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The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C]WAY-100635

  • Patrycja Stein
  • Markus Savli
  • Wolfgang Wadsak
  • Markus Mitterhauser
  • Martin Fink
  • Christoph Spindelegger
  • Leonhard-Key Mien
  • Ulrike Moser
  • Robert Dudczak
  • Kurt Kletter
  • Siegfried Kasper
  • Rupert Lanzenberger
Original Article

Abstract

Purpose

The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT1A) receptor.

Methods

Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-11C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT1A receptor BPND was quantified using (1) the ‘gold standard’ manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling.

Results

The 5-HT1A receptor BPND was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BPND values in every region investigated, with a borderline significant sex difference in the hypothalamus (p = 0.012, uncorrected). There was a high intersubject variability of the 5-HT1A receptor BPND within both sexes compared to the small mean differences between men and women.

Conclusions

To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT1A receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT1A receptor expression.

Keywords

Positron emission tomography 5-HT1A receptor Serotonin Sex [Carbonyl-11C]WAY-100635 

Notes

Acknowledgements

This research was supported by grants from the Austrian National Bank (OENB P11468) and the Medical Science Fund of the City of Vienna (BMF P2515) to R. Lanzenberger and a grant from the Austrian Science Fund (FWF P16549). The authors thank Veronica Witte, Andreas Hahn, Alexander Holik, Alexander Becherer and Christian Bieglmayer for their support.

References

  1. 1.
    Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, et al. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand 2004;420(Suppl 1):21–7.Google Scholar
  2. 2.
    Gater R, Tansella M, Korten A, Tiemens BG, Mavreas VG, Olatawura MO. Sex differences in the prevalence and detection of depressive and anxiety disorders in general health care settings: report from the World Health Organization Collaborative Study on Psychological Problems in General Health Care. Arch Gen Psychiatry 1998;55:405–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Cahill L. Why sex matters for neuroscience. Nat Rev Neurosci 2006;7:477–84.PubMedCrossRefGoogle Scholar
  4. 4.
    Cosgrove KP, Mazure CM, Staley JK. Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 2007;62:847–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Carlsson M, Svensson K, Eriksson E, Carlsson A. Rat-brain serotonin—biochemical and functional evidence for a sex difference. J Neural Transm 1985;63:297–313.PubMedCrossRefGoogle Scholar
  6. 6.
    Haleem DJ, Kennett GA, Curzon G. Hippocampal 5-hydroxytryptamine synthesis is greater in female rats than in males and more decreased by the 5-HT1A agonist 8-OH-DPAT. J Neural Transm 1990;V79:93–101.CrossRefGoogle Scholar
  7. 7.
    Dickinson SL, Curzon G. 5-Hydroxytryptamine-mediated behaviour in male and female rats. Neuropharmacology 1986;25:771–76.PubMedCrossRefGoogle Scholar
  8. 8.
    McBride PA, Tierney H, DeMeo M, Chen J-S, Mann JJ. Effects of age and gender on CNS serotonergic responsivity in normal adults. Biol Psychiatry 1990;27:1143–55.PubMedCrossRefGoogle Scholar
  9. 9.
    Sambeth A, Blokland A, Harmer CJ, Kilkens TOC, Nathan PJ, Porter RJ, et al. Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: a pooled analysis of nine studies. Neurosci Biobehav Rev 2007;31:516–29.PubMedCrossRefGoogle Scholar
  10. 10.
    Kasper S, Tauscher J, Willeit M, Stamenkovic M, Neumeister A, Kufferle B, et al. Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette’s disorder—implications for psychopharmacology. World J Biol Psychiatry 2002;3:133–46.PubMedCrossRefGoogle Scholar
  11. 11.
    Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci U S A 1997;94:5308–13.PubMedCrossRefGoogle Scholar
  12. 12.
    Jovanovic H, Lundberg J, Karlsson P, Cerin A, Saijo T, Varrone A, et al. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. Neuroimage 2008;39:1408–19.PubMedCrossRefGoogle Scholar
  13. 13.
    Biver F, Lotstra F, Monclus M, Wikler D, Damhaut P, Mendlewicz J, et al. Sex difference in 5HT2 receptor in the living human brain. Neurosci Lett 1996;204:25–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46:1375–87.PubMedCrossRefGoogle Scholar
  15. 15.
    Lanzenberger RR, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien L-K, et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 2007;61:1081–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, et al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25:892–903.PubMedCrossRefGoogle Scholar
  17. 17.
    Spindelegger C, Lanzenberger R, Wadsak W, Mien L-K, Stein P, Mitterhauser M, et al. Influence of escitalopram treatment on 5-HT1A receptor binding in limbic regions in patients with anxiety disorders. Mol Psychiatry 2008; in press.Google Scholar
  18. 18.
    Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA, et al. Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res 1997;745:96–108.PubMedCrossRefGoogle Scholar
  19. 19.
    Fink KB, Gothert M. 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev 2007;59:360–417.PubMedGoogle Scholar
  20. 20.
    Hajos Mih l, Gartside SE, Varga V, Sharp T. In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors. Neuropharmacology 2003;45:72–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Klink R, Robichaud M, Debonnel G. Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part I: effects of gender and pregnancy. Neuropharmacology 2002;43:1119–28.PubMedCrossRefGoogle Scholar
  22. 22.
    Dominguez R, Cruz-Morales SE, Carvalho MC, Xavier M, Brandao ML. Sex differences in serotonergic activity in dorsal and median raphe nucleus. Physiol Behav 2003;80:203–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Li Q, Wichems C, Heils A, Lesch KP, Murphy DL. Reduction in the density and expression, but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out mice: gender and brain region differences. J Neurosci 2000;20:7888–95.PubMedGoogle Scholar
  24. 24.
    Schiller L, Jahkel M, Oehler J. The influence of sex and social isolation housing on pre- and postsynaptic 5-HT1A receptors. Brain Res 2006;1103:76–87.PubMedCrossRefGoogle Scholar
  25. 25.
    Boldrini M, Underwood MD, Mann JJ, Arango V. Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. J Psychiatr Res 2007;42:433–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 1995;688:121–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Palego L, Marazziti D, Rossi A, Giannaccini G, Naccarato AG, Lucacchini A, et al. Apparent absence of aging and gender effects on serotonin 1A receptors in human neocortex and hippocampus. Brain Res 1997;758:26–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Matsubara S, Arora RC, Meltzer HY. Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims. J Neural Transm Gen Sect 1991;85:181–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Dillon KA, Gross-Isseroff R, Israeli M, Biegon A. Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: effects of age and alcohol. Brain Res 1991;554:56–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27:1533–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V, et al. Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635. Brain Res 2002;954:173–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Meltzer CC, Drevets WC, Price JC, Mathis CA, Lopresti B, Greer PJ, et al. Gender-specific aging effects on the serotonin 1A receptor. Brain Res 2001;895:9–17.CrossRefGoogle Scholar
  33. 33.
    Pecins-Thompson M, Bethea CL. Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience 1999;89:267–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Tauscher J, Verhoeff NP, Christensen BK, Hussey D, Meyer JH, Kecojevic A, et al. Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET. Neuropsychopharmacology 2001;24:522–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273–89.PubMedCrossRefGoogle Scholar
  36. 36.
    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(Suppl 20):22–33.PubMedGoogle Scholar
  37. 37.
    Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence AD, et al. A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: normative data and relationship to methodological, demographic, physiological, and behavioral variables. Neuroimage 2002;15:620–32.PubMedCrossRefGoogle Scholar
  38. 38.
    Pike VW, McCarron JA, Lammertsma AA, Osman S, Hume SP, Sargent PA, et al. Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635. Eur J Pharmacol 1996;301:R5–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Wadsak W, Mien L-K, Ettlinger DE, Lanzenberger R, Haeusler D, Dudczak R, et al. Simple and fully automated preparation of [carbonyl-11C]WAY-100635. Radiochimica acta 2007;95:417–22.CrossRefGoogle Scholar
  40. 40.
    Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, et al. Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. Neuroimage 1998;8:426–40.PubMedCrossRefGoogle Scholar
  42. 42.
    Wu Y, Carson RE. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab 2002;22:1440–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Mikolajczyk K, Szabatin M, Rudnicki P, Grodzki M, Burger C. A JAVA environment for medical image data analysis: initial application for brain PET quantitation. Med Inform (Lond) 1998;23:207–14.Google Scholar
  44. 44.
    Logan J, Fowler JS, Volkow ND, Ding YS, Wang GJ, Alexoff DL. A strategy for removing the bias in the graphical analysis method. J Cereb Blood Flow Metab 2001;21:307–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Meyer JH, Gunn RN, Myers R, Grasby PM. Assessment of spatial normalization of PET ligand images using ligand-specific templates. Neuroimage 1999;9:545–53.PubMedCrossRefGoogle Scholar
  46. 46.
    Friston KJ, Holmes AP, Poline JB, Grasby PJ, Williams SC, Frackowiak RS, et al. Analysis of fMRI time-series revisited. Neuroimage 1995;2:45–53.PubMedCrossRefGoogle Scholar
  47. 47.
    Bremner JD, Bronen RA, De Erasquin G, Vermetten E, Staib LH, Ng CK, et al. Development and reliability of a method for using magnetic resonance imaging for the definition of regions of interest for positron emission tomography. Clin Positron Imaging 1998;1:145–59.PubMedCrossRefGoogle Scholar
  48. 48.
    Burnet PW, Eastwood SL, Harrison PJ. [3H]WAY-100635 for 5-HT1A receptor autoradiography in human brain: a comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int 1997;30:565–74.PubMedCrossRefGoogle Scholar
  49. 49.
    Moller M, Jakobsen S, Gjedde A. Parametric and regional maps of free serotonin 5HT1A receptor sites in human brain as function of age in healthy humans. Neuropsychopharmacology 2007;32:1707–14.PubMedCrossRefGoogle Scholar
  50. 50.
    Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ. Lack of effect of a single dose of hydrocortisone on serotonin1A receptors in recovered depressed patients measured by positron emission tomography with [11C]WAY-100635. Biol Psychiatry 2003;54:890–95.PubMedCrossRefGoogle Scholar
  51. 51.
    Bethea CL, Lu NZ, Gundlah C, Streicher JM. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol 2002;23:41–100.PubMedCrossRefGoogle Scholar
  52. 52.
    Tauscher J, Bagby RM, Javanmard M, Christensen BK, Kasper S, Kapur S. Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers. Am J Psychiatry 2001;158:1326–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Pecins-Thompson M, Brown NA, Kohama SG, Bethea CL. Ovarian steroid regulation of tryptophan hydroxylase mRNA expression in rhesus macaques. J Neurosci 1996;16:7021–9.PubMedGoogle Scholar
  54. 54.
    Lu NZ, Bethea CL. Ovarian steroid regulation of 5-HT1A receptor binding and G protein activation in female monkeys. Neuropsychopharmacology 2002;27:12–24.PubMedCrossRefGoogle Scholar
  55. 55.
    Flugge G, Pfender D, Rudolph S, Jarry H, Fuchs E. 5HT(1A)-receptor binding in the brain of cyclic and ovariectomized female rats. J Neuroendocrinology 1999;11:243–49.CrossRefGoogle Scholar
  56. 56.
    Jovanovic H, Cerin A, Karlsson P, Lundberg J, Halldin C, Nordstr”m A-L. A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria. Psychiatry Res 2006;148:185–93.PubMedCrossRefGoogle Scholar
  57. 57.
    Drossopoulou G, Antoniou K, Kitraki E, Papathanasiou G, Papalexi E, Dalla C, et al. Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats. Neuroscience 2004;126:849–57.PubMedCrossRefGoogle Scholar
  58. 58.
    Bebbington P. The origins of sex differences in depressive disorder: bridging the gap. Int Rev Psychiatry 1996;8:295–332.CrossRefGoogle Scholar
  59. 59.
    Sakai Y, Nishikawa M, Leyton M, Benkelfat C, Young SN, Diksic M. Cortical trapping of [alpha]-[11C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males. Neuroimage 2006;33:815–24.PubMedCrossRefGoogle Scholar
  60. 60.
    Chugani DC, Muzik O, Chakraborty P, Mangner T, Chugani HT. Human brain serotonin synthesis capacity measured in vivo with alpha-[C-11]methyl-l-tryptophan. Synapse 1998;28:33–43.PubMedCrossRefGoogle Scholar
  61. 61.
    Staley JK, Krishnan-Sarin S, Zoghbi S, Tamagnan G, Fujita M, Seibyl JP, et al. Sex differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse 2001;41:275–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Praschak-Rieder N, Willeit M, Wilson AA, Houle S, Meyer AS. Seasonal variation in human brain serotonin transporter binding. Arch Gen Psychiatry 2008; in press.Google Scholar
  63. 63.
    Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbol S, et al. A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables. Neuroimage 2004;21:1105–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Patrycja Stein
    • 1
  • Markus Savli
    • 1
  • Wolfgang Wadsak
    • 2
  • Markus Mitterhauser
    • 2
    • 3
  • Martin Fink
    • 1
  • Christoph Spindelegger
    • 1
  • Leonhard-Key Mien
    • 2
    • 3
  • Ulrike Moser
    • 1
  • Robert Dudczak
    • 2
  • Kurt Kletter
    • 2
  • Siegfried Kasper
    • 1
  • Rupert Lanzenberger
    • 1
  1. 1.Department of Psychiatry and PsychotherapyMedical University of ViennaViennaAustria
  2. 2.Department of Nuclear MedicineMedical University of ViennaViennaAustria
  3. 3.Department of Pharmaceutical TechnologyUniversity of ViennaViennaAustria

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