Sex differences in availability of β2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers

Arch Gen Psychiatry. 2012 Apr;69(4):418-27. doi: 10.1001/archgenpsychiatry.2011.1465.


Context: Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and response to nicotine therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β(2) subunit (β(2)*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women vs men.

Objectives: To examine β(2)*-nAChR availability in male and female smokers vs nonsmokers and to determine associations among β(2)*-nAChR availability, tobacco smoking characteristics, and female sex steroid hormone levels.

Design: Male (n = 26) and female (n = 28) tobacco smokers participated in an iodide 123-labeled 5-iodo-A-85380 ([(123)I]5-IA) single-photon emission computed tomography (SPECT) imaging session at 7 to 9 days of abstinence. Age-matched male (n = 26) and female (n = 30) nonsmokers participated in a [(123)I]5-IA SPECT imaging session. All participants completed a magnetic resonance imaging study.

Setting: Academic imaging center.

Participants: Tobacco smokers (n = 54) and age- and sex-matched nonsmokers (n = 56).

Main outcome measure: The [(123)I]5-IA SPECT images were converted to equilibrium distribution volumes and were analyzed using regions of interest.

Results: The β(2)*-nAChR availability was significantly higher in male smokers compared with male nonsmokers in striatum, cortex, and cerebellum, but female smokers did not have higher β(2)*-nAChR availability than female nonsmokers in any region. In women, β(2)*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the SPECT imaging day. In female smokers on imaging day, the progesterone level was positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal.

Conclusions: The regulatory effects of nicotine in the brain (ie, tobacco smoking-induced upregulation of β(2)*-nAChRs) seem to be distinctly different between men and women, and female sex steroid hormones likely have a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. To treat female smokers more effectively, it is critical that nonnicotinic-mediated medications should be explored.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Azetidines
  • Behavior, Addictive / blood
  • Behavior, Addictive / metabolism
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Depression / blood
  • Depression / metabolism
  • Estradiol / blood
  • Female
  • Functional Neuroimaging / methods
  • Functional Neuroimaging / psychology
  • Humans
  • Iodine Radioisotopes
  • Male
  • Nicotinic Antagonists
  • Progesterone / blood
  • Pyridines
  • Radioligand Assay / methods
  • Radioligand Assay / psychology
  • Receptors, Nicotinic / metabolism*
  • Sex Characteristics*
  • Smoking / blood
  • Smoking / metabolism*
  • Smoking / psychology
  • Substance Withdrawal Syndrome / blood
  • Substance Withdrawal Syndrome / metabolism
  • Tomography, Emission-Computed, Single-Photon / methods
  • Tomography, Emission-Computed, Single-Photon / psychology


  • 5-iodo-3-(2-azetidinylmethoxy)pyridine
  • Azetidines
  • Iodine Radioisotopes
  • Nicotinic Antagonists
  • Pyridines
  • Receptors, Nicotinic
  • nicotinic receptor beta2
  • Progesterone
  • Estradiol