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CENTURY
Yale University
School of Medicine
SAC-S203
Connecticut
Mental Health Center
34 Park Street
New Haven, CT 06519

Phone:
203-974-7591

Fax:
203-974-7606

E-mail:
infocentury@yale.edu

CENTURY/TTURC Story

[123I]5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Cycle Phase

Abstract
The study of the effects of sex and hormones on brain chemistry and neurotransmission are of increasing importance as evidence emerges for sex differences in behavioral symptoms and treatment response in neuropsychiatric disorders. The nicotinic acetylcholine receptor (nAChR) system has been implicated in a variety of psychiatric disorders including tobacco smoking, for which there is strong evidence supporting sex differences in behaviors and response to smoking cessation treatments.  We examined β2-nAChR availability in healthy men and women, and the influence of phase of menstrual cycle among women.

Methods: 10 men and 19 women nonsmokers participated in one [123I]5-IA-85380 ([123I]5-IA) single photon emission computed tomography (SPECT) scan and one magnetic resonance imaging (MRI) study.  A subset of 9 women, aged 18-39, participated in a second [123I]5-IA scan.  These 9 women were scanned during the early follicular (days 4-7 and one subject on day 11) and midluteal (days19-25) phases of their menstrual cycle.  Hormone levels were obtained in all women to confirm phase of cycle. Results: Regional brain activity (kBq/cc) was higher (39-54%) in women versus men nonsmokers. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (VT’), 10-16 % differences were observed, with women greater than men. Whereas, when regional brain activity was normalized to free plasma parent (VT), there was less than a 4% difference by sex in regional brain β2-nAChR availability. These sex differences in kBq/cc and VT’ resulted from significantly higher levels of total plasma parent, free fraction (f1) and free plasma parent in women versus men nonsmokers. No differences in plasma measures or brain β2-nAChR availability were observed across the menstrual cycle for any of the outcome measures.

Conclusions: Overall these findings demonstrate no significant difference in brain β2-nAChR availability between men and women nonsmokers, or across the menstrual cycle. Importantly, these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding, and highlight the critical need to measure plasma radiotracer levels and the free fraction in studies including both sexes.

Kelly P. Cosgrove, PhD1,2, Effie M. Mitsis, PhD1,2, Frederic Bois, PhD1,2, Erin Frohlich, MA1,2, Gilles D. Tamagnan, PhD1,4, Erica Krantzler1,2, Edward Perry, MD1,2, Paul K. Maciejewski, PhD1, C. Neill Epperson, MD1, Sharon Allen, MD3, Stephanie O’Malley, PhD1, Carolyn M. Mazure, PhD1, John P. Seibyl, MD4, Christopher H. van Dyck, MD1 and Julie K. Staley, PhD1,2

1. Yale University School of Medicine, New Haven, CT
2. Veterans Affairs Connecticut Healthcare System, West Haven, CT
3. University of Minnesota, Minneapolis, MN
4. Institute for Neurodegenerative Disorders, New Haven, CT

Journal of Nuclear Medicine, October, 2007, 48:1633-40