title: Sex differences in availability of β2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Academic imaging center.
  
  
  METHODS
  Tobacco smokers (n = 54) and age- and sex-matched nonsmokers (n = 56).
  
  
  METHODS
  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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, West Haven, CT 06516, USA. kelly.cosgrove@yale.edu
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Cosgrove
authors.forename: Irina
authors.initials: I
authors.lastname: Esterlis
authors.forename: Sherry A
authors.initials: SA
authors.lastname: McKee
authors.forename: Frederic
authors.initials: F
authors.lastname: Bois
authors.forename: John P
authors.initials: JP
authors.lastname: Seibyl
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Mazure
authors.forename: Suchitra
authors.initials: S
authors.lastname: Krishnan-Sarin
authors.forename: Julie K
authors.initials: JK
authors.lastname: Staley
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: O'Malley
mesh_terms: D000328:Adult; D001384:Azetidines; D016739:Behavior, Addictive / Q000097:blood / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D003863:Depression / Q000097:blood / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005260:Female; D059907:Functional Neuroimaging / Q000379:methods / Q000523:psychology; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D018733:Nicotinic Antagonists; D011374:Progesterone / Q000097:blood; D011725:Pyridines; D011869:Radioligand Assay / Q000379:methods / Q000523:psychology; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012727:Sex Characteristics; D012907:Smoking / Q000097:blood / Q000378:metabolism* / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods / Q000523:psychology
chemical_list: D001384:Azetidines; D004958:Estradiol; D007457:Iodine Radioisotopes; D018733:Nicotinic Antagonists; D011374:Progesterone; D011725:Pyridines; D011978:Receptors, Nicotinic; C426745:5-iodo-3-(2-azetidinylmethoxy)pyridine