Sex Differences in Availability of β₂*-Nicotinic Acetylcholine Receptors in Recently Abstinent Tobacco Smokers

Abstract

Context Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and in response to nicotine replacement therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β2 subunit (β2*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women and men. Objective To examine β2*-nAChR availability between male and female smokers and nonsmokers. To determine relationships between β2*-nAChR availability and tobacco smoking characteristics and female sex steroid hormones. Design Male (n=26) and female (n=28) tobacco smokers participated in one [123I]5-IA-85380 ([123I]5-IA) single photon emission computed tomography (SPECT) scan at 7–9 days of abstinence. Age-matched male (n=26) and female (n=30) nonsmokers participated in a single [123I]5-IA SPECT scan. All participants completed 1 magnetic resonance imaging study. Setting Academic Imaging Center Participants Tobacco smokers (n=54) and age- and sex-matched nonsmokers (n=56). Main Outcome Measure [123I]5-IA SPECT images were converted to equilibrium distribution volumes and analyzed using regions-of-interest. Results β2*-nAChR availability was significantly higher in male smokers compared to male nonsmokers in striatum, cortex and cerebellum, but female smokers did not have higher β2*-nAChR availability than female nonsmokers in any region. In women, β2*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the day of the scan. In female smokers, on the day of the scan, progesterone levels were positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal. Conclusions The regulatory effects of nicotine in the brain, i.e., tobacco-smoking induced upregulation of β2*-nAChRs, appear to be distinctly different between men and women, and female sex hormones likely play a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. In order to treat female smokers more effectively, it is critical that non-nicotinic mediated medications are explored.

Treatment for Tobacco Dependence: Effect on Brain Nicotinic Acetylcholine Receptor Density

“…Furthermore, the trend-level findings in several of the exploratory analyses indicate that a larger sample size might provide an enhanced ability to differentiate responses to active vs placebo treatment and to elucidate the extent to which nAChR levels can be used to predict treatment response. A larger sample size would also allow for greater power to determine nAChR differences based on sex, as has been reported previously in smokers (Cosgrove et al, 2012). Additionally, it should be noted that bupropion HCl acts as a noncompetitive nAChR antagonist (Slemmer et al, 2000), which may have affected radiotracer binding or nAChR normalization, though the absence of between-group differences in normalization indicates against a specific effect of bupropion.…”

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

“…SPECT scans were performed 240 min after an intravenous single bolus injection of 187.3 ± 7.2 MBq of 123 I‐5‐IA 9, 10. These data were compared with a group of 12 healthy subjects (HC) age‐ (63.9 ± 11.7 years) and gender‐matched (5 males) 11, 12. Nineteen patients (10 PDSK and 9 PD) also performed a second SPECT with 123 I‐FP‐CIT to measure DAT density.…”

Cigarette Consumption and Related Factors in Schizophrenia, Schizoaffective Disorder and Delusional Disorder

“…Another gender difference in healthy people is the increase in nicotinic acetylcholine receptors containing the β2 subunit (β2*-nAChRs) in brain, which is caused by smoking (42). β2*-nAChRs in the striatum, cortex and cerebellum of smokers are more than that of nonsmokers.…”

“…There is no such difference between smoker and non-smoker women. It is thought that female sex hormones particularly progesterone, which has an inhibitory effect on β2*-nAChRs may have role in this difference (42,43).…”