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

PurposeThe 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.MethodsSixteen 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.ResultsThe 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.ConclusionsTo 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.

[1]  Robert B. Innis,et al.  Development and Reliability of a Method for Using Magnetic Resonance Imaging for the Definition of Regions of Interest for Positron Emission Tomography. , 1998, Clinical positron imaging : official journal of the Institute for Clinical P.E.T.

[2]  F. Mazzi,et al.  Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project , 2004, Acta psychiatrica Scandinavica. Supplementum.

[3]  A. Gjedde,et al.  Parametric and Regional Maps of Free Serotonin 5HT1A Receptor Sites in Human Brain as Function of Age in Healthy Humans , 2007, Neuropsychopharmacology.

[4]  M Diksic,et al.  Cortical trapping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males. , 2006, NeuroImage.

[5]  Donatella Marazziti,et al.  Apparent absence of aging and gender effects on serotonin 1A receptors in human neocortex and hippocampus , 1997, Brain Research.

[6]  G. Curzon,et al.  5-hydroxytryptamine-mediated behaviour in male and female rats , 1986, Neuropharmacology.

[7]  M. Brandão,et al.  Sex differences in serotonergic activity in dorsal and median raphe nucleus , 2003, Physiology & Behavior.

[8]  Christer Halldin,et al.  Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET , 2008, NeuroImage.

[9]  J Tauscher,et al.  Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers. , 2001, The American journal of psychiatry.

[10]  S Kasper,et al.  Influence of escitalopram treatment on 5-HT1A receptor binding in limbic regions in patients with anxiety disorders , 2009, Molecular Psychiatry.

[11]  D L Alexoff,et al.  A Strategy for Removing the Bias in the Graphical Analysis Method , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  J. Streicher,et al.  Diverse Actions of Ovarian Steroids in the Serotonin Neural System , 2002, Frontiers in Neuroendocrinology.

[13]  R Gater,et al.  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. , 1998, Archives of general psychiatry.

[14]  Shitij Kapur,et al.  Serotonin 5-HT1A Receptor Binding Potential Declines with Age as Measured by [11C]WAY-100635 and PET , 2001, Neuropsychopharmacology.

[15]  Rupert Lanzenberger,et al.  Simple and fully automated preparation of [carbonyl-11C]WAY-100635 , 2007 .

[16]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[17]  O Muzik,et al.  Human brain serotonin synthesis capacity measured in vivo with alpha-[C-11]methyl-L-tryptophan. , 1998, Synapse.

[18]  G. Kennett,et al.  Hippocampal 5-hydroxytryptamine synthesis is greater in female rats than in males and more decreased by the 5-HT1A agonist 8-OH-DPAT , 2005, Journal of Neural Transmission / General Section JNT.

[19]  Christer Halldin,et al.  A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria , 2006, Psychiatry Research: Neuroimaging.

[20]  Serge Goldman,et al.  Sex difference in 5HT2 receptor in the living human brain , 1996, Neuroscience Letters.

[21]  C. L. Bethea,et al.  Ovarian steroid regulation of serotonin-1A autoreceptor messenger rna expression in the dorsal raphe of rhesus macaques , 1999, Neuroscience.

[22]  Olaf B. Paulson,et al.  A database of [18F]-altanserin binding to 5-HT2A receptors in normal volunteers: normative data and relationship to physiological and demographic variables , 2004, NeuroImage.

[23]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[24]  H. Wikström,et al.  Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635 , 1997, Brain Research.

[25]  T. Hergueta,et al.  The mini international neuropsychiatric interview , 1998, European Psychiatry.

[26]  Ivo Podreka,et al.  Receptor and Transporter Imaging Studies in Schizophrenia, Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology- , 2002, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[27]  H. Meltzer,et al.  Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims , 1991, Journal of Neural Transmission / General Section JNT.

[28]  Sylvain Houle,et al.  Seasonal variation in human brain serotonin transporter binding. , 2008, Archives of general psychiatry.

[29]  Victoria Arango,et al.  Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims , 2001, Neuropsychopharmacology.

[30]  P A Sargent,et al.  Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635. , 1996, European journal of pharmacology.

[31]  K. Cosgrove,et al.  Evolving Knowledge of Sex Differences in Brain Structure, Function, and Chemistry , 2007, Biological Psychiatry.

[32]  J. Oehler,et al.  The influence of sex and social isolation housing on pre- and postsynaptic 5-HT1A receptors , 2006, Brain Research.

[33]  G. Drossopoulou,et al.  Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats , 2004, Neuroscience.

[34]  G. Debonnel,et al.  Gender and gonadal status modulation of dorsal raphe nucleus serotonergic neurons. Part I: Effects of gender and pregnancy , 2002, Neuropharmacology.

[35]  J. Mann,et al.  Effects of age and gender on CNS serotonergic responsivity in normal adults , 1990, Biological Psychiatry.

[36]  A. Young,et al.  Sex differences in the effect of acute tryptophan depletion on declarative episodic memory: A pooled analysis of nine studies , 2007, Neuroscience & Biobehavioral Reviews.

[37]  Karl J. Friston,et al.  Analysis of fMRI Time-Series Revisited , 1995, NeuroImage.

[38]  K. Lesch,et al.  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 , 2000, The Journal of Neuroscience.

[39]  A. Carlsson,et al.  Rat brain serotonin: Biochemical and functional evidence for a sex difference , 2005, Journal of Neural Transmission.

[40]  Roger N. Gunn,et al.  A Database of [11C]WAY-100635 Binding to 5-HT1A Receptors in Normal Male Volunteers: Normative Data and Relationship to Methodological, Demographic, Physiological, and Behavioral Variables , 2002, NeuroImage.

[41]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[42]  P. Bebbington.  The origins of sex differences in depressive disorder: Bridging the gap , 1996 .

[43]  Roger N. Gunn,et al.  Tracer Kinetic Modeling of the 5-HT1AReceptor Ligand [carbonyl-11C]WAY-100635 for PET , 1998, NeuroImage.

[44]  P. Cowen,et al.  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 , 2003, Biological Psychiatry.

[45]  M. Hajós,et al.  In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors , 2003, Neuropharmacology.

[46]  M. Boldrini,et al.  Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides. , 2008, Journal of psychiatric research.

[47]  Victoria Arango,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 , 2002, Brain Research.

[48]  Ralph Myers,et al.  Assessment of Spatial Normalization of PET Ligand Images Using Ligand-Specific Templates , 1999, NeuroImage.

[49]  D. Sheehan,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. , 1998, The Journal of clinical psychiatry.

[50]  Paul J. Harrison,et al.  [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 , 1997, Neurochemistry International.

[51]  Anat Biegon,et al.  Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: effects of age and alcohol , 1991, Brain Research.

[52]  Flügge,et al.  5HT1A‐Receptor Binding in the Brain of Cyclic and Ovariectomized Female Rats , 1999, Journal of neuroendocrinology.

[53]  D. Kupfer,et al.  Pet imaging of serotonin 1A receptor binding in depression , 1999, Biological Psychiatry.

[54]  Otto Muzik,et al.  Human brain serotonin synthesis capacity measured in vivo with α‐[C‐11]methyl‐L‐tryptophan , 1998 .

[55]  J. John Mann,et al.  Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims , 1995, Brain Research.

[56]  Manfred Göthert,et al.  5-HT Receptor Regulation of Neurotransmitter Release , 2007, Pharmacological Reviews.

[57]  M Fujita,et al.  Sex differences in [123I]β‐CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers , 2001, Synapse.

[58]  M Diksic,et al.  Differences between males and females in rates of serotonin synthesis in human brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Wolfgang Wadsak,et al.  Reduced Serotonin-1A Receptor Binding in Social Anxiety Disorder , 2007, Biological Psychiatry.

[60]  Richard E Carson,et al.  Noise Reduction in the Simplified Reference Tissue Model for Neuroreceptor Functional Imaging , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[61]  Chester A. Mathis,et al.  Gender-specific aging effects on the serotonin 1A receptor , 2001, Brain Research.

[62]  C. Bethea,et al.  Ovarian Steroid Regulation of 5-HT1A Receptor Binding and G protein Activation in Female Monkeys , 2002, Neuropsychopharmacology.

[63]  Yasuyuki Sakai,et al.  Cortical trapping of α-[11C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males , 2006, NeuroImage.

[64]  C Burger,et al.  A JAVA environment for medical image data analysis: initial application for brain PET quantitation. , 1998, Medical informatics = Medecine et informatique.

[65]  S. Kohama,et al.  Ovarian Steroid Regulation of Tryptophan Hydroxylase mRNA Expression in Rhesus Macaques , 1996, The Journal of Neuroscience.

[66]  L. Cahill.  Why sex matters for neuroscience , 2006, Nature Reviews Neuroscience.