D, Jamain S, Kollenbach K, Alvarez JC, Lecrubier Y, Gilton A, et al. CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects. Biol Psychiatry 1999;45:1572–9.Google Scholar
  3. 3.
    Higley JD, Mehlman PT, Higley SB, Fernald B, Vickers J, Lindell SG, et al. Excessive mortality in young free-ranging male nonhuman primates with low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. Arch Gen Psychiatry 1996;53:537–43.Google Scholar
  4. 4.
    Fairbanks L, Melega W, Jorgensen M, Kaplan J, McGuire M. Social impulsivity inversely associated with CSF 5-HIAA and fluoxetine exposure in vervet monkeys. Neuropsychopharmacology 2001;24:370–8.Google Scholar
  5. 5.
    Reisner IR, Mann JJ, Stanley M, Huang Y, Houpt KA. Comparison of cerebrospinal fluid monoamine metabolite levels in dominant-aggressive and non-aggressive dogs. Brain Res 1996;714:57–64.Google Scholar
  6. 6.
    Soloff P, Kelly T, Strotmeyer S, Malone K, Mann J. Impulsivity, gender, and response to fenfluramine challenge in borderline personality disorder. Psychiatry Res 2003;119:11–24.Google Scholar
  7. 7.
    Rinne T, Westenberg H, Den Boer J, van den Brink W. Serotonergic blunting to meta-chlorophenylpiperazine (m-CPP) highly correlates with sustained childhood abuse in impulsive and autoaggressive female borderline patients. Biol Psychiatry 2000;47:548–56.Google Scholar
  8. 8.
    Tiefenbacher S, Davenport M, Novack M, Pouliot A, Meyer J. Fenfluramine challenge self-injurious behaviour, and aggression in rhesus monkeys. Physiol Behav 2003;80:327–31.Google Scholar
  9. 9.
    Popova NK, Voitenko NN, Kulikov AV, Avgustinovich DF. Evidence for the involvement of central serotonin in mechanism of domestication of silver foxes. Pharmacol Biochem Behav 1991;40:751–6.Google Scholar
  10. 10.
    Popova NK, Kulikov AV, Nikulina EM, Kozlachkova EY, Maslova GB. Serotonin metabolism and serotonergic receptors in Norway rats selected for low aggressiveness towards man. Aggressive Behav 1991;17:207–13.Google Scholar
  11. 11.
    Coccaro E, Kavoussi R. Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 1997;54:1081–8.Google Scholar
  12. 12.
    Cherek DR, Lane SD, Pietras CJ, Steinberg JL. Effects of chronic paroxetine administration on measures of aggressive and impulsive responses of adult males with a history of conduct disorder. Psychopharmacology (Berlin) 2002;159:266–74.Google Scholar
  13. 13.
    Reist C, Nakamura K, Sagart E, Sokolski KN, Fujimoto KA. Impulsive aggressive behavior: open-label treatment with citalopram. J Clin Psychiatry 2003;64:81–5.Google Scholar
  14. 14.
    Verkes R, Van der Mast R, Hengeveld M, Tuyl J, Zwinderman A, Van Kempen G. Reduction by paroxetine of suicidal behavior in patients with repeated suicide attempts but no major depression. Am J Psychiatry 1998;155:543–7.PubMedGoogle Scholar
  15. 15.
    Perreault HA, Semsar K, Godwin J. Fluoxetine treatment decreases territorial aggression in a coral reef fish. Physiol Behav 2003;79:719–24.Google Scholar
  16. 16.
    Sperry TS, Thompson CK, Wingfield JC. Effects of acute treatment with 8-OH-DPAT and fluoxetine on aggressive behaviour in male song sparrows (Melospiza melodia morphna). J Neuroendocrinol 2003;15:150–60.Google Scholar
  17. 17.
    Medeiros JM, Silva CM, Sougey EB, Costa JA, Castro CM, Castro RM. Action of selective serotonin reuptake inhibitor on aggressive behavior in adult rat submitted to the neonatal malnutrition. Arq Neuropsiquiatr 2001;59:499–503.Google Scholar
  18. 18.
    Neuger J, Wistedt B, Aberg-Wistedt A, Stain-Malmgren R. Effect of citalopram treatment on relationship between platelet serotonin functions and the Karolinska scales of personality in panic patients. J Clin Psychopharmacol 2002;22:400–5.Google Scholar
  19. 19.
    Berton O, Durand M, Aguerre S, Mormede P, Chaouloff F. Behavioral, neuroendocrine and serotonergic consequences of single social defeat and repeated fluoxetine pretreatment in the Lewis rat strain. Neuroscience 1999;92:327–41.Google Scholar
  20. 20.
    Benmansour S, Cecchi M, Morilak D, Gerhardt G, Javors M, Gould G, et al. Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci 1999;19:10494–501.PubMedGoogle Scholar
  21. 21.
    Chen F, Lawrence A. The effects of antidepressant treatment on serotonergic and dopaminergic systems in Fawn-hooded rats: a quantitative autoradiography study. Brain Res 2003;976:22–9.Google Scholar
  22. 22.
    Lepoul E, Laaris N, Doucet E, Laporte A, Hamon M, Lanfumey L. Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine. Naunyn Schmiedebergs Arch Pharmacol 1995;352:141–8.Google Scholar
  23. 23.
    Audenaert K, Van Laere K, Dumont F, Slegers G, Mertens J, van Heeringen C, et al. Decreased frontal serotonin 5-HT2a receptor binding index in deliberate self harm patients. Eur J Nucl Med 2001;28:175–82.Google Scholar
  24. 24.
    Parsey R, Oquendo M, Simpson N, Ogden R, Van Heertum R, Arango V, et al. Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A binding potential measured by PET using [C-11] WAY-100635. Brain Res 2002;954:173–182.Google Scholar
  25. 25.
    Tiihonen J, Kuikka J, Bergstrom K, Karhu J, Viinamaki H, Lehtonen J, et al. Single-photon emission tomography imaging of monoamine transporters in impulsive violent behaviour. Eur J Nucl Med 1997;24:1253–60.Google Scholar
  26. 26.
    Peremans K, Audenaert K, Coopman F, Blanckaert P, Jacobs F, Otte A, et al. Estimates of regional cerebral blood flow and 5-HT2A receptor density in impulsive, aggressive dogs with 99mTc-ECD and 123I-5-I-5-R91150. Eur J Nucl Med Mol Imaging 2003;30:1538–46.Google Scholar
  27. 27.
    Mertens J, Terriere D, Sipido V, Gommeren W, Janssen PMF, Leysen JE. Radiosynthesis of a new radioiodinated ligand for serotonin-5HT2-receptors, a promising tracer for gamma-emission tomography. J Label Compd Radiopharm 1995;34:795–801.Google Scholar
  28. 28.
    Peremans K, Audenaert K, Jacobs F, Dumont F, De Vos F, Van de Wiele C, et al. Biodistribution and displacement studies of the selective 5-HT2A receptor antagonist 123I-5-I-R91150 in the normal dog. Nucl Med Commun 2002;23:1019–27.Google Scholar
  29. 29.
    Peremans K, De Bondt P, Audenaert K, Van Laere K, Gielen I, Koole M, et al. Regional brain perfusion in 10 healthy dogs measured using technetium-99m ethyl cysteinate dimer SPECT: a normal database. Vet Radiol Ultrasound 2001;42:562–8.Google Scholar
  30. 30.
    Peremans K, Audenaert K, Coopman F, Jacobs F, Blanckaert P, Verschooten F, et al. Effects of aging on brain perfusion and serotonin-2A receptor binding in the normal canine brain measured with single photon emission tomography. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:1393–404.Google Scholar
  31. 31.
    Pazos A, Cortes R, Palacios JM. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 1985;346:231–49.Google Scholar
  32. 32.
    Pazos A, Probst A, Palacios J. Serotonin receptors in the human brain—IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience 1987;21:123–39.Google Scholar
  33. 33.
    Travis M, Busatto G, Pilowsky L, Mulligan R, Acton P, Gacinovic S, et al. 5-HT2A receptor blockade in patients with schizophrenia treated with risperidone and clozapine. A SPET study using the novel 5-HT2A ligand 123I-5-I-R-91150. Br J Psychiatry 1998;173:236–41.Google Scholar
  34. 34.
    Kerwin R, Pilowsky L. Traditional receptor theory and its application to neuroreceptor measurements in functional imaging. Eur J Nucl Med 1995;22:699–710.Google Scholar
  35. 35.
    Van der Linden G., van Heerden B, Warwick J, Wessels C, van Kradenburg J, Zungu-Dirwayi N, et al. Functional brain imaging and pharmacotherapy in social phobia: single photon emission computed tomography before and after treatment with the selective serotonin reuptake inhibitor citalopram. Prog Neuropsychopharmacol Biol Psychiatry 2000;24:419–38.CrossRefPubMedGoogle Scholar
  36. 36.
    Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, et al. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry 2001;158:899–905.Google Scholar
  37. 37.
    Bonne O, Krausz Y, Aharon Y, Gelfin Y, Chisin R, Lerer B. Clinical doses of fluoxetine and cerebral blood flow in healthy volunteers. Psychopharmacology (Berlin) 1999;143:24–8.Google Scholar
  38. 38.
    Massou JM, Trichard C, Attar-Levy D, Feline A, Corruble E, Beaufils B, et al. Frontal 5-HT2A receptors studied in depressive patients during chronic treatment by selective serotonin reuptake inhibitors. Psychopharmacology (Berlin) 1997;133:99–101.Google Scholar
  39. 39.
    Meyer JH, Kapur S, Eisfeld B, Brown GM, Houle S, DaSilva J, et al. The effect of paroxetine on 5-HT2A receptors in depression: an [18F]setoperone PET imaging study. Am J Psychiatry 2001;158:78–85.Google Scholar
  40. 40.
    Zanardi R, Artigas F, Moresco R, Colombo C, Messa C, Gobbo C, et al. Increased 5-hydroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding to paroxetine treatment: a positron emission tomography scan study. J Clin Psychopharmacol 2001;21:53–8.Google Scholar
  41. 41.
    Messa C, Colombo C, Moresco RM, Gobbo C, Galli L, Lucignani G, et al. 5-HT2A receptor binding is reduced in drug-naive and unchanged in SSRI-responder depressed patients compared to healthy controls: a PET study. Psychopharmacology (Berlin) 2003;167:72–8.Google Scholar
  42. 42.
    Rilke O, Will K, Jahkel M, Oehler J. Behavioral and neurochemical effects of anpirtoline and citalopram in isolated and group housed mice. Prog Neuropsychopharmacol Biol Psychiatry 2001;25:1125–44.Google Scholar
  43. 43.
    Rutter JJ, Gundlah C, Auerbach SB. Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine. Neurosci Lett 1994;171:183–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Meyer JH, Cho R, Kennedy S, Kapur S. The effects of single dose nefazodone and paroxetine upon 5-HT2A binding potential in humans using [18F]-setoperone PET. Psychopharmacology (Berlin) 1999;144:279–81.Google Scholar
  45. 45.
    Reisner IR. Assessment, management, and prognosis of canine dominance-related aggression. Vet Clin North Am Small Anim Pract 1997;27:479–95.Google Scholar
  46. 46.
    Dodman NH, Donnelly R, Shuster L, Mertens P, Rand W, Miczek K. Use of fluoxetine to treat dominance aggression in dogs. J Am Vet Med Assoc 1996;209:1585–7.Google Scholar
  47. 47.
    Raleigh MJ, McGuire MT, Brammer GL, Pollack DB, Yuwiler A. Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys. Brain Res 1991;559:181–90.CrossRefPubMedGoogle Scholar
  48. 48.
    Fuller RW. The influence of fluoxetine on aggressive behavior. Neuropsychopharmacology 1996;14:77–81.Google Scholar
  49. 49.
    Wolff MC, Leander JD. Selective serotonin reuptake inhibitors decrease impulsive behavior as measured by an adjusting delay procedure in the pigeon. Neuropsychopharmacology 2002;27:421–9.Google Scholar
  50. 50.
    Takao K, Nagatani T, Kitamura Y, Kawasaki K, Hayakawa H, Yamawaki S. Chronic forced swim stress of rats increases frontal cortical 5-HT2 receptors and the wet-dog shakes they mediate, but not frontal cortical beta-adrenoceptors. Eur J Pharmacol 1995;294:721–6.Google Scholar
  51. 51.
    Koskinen T, Ruotsalainen S, Puumala T, Lappalainen R, Koivisto E, Mannisto PT, et al. Activation of 5-HT2A receptors impairs response control of rats in a five-choice serial reaction time task. Neuropharmacology 2000;39:471–81.CrossRefPubMedGoogle Scholar
  52. 52.
    Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, Glennon JC, Robbins TW. Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology (Berlin) 2003;167:304–14.Google Scholar
  53. 53.
    Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J Nucl Med 1998;39:208–14.Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • K. Peremans
    • 1
  • K. Audenaert
    • 2
  • Y. Hoybergs
    • 1
  • A. Otte
    • 3
  • I. Goethals
    • 3
  • I. Gielen
    • 1
  • P. Blankaert
    • 4
  • M. Vervaet
    • 2
  • C. van Heeringen
    • 2
  • R. Dierckx
    • 3
  1. 1.Department of Medical Imaging, Faculty of Veterinary MedicineGhent UniversityMerelbekeBelgium
  2. 2.Department of Psychiatry and Medical Psychology, Faculty of MedicineGhent UniversityGentBelgium
  3. 3.Division of Nuclear MedicineGhent University HospitalGentBelgium
  4. 4.Laboratory of Radiopharmacy, Faculty of Pharmaceutical SciencesGhent UniversityBelgium

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