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Pharmacopsychiatry 2004; 37(6): 286-291
DOI: 10.1055/s-2004-832685
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Neuroimaging and 5-HT2C Receptor Polymorphism: A HMPAO-SPECT Study in Healthy Male Probands Using mCPP-Challenge of the 5-HT2C Receptor

K.-U. Kühn1 , A. Y. Joe2 , K. Meyer1 , K. Reichmann2 , W. Maier1 , M. L. Rao1 , M. J. Reinhardt2 , H.-J. Biersack2 , B. B. Quednow1
  • 1Department of Psychiatry, University of Bonn, Germany
  • 2Department of Nuclear Medicine, University of Bonn, Germany
Further Information

Publication History

Received: 3.7.2003 Revised: 3.12.2003

Accepted: 3.12.2003

Publication Date:
19 November 2004 (online)

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Background: The human 5-HT2C receptor gene has been localized on the X chromosome and is expressed in two genetic variants. Whereas previous investigations have suggested that the 5-HT2C receptor gene polymorphism is critically involved in the pathogenesis of affective and eating disorders, as yet the functional consequences being associated with the rare serine variant of the 5-HT2C receptor in humans are unclear. Methods: We explored by HMPAO-SPECT if a challenge with the serotonin agonist mCPP, that interacts mainly with the 5-HT2C receptor, provokes different patterns of regional cerebral bloodflow (rCBF) as a function of the genetic variant of the receptor. Thus we studied its action in 16 healthy male volunteers carrying the common 5-HT2C-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT2C-ser-23 receptor gene. Results: We found significant differences in rCBF between the two genotypes after mCPP infusion compared to placebo: In the cysteine group rCBF was increased in the left medial prefrontal cortex and decreased in the left anterior cingulate and right medio-temporal cortex, whereas the serine group showed an increase of rCBF in the left medio- and superior-temporal cortex and in cerebellum and a reduced rCBF in the right medial prefrontal cortex. In addition, there was a significant disordinal interaction of the genotype factors and challenge with an increase of rCBF in the serine group and a decrease in the cysteine group in the left motor cortex and calcarine cortex. Additionally, a decrease of rCBF in the serine-group and a simultaneous increase in the cysteine group was found in the right anterior and the left posterior cingulate cortex. Conclusion: These findings suggest that differences in the 5-HT2C receptor gene polymorphism has functional consequences due to a different responsiveness of the expressed 5-HT2C receptor variants.

References

  • 1 Abramovski D, Rigo M, Duc D, Hoyer D, Staufenbiel N. Generation of antisera against the 5-hydroxithryptamine2Creceptor and its localisation in human and rat brain.  Neuropharmacology. 1995;  34 1635-1645
    CrossrefPubMedGoogle Scholar
  • 2 Anderson I M, Clark L, Elliott R, Kulkarni B, Williams S R, Deakin J F. 5-HT(2C) receptor activation by m-chlorophenylpiperazine detected in humans with fMRI.  Neuroreport. 2002;  12 1547-1551
    PubMedGoogle Scholar
  • 3 Baptista T, Kin N M, Beaulieu S, de Baptista E A. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives.  Pharmacopsychiatry. 2002;  35 205-219
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Bromidge S M, Dabbs S, Davies D T, Duckworth D M, Forbes I T, Ham P, Jones G E, King F D, Saunders D V, Starr S, Thewlis K M, Wyman P A, Blaney F E, Naylor C B, Bailey F, Blackburn T P, Holland V, Kennett G A, Riley G J, Wood M D. Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.  J Med Chem. 1998;  41 1598-1612
    CrossrefPubMedGoogle Scholar
  • 5 Charney D S, Woods S W, Goodman W K, Heninger G R. Serotonin function in anxiety. II. Effects of the serotonin agonist mCPP in panic disorder patients and healthy subjects.  Psychopharmacology. 1987;  92 14-24
    CrossrefPubMedGoogle Scholar
  • 6 Charney D S, Deutch A. A functional neuroanatomy of anxiety and fear: implications for the pathophysiology and treatment of anxiety disorders.  Crit Rev Neurobiol. 1996;  10 419-446
    PubMedGoogle Scholar
  • 7 Cloninger C R, Svrakic D M, Przybeck T R. A psychobiological model of temperament and character.  Arch Gen Psychiatry. 1993;  50 975-990
    PubMedGoogle Scholar
  • 8 Davidson R J, Abercrombie H, Nitschke J B, Putnam K. Regional brain function, emotion and disorders of emotion.  Curr Opin Neurobiol. 1999;  9 228-234
    CrossrefPubMedGoogle Scholar
  • 9 Davidson R J, Irwin W. The functional neuroanatomy of emotion and affective style.  Trends Cogn Sci. 1999;  3 11-21
    CrossrefPubMedGoogle Scholar
  • 10 Davidson R J. Anxiety and affective style: role of prefrontal cortex and amygdala.  Biol Psychiatry. 2002;  51 68-80
    CrossrefPubMedGoogle Scholar
  • 11 Fredrikson M, Fischer H, Wik G. Cerebral blood flow during anxiety provocation.  J Clin Psychiatry. 1997;  58 (Suppl 16) 16-21
    PubMedGoogle Scholar
  • 12 Genna S, Smith A P. The development of ASPECT, an annular single crystal brain camera for high efficacy SPECT. IEEE Trans.  Nuclear Science. 1988;  35 654-658
    PubMedGoogle Scholar
  • 13 Goldman D, Lappalainen J, Ozaki N, Nakkai B, Bergen A, Pesonen U -M, Koulu M, Dean M, Zhang L, Weight F, Eggert M, Virkkunen M, Linniola M. Natural structural variants of human serotonin receptors.  Psychiatric Genet. 1995;  5 (Suppl 1) 22-29
    PubMedGoogle Scholar
  • 14 Göthert M, Propping P, Bönisch H, Bruss M, Nöthen M M. Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role.  Ann N Y Acad Sci. 1998;  861 26-30
    PubMedGoogle Scholar
  • 15 Heisler L K, Tecott L H. Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation.  Int J Neuropsychopharmcol. 1999;  2 67-69
    PubMedGoogle Scholar
  • 16 Hoyer D, Clarke D E, Fozard J R, Hartig P R, Martin G R, Mylecharane E J, Saxena P R, Humphrey P P. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).  Pharmacol Rev. 1994;  46 157-203
    PubMedGoogle Scholar
  • 17 Hoyer D, Hannon J P, Martin G R. Molecular, pharmacological and functional diversity of 5-HT receptors.  Pharmacol Biochem Behav. 2002;  71 533-554
    CrossrefPubMedGoogle Scholar
  • 18 Kahn R S, Wetzler . m-Chlorophenylpiperazine as a probe of serotonin function.  Biol Psychiatry. 1991;  30 1139-1166
    CrossrefPubMedGoogle Scholar
  • 19 Kennett G A, Wood M D, Bright F, Trail B, Riley G, Holland V, Avenell K Y, Stean T, Upton N, Bromidge S, Forbes I T, Brown A M, Middlemiss D N, Blackburn T P. SB 242 084, a selective and brain penetrant 5-HT2C receptor antagonist.  Neuropharmacology. 1997;  36 609-620
    CrossrefPubMedGoogle Scholar
  • 20 Kühn K U, Quednow B B, Bagli M, Meyer M, Feuchtl A, Westheide J, Frahnert C, Maier W, Rao M L. Allelic Variants in the serotonin receptor 5-HT2C and neuroendocrinological responses to the 5-HT2C receptor agonist m-chlorophenylpiperazine in healthy male volunteers.  Pharmacopsychiatry. 2002;  35 226-230
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu D H, Virkkunen M, Weight F, Linnoila M, Goldman D. Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2C receptor gene (HTR2C).  Genomics. 1995;  27 274-279
    CrossrefPubMedGoogle Scholar
  • 22 Lerer B, Macciardi F, Segman R H, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos D G, Kaneva R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou G N, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz J. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.  Mol Psychiatry. 2001;  6 579-585
    CrossrefPubMedGoogle Scholar
  • 23 Marazziti D, Rossi A, Giannaccini G, Zavaglia K M, Dell'Osso L, Lucacchini A, Cassano G B. Distribution and characterization of [3H]mesulergine binding in human brain postmortem.  Eur Neuropsychopharmacol. 1999;  10 21-26
    CrossrefPubMedGoogle Scholar
  • 24 Murphy D L, Lesch K P, Auklah C S, Pigeott T A. Serotonin-selective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans.  Pharmacol Rev. 1991;  43 527-552
    PubMedGoogle Scholar
  • 25 Phan K L, Wager T, Taylor S F, Liberzon I. Functional Neuroanatomy of Emotion: A Meta-Analysis of Emotion Activation Studies in PET and fMRI.  Neuroimage. 2001;  16 331-348
    PubMedGoogle Scholar
  • 26 Quested D J, Whale R, Sharpley A L, McGavin C L, Crossland N, Harrison P J, Cowen P J. Allelic variation in the 5-HT2C receptor (HTR2C) and functional responses to the 5-HT2C receptor agonist, m-chlorophenylpiperazine.  Psychopharmacology. 1999;  144 306-307
    CrossrefPubMedGoogle Scholar
  • 27 Reiman E M. The application of positron emission tomography to the study of normal and pathologic emotions.  J Clin Psychiatry. 1997;  58 (Suppl 16) 4-12
    PubMedGoogle Scholar
  • 28 Rietschel M, Naber D, Fimmers R, Möller H J, Propping P, Nöthen M M. Efficacy an side-effects of clozapine not associated with variation in the 5-HT2C receptor.  Neuroreport. 1997;  8 1999-2003
    PubMedGoogle Scholar
  • 29 Sodhi M S, Arranz M J, Curtis D, Ball D M, Sham P, Roberts G W, Price J, Collier D A, Kerwin R. Association between clozapine response and allelic variation in the 5-HT2C receptor gene.  Neuroreport. 1995;  7 169-172
    PubMedGoogle Scholar
  • 30 Talairach J, Tournoux P. Coplanar Stereotaxic Atlas of the Human Brain. New York; Thieme Medical 1988
    Google Scholar
  • 31 Westberg L, Bah J, Rastam M, Gillberg C, Wentz E, Melke J, Hellstrand M, Eriksson E. Association between a polymorphism of the 5-HT2C receptor and weight loss in teenage girls.  Neuropsychopharmacology. 2002;  26 789-793
    CrossrefPubMedGoogle Scholar

Dr. Kai-Uwe Kühn

Universitätsklinik für Psychiatrie und Psychotherapie

Sigmund-Freud-Straße 25

53105 Bonn

Germany

Phone: +49 228 287 5681

Fax: +49 228 287 6949

Email: k.u.kuehn@uni-bonn.de

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