Abstract
There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20–80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [11C]WAY100635 and [18F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (VT) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age2, sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004–0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05–0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03–0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex–hormone–serotonin receptor relationships.
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Acknowledgements
This research study was supported by R01s MH67602 and MH71944. Support to CC Meltzer, EL Moses-Kolko, S Berga, SM Sereika, JC Price, R Coleman, and C Becker was provided by R01 MH067602. Dr Price received additional support through K02 AG027998, and EL Moses-Kolko received additional support through RO1 MH079164. Support for Nilesh Shah was through 5T32 GM074927. Support for Patrick M Fisher was through the Multi-modal Neuroimaging Training Program at the University of Pittsburgh (DA023420).
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Dr Moses-Kolko received a small honorarium as a guest speaker for La Leche League regional conference, Summer 2009. Over the past 3 years, N Scott Mason has received compensation from Janssen Pharmaceuticals, Elan Pharmaceuticals, Banner Alzheimer's Institute, and the Gollman Group (Dallas, TX). Dr Sarah Berga has served on the Board of Directors and as a consultant for numerous organizations (itemized below). Member of University of Virginia Medical Alumni Association Board of Directors, 2007 to present (Gratis); consultant for Agile Therapeutics Medical Advisory Board—March 2011; AHC Media, LLC—consultant, Annual business meeting—April 2008, April 2009, June 2010, Noven Pharmaceutical Medical Advisory Board—Feb 2010, Promedica Communications—Bayer Pharmaceutical Medical Advisory Board, Meeting—June 2009, August 2009, Watson Pharmaceutical Women's Health Strategic Advisory Board—April 2010; Legal consulting for Kirkland and Ellis, LLCLeydig, Voit & Mayer, LLC, and Reed Smith, LLC; Editorial board for ACOG, Editorial Committee, Guidelines for Women's Health Care, 2009–2011 (Gratis), American Journal of Obstetrics and Gynecology, 2003 to present (Gratis), Advisory Board for Subspecialty Neuroendocrinology and Reproductive Neurobiology, The Endocrine Society Member, Endocrine Self-Assessment Program Committee (June 2007–June 2011), Clinical Practice Guideline Task Force on Hypothalamic Amenorrhea, January 2011 to present (Gratis), Editorial Board for Endocrinology, January 2010 to present (Gratis), Menopause, Editorial Board, 1999 to present (Gratis). NIH Study Section reviewer; Society for Women's Health Research, ISIS CVD Network Member, 2009 to present; UpToDate Peer Review Board, 2005 to present. Julie C Price, Susan M Sereika, Patrick M Fisher, Rhaven Coleman, Carl Becker, Tammy Loucks, Carolyn C Meltzer, and Nilesh Shah declare no conflict of interest.
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Moses-Kolko, E., Price, J., Shah, N. et al. Age, Sex, and Reproductive Hormone Effects on Brain Serotonin-1A and Serotonin-2A Receptor Binding in a Healthy Population. Neuropsychopharmacol 36, 2729–2740 (2011). https://doi.org/10.1038/npp.2011.163
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