123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Phase
Kelly P. Cosgrove 1*,
Effie M. Mitsis 1,
Frederic Bois 1,
Erin Frohlich 1,
Gilles D. Tamagnan 2,
Erica Krantzler 1,
Edward Perry 1,
Paul K. Maciejewski 3,
C. Neill Epperson 3,
Sharon Allen 4,
Stephanie O'Malley 3,
Carolyn M. Mazure 3,
John P. Seibyl 5,
Christopher H. van Dyck 3,
and
Julie K. Staley 1
1 Yale University School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
2 Yale University School of Medicine, New Haven, Connecticut; Institute for Neurodegenerative Disorders, New Haven, Connecticut
3 Yale University School of Medicine, New Haven, Connecticut
4 University of Minnesota, Minneapolis, Minnesota
5 Institute for Neurodegenerative Disorders, New Haven, Connecticut
* To whom correspondence should be addressed. E-mail: kelly.cosgrove{at}yale.edu.
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Abstract |
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The study of the effects of sex and hormones on brain chemistry and neurotransmission is of increasing importance as evidence emerges of 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 the availability of nAChR containing the 
2 subunit in healthy men and women and the influence of menstrual phase among women. Methods: Ten men and 19 women nonsmokers underwent one 123I-5-IA-85380 (123I-5-IA) SPECT scan and one MRI scan. A subset of 9 women, aged 18–39 y, underwent a second 123I-5-IA scan. These 9 women were scanned during the early follicular (days 4–7 in 8 subjects and day 11 in 1 subject) and mid-luteal (days 19–25) phases of their menstrual cycle. Hormone levels were measured in all women to confirm the phase of the cycle. Results: Regional brain activity (kBq/cm3) was higher (39%–54%) in women than in men nonsmokers. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (VT'), differences of 10%–16% were observed, with women greater than men. In contrast, when regional brain activity was normalized to free plasma parent (VT), there was less than a 4% difference by sex in regional brain 2-nAChR availability. These sex differences in kBq/cm3 and VT' resulted from significantly higher levels of total plasma parent, free fraction (f1), and free plasma parent in women than in men nonsmokers. No differences in plasma measures or brain 2-nAChR availability were observed across the menstrual cycle for any outcome measure. Conclusion: Overall, these findings demonstrate no significant difference in brain 2-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 f1 in studies that include both sexes.
Key Words:
nicotinic, 123I-5-IA-85380, free fraction, sex, menstrual cycle, SPECT
