Nicotinic acetylcholine receptor availability in nonsmoker men and women

Abstract

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Objectives: To determine whether sex and cyclical differences in tobacco smoking are due to variations in the nicotinic acetylcholine receptor (nAChR) in brain. nAChRs containing the beta2 subunit (beta2-nAChR) are one of the initial sites of action of nicotine, and are critical for the reinforcing effects of nicotine. Methods: In the present study, we evaluated beta2-nAChR availability using single photon emission computed tomography (SPECT) and the nicotinic agonist radiotracer [I-123]5-IA-85380 ([I-123]5-IA) (1) in nonsmoker men and women and (2) in women nonsmokers across the menstrual cycle. Ten men and 19 age-matched women participated in one [I-123]5-IA scan and one MRI. Nine women participated in a second [I-123]5-IA scan, with scans performed during the (1)early follicular and (2)midluteal phases of the menstrual cycle. [I-123]5-IA was administered using a bolus to infusion ratio of 7.0 h and 3 consecutive 30 min scans were obtained between 6-8 h of infusion. nAChR availability was evaluated based on two outcome measures, VT’= regional activity/total parent and VT = regional activity /free plasma parent. Results: Using the outcome measure VT’, women vs. men had increased beta2-nAChR availability (12-16 % differences were observed in the thalamus, striatum and cortex); however, using the outcome measure VT, no sex differences in beta2-nAChR availability were apparent. The difference in findings between outcome measures was due to a statistically significant difference in the free fraction between men and women (men: 0.31+.04; women: 0.35 +.04; p= 0.01). Beta2-nAChR availability did not differ across the menstrual cycle for either VT’ or VT. Women also had significantly higher free parent (p=0.05) and a trend (p=.052) toward higher total parent compared to men. Conclusions: These findings indicate no sex difference or menstrual cycle effect on beta2-nAChR availability in nonsmokers. Importantly, these findings demonstrate sex differences in protein binding, and the importance of measuring the free fraction (f1) in human subjects.

Research Support (if any): Supported by RO1DA015577, P50AA15632, KO1DA020651, and the Ethel F. Donaghue Women’s Health Investigator Program of Women’s Health Research at Yale.