Context β2*-nicotinic acetylcholine receptor (β2*-nAChR) availability is higher in recently abstinent smokers compared to never smokers. Variations in β2*-nAChR availability over the course of abstinence may be related to the urge to smoke, the extent of nicotine withdrawal and successful abstinence. Objective To examine changes in β2*-nAChR availability during acute and prolonged abstinence from tobacco smoking and to determine how changes in β2*-nAChR availability were related to clinical features of tobacco smoking. Design Tobacco smokers participated in up to 4 [123I]5-IA-85380 ([123I]5-IA) single photon emission computed tomography (SPECT) scans during abstinence: 1 day (n=7), 1 week (n=17), 2 weeks (n=7), 4 weeks (n=11), and 6-12 weeks (n=6). Age-matched nonsmokers participated in 1 [123I]5-IA SPECT scan. All subjects completed 1 magnetic resonance imaging study. Setting Academic imaging center. Participants Tobacco smokers (n=19) and an age-matched nonsmoker comparison group (n=20). Main Outcome Measure [123I]5-IA SPECT images were converted to distribution volume and were analyzed using regions of interest. Results Compared to nonsmokers, β2*-nAChR availability in the striatum, cortex and cerebellum of smokers was not different at one day of abstinence, significantly higher at 1week of abstinence and not different at 4 or 6-12 weeks of abstinence. In smokers, at 6-12 weeks of abstinence, β2*-nAChR availability was significantly lower in the cortex and cerebellum compared to 1 week of abstinence. Additionally, cerebellar β2*-nAChR availability at 4 weeks of abstinence was positively correlated with craving on the day of scan. Conclusions These data suggest higher β2*-nAChR availability persists up to 1 month of abstinence, and normalizes to nonsmoker levels by 6-12 weeks of abstinence from tobacco smoking. These marked and persistent changes in β2*-nAChR availability may contribute to difficulties with tobacco cessation.

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Inhalant abuse is a world-wide public health concern among adolescents. Most preclinical studies have assessed inhalant effects in adult animals leaving unclear how behavioral effects differ in younger animals. We exposed adolescent (postnatal day [PN] 28) and adult (PN90) male rats to toluene using 1 of 3 exposure patterns. These patterns modeled those reported in toluene abuse in teens and varied concentration, number and length of exposures, as well as the inter-exposure interval. Animals were exposed repeatedly over 12 days to toluene concentrations of 0, 8,000 or 16,000 parts per million (ppm). Locomotor activity was quantified during toluene exposures and for 30 min following completion of the final daily toluene exposure. For each exposure pattern, there were significant toluene concentration-related increases and decreases in locomotor activity compared to the 0-ppm "air" controls at both ages. These changes depended upon when activity was measuredduring or following exposure. Compared to adults, adolescents displayed greater locomotor activity on the first day and generally greater increases in activity over days than adults during toluene exposure. Adults displayed greater locomotor activity than adolescents in the "recovery" period following exposure on the first and subsequent days. Age group differences were clearest following the pattern of paced, brief (5-min) repeated binge exposures. The results suggest that locomotor behavior in rats during and following inhalation of high concentrations of toluene depends on age and the pattern of exposure. The results are consistent with dose-dependent shifts in sensitivity and sensitization or tolerance to repeated toluene in the adolescent animals compared to the adult animals. Alternate interpretations are possible and our interpretation is limited by the range of very high concentrations of toluene used. The results imply that both pharmacological and psychosocial factors contribute to the teen prevalence of inhalant abuse.

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.

The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs). Previous studies examined β2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of β2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of β2*-nAChRs 2–5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5–5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of β2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms.

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In vivo imaging of adenosine 2A receptors (A 2A ) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of 123 I-MNI-420, a SPECT radiotracer for the in vivo imaging of A 2A in the brain. Methods: Nine healthy human subjects were enrolled in this study; 7 completed 123 I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating 123 I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. Results: 123 I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A 2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average testretest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. Conclusion: The data indicate that 123 I-MNI-420 is a useful SPECT radiotracer for imaging A 2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of 123 I-MNI-420 offers the possibility of investigating A 2A activity in specific conditions and evaluating drug occupancy for A 2A candidate therapeutics.