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1.  Treatment for Tobacco Dependence: Effect on Brain Nicotinic Acetylcholine Receptor Density 
Neuropsychopharmacology  2013;38(8):1548-1556.
Cigarette smoking leads to upregulation of brain nicotinic acetylcholine receptors (nAChRs), including the common α4β2* nAChR subtype. Although a substantial percentage of smokers receive treatment for tobacco dependence with counseling and/or medication, the effect of a standard course of these treatments on nAChR upregulation has not yet been reported. In the present study, 48 otherwise healthy smokers underwent positron emission tomography (PET) scanning with the radiotracer 2-FA (for labeling α4β2* nAChRs) before and after treatment with either cognitive-behavioral therapy, bupropion HCl, or pill placebo. Specific binding volume of distribution (VS/fP), a measure proportional to α4β2* nAChR density, was determined for regions known to have nAChR upregulation with smoking (prefrontal cortex, brainstem, and cerebellum). In the overall study sample, significant decreases in VS/fP were found for the prefrontal cortex, brainstem, and cerebellum of −20 (±35), −25 (±36), and −25 (±31)%, respectively, which represented movement of VS/fP values toward values found in non-smokers (mean 58.2% normalization of receptor levels). Participants who quit smoking had significantly greater reductions in VS/fP across regions than non-quitters, and correlations were found between reductions in cigarettes per day and decreases in VS/fP for brainstem and cerebellum, but there was no between-group effect of treatment type. Thus, smoking reduction and cessation with commonly used treatments (and pill placebo) lead to decreased α4β2* nAChR densities across brain regions. Study findings could prove useful in the treatment of smokers by providing encouragement with the knowledge that decreased smoking leads to normalization of specific brain receptors.
doi:10.1038/npp.2013.53
PMCID: PMC3682149  PMID: 23429692
Addiction & Substance Abuse; Biological Psychiatry; Bupropion; Cognitive-Behavioral Therapy; Imaging; Clinical or Preclinical; Nicotine; Nicotinic Acetylcholine Receptor; Psychiatry & Behavioral Sciences; Tobacco Dependence; tobacco dependence; nicotine; nicotinic acetylcholine receptor; bupropion; cognitive-behavioral therapy; positron emission tomography
2.  Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers 
One-third of smokers primarily use menthol cigarettes and usage of these cigarettes leads to elevated serum nicotine levels and more difficulty quitting in standard treatment programmes. Previous brain imaging studies demonstrate that smoking (without regard to cigarette type) leads to up-regulation of β2*-containing nicotinic acetylcholine receptors (nAChRs). We sought to determine if menthol cigarette usage results in greater nAChR up-regulation than non-menthol cigarette usage. Altogether, 114 participants (22 menthol cigarette smokers, 41 non-menthol cigarette smokers and 51 non-smokers) underwent positron emission tomography scanning using the α4β2* nAChR radioligand 2-[18F]fluoro-A-85380 (2-FA). In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9–28% higher α4β2* nAChR densities than non-menthol smokers across regions. In comparing the entire group of smokers to non-smokers, an overall test revealed a significant between-group difference, resulting from smokers having higher α4β2* nAChR levels in all regions studied (36–42%) other than thalamus (3%). Study results demonstrate that menthol smokers have greater up-regulation of nAChRs than non-menthol smokers. This difference is presumably related to higher nicotine exposure in menthol smokers, although other mechanisms for menthol influencing receptor density are possible. These results provide additional information about the severity of menthol cigarette use and may help explain why these smokers have more trouble quitting in standard treatment programmes.
doi:10.1017/S1461145712001022
PMCID: PMC3758251  PMID: 23171716
Age; nicotine dependence; nicotinic acetylcholine receptor; positron emission tomography; tobacco
3.  The Biology of Tobacco and Nicotine: Bench to Bedside 
Strong epidemiologic evidence links smoking and cancer. An increased understanding of the molecular biology of tobacco-related cancers could advance progress toward improving smoking cessation and patient management. Knowledge gaps between tobacco addiction, tumorigenesis, and cancer brought an interdisciplinary group of investigators together to discuss “The Biology of Nicotine and Tobacco: Bench to Bedside.” Presentations on the signaling pathways and pathogenesis in tobacco-related cancers, mouse models of addiction, imaging and regulation of nicotinic receptors, the genetic basis for tobacco carcinogenesis and development of lung cancer, and molecular mechanisms of carcinogenesis were heard. Importantly, new opportunities to use molecular biology to identify and abrogate tobacco-mediated carcinogenesis and to identify high-risk individuals were recognized.
doi:10.1158/1055-9965.EPI-04-0652
PMCID: PMC3459058  PMID: 15824140
4.  Effect of Secondhand Smoke on Occupancy of Nicotinic Acetylcholine Receptors in Brain 
Archives of General Psychiatry  2011;68(9):953-960.
Context
Despite progress in tobacco control, secondhand smoke (SHS) exposure remains prevalent worldwide and is implicated in the initiation and maintenance of cigarette smoking.
Objective
To determine whether moderate SHS exposure results in brain α4β2* nicotinic acetylcholine receptor (nAChR) occupancy.
Design, Setting, and Participants
Positron emission tomography scanning and the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (also known as 2-[18F]fluoro-A-85380, or 2-FA) were used to determine α4β2* nAChR occupancy from SHS exposure in 24 young adult participants (11 moderately dependent cigarette smokers and 13 nonsmokers). Participants underwent two bolus-plus-continuous-infusion 2-FA positron emission tomography scanning sessions during which they sat in the passenger’s seat of a car for 1 hour and either were exposed to moderate SHS or had no SHS exposure. The study took place at an academic positron emission tomography center.
Main Outcome Measure
Changes induced by SHS in 2-FA specific binding volume of distribution as a measure of α4β2* nAChR occupancy.
Results
An overall multivariate analysis of variance using specific binding volume of distribution values revealed a significant main effect of condition (SHS vs control) (F1,22=42.5, P <.001) but no between-group (smoker vs nonsmoker) effect. Exposure to SHS led to a mean 19% occupancy of brain α4β2* nAChRs (1-sample t test, 2-tailed, P <.001). Smokers had both a mean 23% increase in craving with SHS exposure and a correlation between thalamic α4β2* nAChR occupancy and craving alleviation with subsequent cigarette smoking (Spearman ρ= −0.74, P =.01).
Conclusions
Nicotine from SHS exposure results in substantial brain α4β2* nAChR occupancy in smokers and nonsmokers. Study findings suggest that such exposure delivers a priming dose of nicotine to the brain that contributes to continued cigarette use in smokers. This study has implications for both biological research into the link between SHS exposure and cigarette use and public policy regarding the need to limit SHS exposure in cars and other enclosed spaces.
doi:10.1001/archgenpsychiatry.2011.51
PMCID: PMC3380615  PMID: 21536968
5.  Baseline expression of α4 β2* nicotinic acetylcholine receptors predicts motivation to self-administer nicotine 
Biological psychiatry  2008;65(8):714-716.
Background
Marked inter-individual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of inter-individual differences in midbrain nAChR levels on motivation to self-administer nicotine.
Methods
Baseline levels of α4β2* nAChRs were measured using 2-[18F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine was subsequently measured using a progressive-ratio (PR) schedule of reinforcement.
Results
Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs.
Conclusions
The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D2 receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and non-human primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems.
doi:10.1016/j.biopsych.2008.09.036
PMCID: PMC2687082  PMID: 19095220
positron emission tomography; non-human primates; nicotinic receptors; nicotine self-administration; in vivo binding
6.  Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates 
Biological psychiatry  2008;64(11):930-937.
Background
CB1 cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors, however, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys.
Methods
We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Δ9-tetrahydrocannabinol (THC), anandamide or cocaine, and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay.
Results
URB597 (0.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597 and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine even though, as expected, it significantly potentiated anandamide self-administration.
Conclusions
In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system, and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.
doi:10.1016/j.biopsych.2008.08.008
PMCID: PMC2701259  PMID: 18814866
Anandamide; FAAH; self-administration; reinstatement; URB597; 2-arachidonoylglycerol
7.  Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette 
Our group recently reported that smoking a regular cigarette (1.2–1.4 mg nicotine) resulted in 88% occupancy of brain α4β2* nicotinic acetylcholine receptors (nAChRs). However, this study did not determine whether nicotine inhalation or the many other pharmacological and behavioural factors that occur during smoking resulted in this receptor occupancy. If nicotine is solely responsible for α4β2* nAChR occupancy from smoking, then (as estimated from our previous data) smoking a denicotinized (0.05 mg nicotine) or a low-nicotine (0.6 mg nicotine) cigarette (commonly used for research and clinical purposes) would result in substantial 23% and 78% α4β2* nAChR occupancies, respectively, and a plasma nicotine concentration of 0.87 ng/ml would result in 50% α4β2* nAChR occupancy (EC50). Twenty-four positron emission tomography sessions were performed on tobacco-dependent smokers, using 2-[F-18]fluoro-A-85380 (2-FA), a radiotracer that binds to α4β2* nAChRs. 2-FA displacement was determined from before to 3.1 hours after either: no smoking, smoking a denicotinized cigarette, or smoking a low-nicotine cigarette. Analysis of this PET data revealed that smoking a denicotinized and a low-nicotine cigarette resulted in 26% and 79% α4β2* nAChR occupancies, respectively, across three regions of interest. The EC50 determined from this dataset was 0.75 ng/ml. Given the consistency of findings between our previous study with regular cigarettes and the present study, nicotine inhalation during smoking appears to be solely responsible for α4β2* nAChR occupancy, with other factors (if present at all) having either short-lived or very minor effects. Furthermore, smoking a denicotinized cigarette resulted in substantial nAChR occupancy.
doi:10.1017/S146114570800922X
PMCID: PMC2773668  PMID: 18706128
Denicotinized cigarette; nicotine; nicotinic acetylcholine receptors; positron emission tomography; thalamus; tobacco
8.  Cigarette Smoking Saturates Brain α4 β2 Nicotinic Acetylcholine Receptors 
Archives of general psychiatry  2006;63(8):907-915.
Context
2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a recently developed radioligand that allows for visualization of brain α4β2* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans.
Objective
To determine the effect of cigarette smoking on α4β2* nAChR occupancy in tobacco-dependent smokers.
Design
Fourteen 2-FA PET scanning sessions were performed. During the PET scanning sessions, subjects smoked 1 of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2½ to 3 cigarettes]).
Setting
Academic brain imaging center.
Participants
Eleven tobacco-dependent smokers (paid volunteers).
Main Outcome Measure
Dose-dependent effect of smoking on occupancy of α4β2* nAChRs, as measured with 2-FA and PET in nAChR-rich brain regions.
Results
Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of α4β2* nAChRs for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. A venous plasma nicotine concentration of 0.87 ng/mL (roughly 125th of the level achieved in typical daily smokers) was associated with 50% occupancy of α4β2* nAChRs.
Conclusions
Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of α4β2* nAChRs, indicating that tobacco-dependent smokers maintain α4β2* nAChR saturation throughout the day. Because prolonged binding of nicotine to α4β2* nAChRs is associated with desensitization of these receptors, the extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChRs in the desensitized state.
doi:10.1001/archpsyc.63.8.907
PMCID: PMC2773659  PMID: 16894067
9.  Greater Nicotinic Acetylcholine Receptor Density in Smokers Than in Nonsmokers: A PET Study with 2-18F-FA-85380 
Assays of human postmortem brain tissue have revealed that smokers have greater densities of high-affinity nicotinic acetylcholine receptors (nAChRs) in several brain regions than do nonsmokers or exsmokers. Quantitative PET imaging of nAChRs in humans has recently been reported using the α4β2* subtype–specific radioligand 2-18F-FA-85380 (2FA).
Methods
We used PET and 2FA to measure total volumes of distribution corrected for the free fraction of 2FA in plasma (VT/fP) in 10 nonsmokers and 6 heavy smokers (>14 cigarettes/d; abstinent for >36 h). Dynamic PET scans were performed over 8 h, commencing immediately after a bolus injection of 2FA. Anatomic sampling was performed on PET images that were coregistered to MR images acquired from each volunteer. Data were analyzed by Logan plots and by 1- and 2-tissue-compartment models using unbound, unmetabolized arterial 2FA concentration as the input function.
Results
All modeling methods yielded similar results. VT/fP was significantly higher in smokers than in nonsmokers in all brain regions tested, except the thalamus. We used measures of VT/fP and estimates of nondisplaceable volume of distribution and found 25%–200% higher values in smokers than in nonsmokers for the volume of distribution for the specific binding compartment in the frontal cortex, midbrain, putamen, pons, cerebellum, and corpus callosum. These findings were consistent with voxel-based analysis using statistical parametric mapping.
Conclusion
Our findings suggest that PET with 2FA can be used to study the role of nicotine-induced upregulation of nAChRs in active smokers and during smoking cessation.
doi:10.2967/jnumed.108.050716
PMCID: PMC2766917  PMID: 18794265
molecular imaging; PET; radiotracer tissue kinetics; neuroimaging; nicotinic acetylcholine receptors; smoking
10.  Quantification of nicotinic acetylcholine receptors in the human brain with PET: Bolus plus infusion administration of 2-[18F]F-A85380 
NeuroImage  2007;39(2):717-727.
Quantitative analysis of most positron emission tomography (PET) data requires arterial blood sampling and dynamic scanning when the radioligand is administered as a bolus injection. Less invasive studies can be accomplished if the radioligand is administered as a bolus plus constant infusion (B/I). The purpose of the current study was to evaluate a B/I paradigm for quantifying high affinity nicotinic acetylcholine receptors (nAChRs) with PET and 2-[18F]F-A85380 (2FA). Seven volunteers underwent a study in which 2FA was administered as a bolus injection and another study in which the 2FA was administered by B/I (Kbolus = 500 min). We evaluated the feasibility of using scans of a 2 h duration starting 6 h after the start of the 2FA administration and data from venous blood. Radioactivity in the brain and in arterial and venous plasma reached steady state by 6 h. Volumes of distribution (VT) calculated from the ratio of radioactivity in the brain areas of interest to the radioactivity corresponding to unbound, unmetabolized 2FA in venous plasma at steady state in the B/I studies were very similar to those calculated from time activity curves of unbound, unmetabolized 2FA in arterial plasma and regional brain radioactivity from 8-h dynamic scans after bolus administration of 2FA. The results of repeated PET studies with 2FA showed a high reproducibility of VT measurements. We conclude that B/I methodology will be useful for clinical and research studies of brain nAChRs.
doi:10.1016/j.neuroimage.2007.09.01
PMCID: PMC2386978  PMID: 17962044
11.  Quantification of α4β2* nicotinic receptors in the rat brain with microPET® and 2-[18F]F-A-85380 
NeuroImage  2006;34(4):1352-1362.
The radioligand 2-[18F]F-A-85380 has been used for PET studies of the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) in the living brain of humans and nonhuman primates. In order to extend the capacity of microPET to quantify neuroreceptors in rat brain, we carried out studies of 2-[18F]F-A-85380 to measure the apparent bindng potential BP* in individual rats, which were studied repeatedly over several months. Using a bolus-plus-infusion paradigm, 2-[18F]F-A-85380 (specific activity 20 - 1300 GBq/μmol) was administered intravenously over 8 to 9 h with Kbol values of 350 to 440 min and a mean infusion rate of 0.03 ± 0.01 nmol/kg/h. Studies included a 2-h nicotine infusion initiated 2 h before the end of scanning to displace specifically bound radioactivity. Steady state binding in brain was obtained within 5 h as defined by the occurrence of constant radioactivity concentrations in brain regions and constant, free arterial plasma levels of nonmetabolized radioligand. BP* averages (± SEM) for thalamus, forebrain, and cerebellum were 5.9 ± 0.7, 2.6 ± 0.4, and 1.0 ± 0.1, respectively, which are consistent with the α4β2* nAChR distribution in rat brain measured in vitro. Studies of receptor occupancy determined the ED50 to be 0.29 nmol/kg/h. The demonstration that α4β2* nAChRs are quantifiable in the rat brain using PET measurements, coupled with the ability to conduct longitudinal studies over several months in the same rats, suggests potential applications to studies of chronic nicotine use, its treatment, and abnormal functioning of α4β2* receptors in a rat model.
doi:10.1016/j.neuroimage.2006.10.036
PMCID: PMC2023973  PMID: 17187994

Results 1-11 (11)