Quantification of Smoking-Induced Occupancy of β₂-Nicotinic Acetylcholine Receptors: Estimation of Nondisplaceable Binding

Abstract

5-123I-iodo-85380 (123I-5-IA) is used to quantitate high-affinity nicotinic acetylcholine receptors (β2-nAChRs) on human SPECT scans. The primary outcome measure is VT/fP, the ratio at equilibrium between total tissue concentration (free, nonspecifically bound, and specifically bound) and the free plasma concentration. Nondisplaceable uptake (free plus nonspecific) of 123I-5-IA has not been measured in human subjects. Nicotine has high affinity for β2*-nAChRs (nAChRs containing the β2* subunit, for which * represents other subunits that may also be part of the receptor) and displaces specifically bound 123I-5-IA. In this study, we measured nicotine occupancy and nondisplaceable binding in healthy smokers after they had smoked to satiety. Methods Eleven nicotine-dependent smokers (mean age ± SD, 35.6 ± 14.4 y) completed the study. One subject was excluded from subsequent analyses because of abnormal blood nicotine levels. Subjects abstained from tobacco smoke for 5.3 ± 0.9 d and participated in a 15- to 17-h SPECT scanning day. 123I-5-IA was administered by bolus plus constant infusion, with a total injected dose of 361 ± 20 MBq. At approximately 6 h after the start of the infusion, three 30-min SPECT scans and a 15-min transmission–emission scan were acquired to obtain baseline β2*-nAChR availability. Subjects then smoked to satiety (2.4 ± 0.7 cigarettes), and arterial (first 40 min) and venous (until study completion) plasma nicotine and cotinine levels were collected. About 1 h after subjects had smoked to satiety, up to six 30-min SPECT scans were acquired. VT/fP data, computed from the tissue and plasma radioactivity measurements from the presmoking baseline and postsmoking scans, were analyzed using the Lassen plot method. Results Receptor occupancy after subjects had smoked to satiety was 67% ± 9% (range, 55%–80%). Nondisplaceable uptake was estimated as 19.4 ± 5.8 mL·cm−3 (range, 15–28 mL·cm−3). Thus, in the thalamus, where mean VT/fP is 93 mL·cm−3, nondisplaceable binding represents approximately 20% of the total binding. Conclusion These results are in agreement with previous findings and suggest that when satiating doses of nicotine are administered to smokers, imaging of receptor availability can yield valuable data, such as quantifiable measures of nondisplaceable binding.

Nicotinic acetylcholine receptor availability in cigarette smokers: effect of heavy caffeine or marijuana use

“…In addition to the participants described in this paper, 11 smokers completed study procedures, but were excluded from the data analysis because their plasma nicotine levels were unacceptably high (> 0.4 ng/mL) (determined after study participation). This issue of smokers using nicotine/tobacco during the abstinence period of a brain-imaging study has been reported in prior studies by our group and others (Brody et al 2013; Esterlis et al 2010; Staley et al 2006), presumably related to difficulty in having tobacco-dependent smokers remain abstinent for a prolonged period.…”

In Vivo Evidence for β2 Nicotinic Acetylcholine Receptor Subunit Upregulation in Smokers as Compared With Nonsmokers With Schizophrenia

“…Comparison subjects were excluded for lifetime exposure to psychiatric medication, except for smoking cessation attempts (and none in the past year). Nicotine dependence was evaluated with the Fagerström Test for Nicotine Dependence (20). Smoking status at screening was verified by a plasma cotinine level > 150 ng/ml, urine cotinine level > 100 ng/ml, and carbon monoxide (CO) level > 11 ppm at baseline.…”

“…β 2 * -nAChRs have been previously quantified with high affinity radioligand [ 123 I]-5 -iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([ 123 I]5-IA) (17) and SPECT (18). in a range of clinical samples including individuals with nicotine addiction (19, 20), alcohol use disorders (21), major depressive disorder (22), bipolar disorder (23), and schizophrenia (16)) [ 123 I]5-IA has slow dissociation from the receptor–ligand complex, a good specific to nonspecific binding ratio, and high selectivity for β 2 * -nAChRs (18, 24). We hypothesized that although there would be overall lower β 2 * -nAChR availability in individuals with vs. without schizophrenia, we would observe higher β 2 * -nAChR availability in smokers vs. nonsmokers with schizophrenia in the cortex, hippocampus, and striatum based on previous postmortem findings (15).…”

Measuring α4β2∗Nicotinic Acetylcholine Receptor Densityin Vivowith [18F]nifene PET in the Nonhuman Primate

“…Alternatively, previous PET and SPECT experiments found that smoking to satiety resulted in a4b2* nAChR occupancies of 70% to 100%. 36,38 These data suggest the possibility of incorporating a complete displacement dose of nicotine to regionally determine V ND in MI studies.…”