Sex steroid hormone effects on cerebral serotonin-1 A receptor binding measured by positron emission tomography

Background: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin1A (5-HT 1A ) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT 1A receptor binding in healthy male subjects. Methods: Molecular neuroimaging of the 5-HT 1A receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. Results: Plasma P levels explained up to 65% of the variability in 5-HT 1A receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5-HT 1A binding attributed to P. Conclusions: The results of this study provide further support for the effect of P on 5-HT 1A receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system. Copyright © 2011 S. Karger AG, Basel Received: November 23, 2010 Accepted after revision: April 2, 2011 Published online: May 21, 2011 Rupert Lanzenberger Department of Psychiatry and Psychotherapy, Medical University of Vienna Währinger Gürtel 18–20 AT–1090 Vienna (Austria) Tel. +43 1 40400 3825, E-Mail rupert.lanzenberger @ meduniwien.ac. at © 2011 S. Karger AG, Basel 0028–3835/11/0941–0084$38.00/0 Accessible online at: www.karger. com/nen Progesterone and Serotonergic Neurotransmission Neuroendocrinology 2011;94:84–88 85 transrepression of the 5-HT 1A receptor promoter, thereby reducing the 5-HT 1A receptor expression [7] . Variations in P plasma level should thus predict variations of 5-HT 1A receptor expression (a comprehensive schematic of the 5-HT 1A receptor transrepression mechanism is given in the online suppl. fig.; for all online supplementary material, see www.karger.com/doi/10.1159/000328432). We therefore investigated the influence of endogenous P plasma level upon 5-HT 1A receptor binding potential using positron emission tomography (PET) and the radioligand [ carbonyl 11 C]WAY-100635 in 18 healthy male volunteers. Materials and Methods Subjects Subjects were 18 male healthy volunteers with a mean age of 25.6 years (SD = 5.8), assessed by psychiatric and physical examination (online suppl. methods and online suppl. table 1 ). Only male subjects were analyzed, given the expected limitations in measuring this potential mechanism in females, due to their cyclic (luteal and follicular phase of the menstrual cycle) and relative (e.g. P, estradiol) changes of several hormone levels. Some data from these subjects were already included in previous publications [1, 2] . The study was approved by the Ethics Committee of the Medical University of Vienna, and all participants provided written informed consent after receiving written and verbal explanation of the study. Positron Emission Tomography PET measurements with the GE Advance Scanner and procedures were done as published elsewhere [2] . [ Carbonyl 11 C]WAY100635 was prepared using a 11 C methylation synthesizer from Nuclear Interface (GE Medical Systems; for details, see online supplementary methods). Dynamic PET scans started simultaneously with intravenous bolus injection of [ carbonyl 11 C]WAY100635 in phosphate-buffered saline (pH 7.4). We collected 30 time frames in the total acquisition time of 90 min, divided into 15 frames of 1-min and 15 frames of 5-min measurement time. Volumes of interest (VOIs) were drawn manually on individual co-registered MR images. No realignment for head movement or partial volume correction was applied. Hormone Assays Hormonal levels used for statistics were the mean values of two plasma samples which were taken in the morning hours at 8: 51 a.m. (SD = 72.6 min) and 21 (SD = 10.4) minutes later. Assays were performed using the E170 Module (Roche E170 Modular Analytical System ! ). Electrochemiluminescence (ECLIA) was used for quantification of total P and cortisol, in plasma (for more details, see online suppl. methods and online suppl. table 2 ). Data Analysis For quantification of the 5-HT 1A receptor binding potential (BP ND ) we used the kinetic modeling tool of the image quantification and kinetic modeling software PMOD 2.7. (PMOD Technologies Ltd, Zurich, Switzerland; http://www.pmod.com/) [2] . The Simplified Reference Tissue Model (SRTM) based on a two-tissue compartmental model implemented in PMOD was applied using the cerebellar cortex as reference region (details are given in the online suppl. methods). A structural MR image from each subject was co-registered to the summed PET image using the statistical parametric mapping software SPM2 (http://www.fil.ion.ucl.ac.uk/spm/). Eight a priori defined regions of interest (ROIs) were delineated on co-registered MR images using PMOD 2.7 and on the summed PET image (raphe region). ROIs included the dorsal raphe nucleus, amygdala, hippocampus, orbitofrontal cortex, anterior cingulate cortex, posterior cingulate cortex, retrosplenial cortex and insula. Further details on data analysis and statistics are given in the online supplementary methods.