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Original Article |

Cigarette Smoking Saturates Brain α4β2 Nicotinic Acetylcholine Receptors FREE

[+] Author Affiliations

Author Affiliations: Department of Psychiatry and Biobehavioral Sciences (Drs Brody and London, Mr Scheibal, and Mss Jou, Allen, and Tiongson), University of California, Los Angeles; Greater Los Angeles Veterans Affairs Healthcare System Positron Emission Tomography Center (Drs Brody, Mandelkern, London, Olmstead, and Farahi, Mr Scheibal, and Mss Jou, Allen, and Tiongson), Los Angeles; Department of Physics, University of California, Irvine (Dr Mandelkern); Intramural Research Program, Neuroimaging Research Branch, National Institute on Drug Abuse, Rockville, Md (Drs Chefer and Mukhin); and Institute for Neurodegenerative Disorders, New Haven, Conn (Dr Koren).


Arch Gen Psychiatry. 2006;63(8):907-914. doi:10.1001/archpsyc.63.8.907.
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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 1/25th 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.

Figures in this Article

Tobacco dependence (primarily through cigarette smoking) is a major risk factor for death and disability worldwide.1,2 This condition is relatively resistant to treatment, as evidenced by the fact that most smokers endorse a desire to quit3 but very few are able to do so on their own4 and fewer than half are able to quit long-term even with comprehensive treatment.3,5 A greater understanding of the mechanisms that underlie tobacco dependence may aid in the development of improved treatments for this condition.

Of the thousands of components of tobacco smoke, nicotine is the one that is most closely linked to tobacco dependence.6 Nicotine administration provides positive reinforcement7,8 and ameliorates a range of behavioral states that accompany smoking abstinence, including irritability,9 anxiety,9 and deficits in cognitive performance.1012 Extensive animal research demonstrates that the interaction of nicotine with nicotinic acetylcholine receptors (nAChRs)13 (along with associated actions of nicotine) activates dopamine pathways projecting to the nucleus accumbens,1419 leading to positive reinforcement.8,20

The nAChR containing α4 and β2 subunits (α4β2* subtype) is the predominant receptor subtype in the mammalian brain, and the α421 and β22225 subunits have been linked to the positive-reinforcing (and cognitive function–enhancing) effects of nicotine. Nicotine has high affinity for α4β2* receptors, and therefore, these receptors are considered as primary targets for the actions of nicotine during cigarette smoking. Studies with engineered mutant mice suggest that α4β2* nAChRs are necessary and sufficient to exhibit in vivo effects of smoking, such as tolerance and sensitization.21

The affinity of nicotine for the α4β2* nAChR measured in vitro is in the range of 0.5 to 14 nmol,26 which is equal to a concentration of 0.01 to 2.3 ng/mL. Typical human smokers have venous plasma nicotine concentrations of 10 to 50 ng/mL during the day.27 Based on these reports, we hypothesized that human cigarette smoking results in nearly complete saturation of α4β2* nAChRs.

2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a radiotracer recently developed for the in vivo imaging of α4β2* nAChRs with positron emission tomography (PET).2830 Positron emission tomography studies in nonhuman primates demonstrate that receptor binding of 2-FA31 (and another PET radiotracer for α4β2* nAChRs32) can be decreased by administration of nicotine or inhalation of tobacco smoke. Recent studies have demonstrated the safety of this radiotracer for use in humans.30,3335 Using 2-FA and PET, we sought to determine the effect of cigarette smoking on brain α4β2* nAChR occupancy in tobacco-dependent smokers.

SUBJECTS

Eleven tobacco-dependent smokers (≥20 cigarettes per day), who were recruited through advertisements in local newspapers and the Internet, participated in the study. Eight subjects were scanned only once in an experimental (smoking) condition, while 3 subjects underwent 2 scanning sessions, 1 in an experimental (smoking) condition and 1 in a control (no smoking) condition, as described later, so that a total of 14 PET scanning sessions were performed for this study. Subjects met DSM-IV criteria for nicotine dependence but were otherwise healthy.

Initial screening consisted of an anonymous telephone interview in which medical, psychiatric, and substance abuse histories were obtained. Qualified subjects were then assessed in person using screening questions from the Structured Clinical Interview for DSM-IV36 2 days prior to PET scanning. The central inclusion criterion was the DSM-IV diagnosis of nicotine dependence, while any history of an Axis I psychiatric or substance abuse/dependence diagnosis other than nicotine dependence was exclusionary. Other exclusion criteria were pregnancy and current use of medications or any history of a medical condition that might affect the central nervous system at the time of scanning (eg, current treatment with a β-blocker or analgesic medication or history of head trauma with loss of consciousness or epilepsy). Women of childbearing potential had a urine pregnancy test. Subjects who occasionally used alcohol, caffeine, or other drugs, but did not meet criteria for abuse or dependence, were allowed to participate in the study but were instructed to abstain for the 2 days prior to PET scanning. Subjects who drank more than the equivalent of 2 cups of coffee per day (300 mg of caffeine per day) were also excluded, as were subjects who experienced caffeine withdrawal symptoms (such as irritability, flushing, or headache) temporally associated with caffeine ingestion. After complete description of the study to subjects, written informed consent was obtained using forms approved by the local institutional review board.

During the initial visit, additional screening data were obtained, including the smoker's profile form (which includes smoking history data, such as current smoking level, years smoked, brand of cigarette smoked, and quit periods) and scores on the Fagerström Test for Nicotine Dependence,37,38 the Beck Depression Inventory,39 the Spielberger State-Trait Anxiety Inventory,40 and the Shiffman-Jarvik Withdrawal Scale.41 An exhaled carbon monoxide (CO) level was obtained using the MicroSmokerlyzer (Bedfont Scientific Ltd, Kent, England) at the initial visit to verify smoking status (subjects were considered to be active smokers if a CO level of ≥8 ppm was obtained).

GENERAL STUDY DESIGN

Participants underwent the following sequence of procedures (described in greater detail later): abstinence from cigarettes and nicotine-containing products for 2 days, a bolus-plus–continuous infusion 2-FA PET scanning session including smoking between 0 and 3.5 cigarettes, blood sampling for plasma nicotine levels and withdrawal symptom monitoring during the PET scanning session, and structural magnetic resonance imaging (MRI) of the brain within 1 week of PET scanning to aid in localization of regions of interest on PET scans.

ABSTINENCE PERIOD

After the initial screening, participants were instructed to begin smoking/nicotine abstinence at 6 PM 2 nights prior to PET scanning. They reported to our laboratory at 1 PM the day after initiating abstinence. At that time, an exhaled CO level was measured and a brief clinical interview was performed. Participants were deemed to be compliant with study protocol if they reported no smoking since 6 PM the previous night and had an exhaled CO measurement of 8 ppm or less. Subjects were then seen the following day for PET scanning and were required to report continuous abstinence since 2 nights previously and have an exhaled CO level of 3 ppm or less to undergo PET scanning.

PET PROTOCOL

At noon on the day of PET scanning, subjects arrived at the Greater Los Angeles Veterans Affairs Healthcare System PET Center, and abstinence was verified as described earlier. Each participant then had an intravenous catheter placed at 12:45 PM in a room adjacent to the PET scanner. At 1 PM, bolus-plus–continuous infusion 2-FA was initiated. In this study, the amount of 2-FA administered as a bolus was equal to the amount infused over 500 minutes (Kbolus = 500 minutes).42,43 Consistent with this paradigm, 144 MBq (mean ± SD, 3.88 ± 0.16 mCi) of 2-FA was administered as an intravenous bolus, followed by continuous infusion of 138 MBq (mean ± SD, 3.72 ± 0.15 mCi) in 57.6 mL of saline over the next 480 minutes (7.2 mL per hour) for a total effective dose of radioactivity of 187.5 MBq (mean ± SD, 5.08 ± 0.21 mCi). All PET scans were obtained as series of 10-minute frames.

Three PET scanning sessions were performed without smoking, as control sessions. For 2 of these sessions, subjects were positioned in the scanner before administration of 2-FA, and PET scanning began at the time of bolus injection and continued for 8 hours with 7 scheduled breaks and no smoking to demonstrate the full time-activity curves for the 2-FA method used herein (Figure 1). For the third session, a subject preferred not to be scanned for the full 8 hours and was scanned without smoking, using the shorter (5 hours) scanning protocol as in the experimental sessions described next.

Place holder to copy figure label and caption
Figure 1.

Time-activity curves (mean ± SEM) for the 2 subjects undergoing full (8 hours) scanning with no smoking. The graphs demonstrate that 3 to 4 hours from the beginning of radioligand infusion are needed to reach a near steady state in the primary regions of interest for the bolus/infusion paradigm used herein. The average increase in radioactivity starting 3.5 hours after initiation of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380) administration was 3.2%, 3.2%, and 2.6% per hour for the thalamus, brainstem, and cerebellum, respectively.

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For the 11 experimental sessions with smoking, subjects received the bolus injection of 2-FA in a room adjacent to the PET scanner. They then remained seated in this room for the next 3 hours to allow the radiotracer to reach a relatively steady state. At 4 PM, brain scanning commenced and continued for 60 minutes. At 5 PM (4 hours after the initiation of 2-FA administration), subjects had a 10-minute break in scanning, during which they smoked between 0 and 3 cigarettes of their favorite brand (because we were interested in studying α4β2* nAChR occupancy from typical smoking conditions). All subjects smoked regular (not light) cigarettes with similar nicotine yields (range, 1.2-1.4 mg).44 The 5 smoking levels for this study were no smoking (n = 3); a single puff, which included only lighting a cigarette and inhaling (measured as roughly one twelfth of a cigarette) (n = 2); 3 puffs of a cigarette (measured as approximately one quarter of a cigarette) (n = 3); a full cigarette (n = 3); and satiety (2½ -3 cigarettes) (n = 3). Subjects were then scanned for 3 hours 50 minutes more with 3 scheduled 10- or 15-minute breaks. Scanning ended at 9 PM.

Blood samples (5 mL) for assay of venous plasma nicotine levels were drawn immediately before and at 10 and 185 minutes following the smoke break from a dual port in the intravenous catheter placed for 2-FA infusion. Two subjects who smoked a full cigarette had a full series of venous plasma nicotine levels drawn prior to the smoke break and at 2, 10, 30, 65, and 185 minutes after the smoke break. Samples were centrifuged, and concentrations of venous plasma nicotine were determined in the laboratory of Peyton Jacob III, PhD, at the University of California, San Francisco, by gas chromatography with nitrogen-phosphorus detection,45 using 5-methylnicotine as an internal standard. The lower limit of quantitation was 1 ng/mL.

Cigarette craving was monitored with the Urge to Smoke Scale,46,47 an analog scale (range, 0-6) with 10 craving-related questions. This scale was filled out at the beginning of the first break in scanning (prior to smoking), at the end of the first break (after smoking), and during each of the 3 remaining breaks in scanning.

The PET scans were obtained on a General Electric Advance NXi scanner (General Electric Medical Systems, Milwaukee, Wis) with 35 slices in 3-dimensional mode, transaxial resolution full width at half maximum 5.2 to 7.7 mm.48 Scans were acquired as series of 10-minute frames. Attenuation correction scanning was performed with the germanium rotating rod source built into the General Electric scanner for 5 minutes at the end of the scanning session, and this attenuation correction was applied to all scans from the session. F 18 was prepared with the CP-45 variable proton energy negative ion cyclotron (The Cyclotron Corporation) and 2-FA was prepared by a published method.49 Specific activities ranged from 122 to 241 GBq/μmol (range, 3.3-6.5 Ci/μmol).

MAGNETIC RESONANCE IMAGING

An MRI of the brain was obtained within a week of PET scanning to aid in localization of brain regions on the PET scans, with the following specifications: 3-dimensional Fourier-transform spoiled gradient-recalled acquisition with repetition time = 30 milliseconds, echo time = 7 milliseconds, 30° angle, 2 acquisitions, and 256 × 192 view matrix. The acquired volume was reconstructed as roughly 90 contiguous 1.5-mm-thick transaxial sections.

REGION OF INTEREST PLACEMENT

Magnetic resonance imaging to PET coregistration was performed using an automated image registration method.50 Regions of interest were drawn on MRI and transferred to coregistered PET scans. Regions of interest included the thalamus, brainstem, cerebellum, prefrontal cortex, and corpus callosum. The thalamus, brainstem, and cerebellum were analyzed as whole structures while representative sections of the prefrontal cortex (middle frontal gyrus parallel to the body of cingulate) and genu of the corpus callosum (on sagittal images) were drawn. These brain regions were chosen based on prior reports indicating a range of nAChR densities in these regions from highest (thalamus) to lowest (corpus callosum).5154 Mean ± SD volumes for the thalamus, brainstem, and cerebellum were 4.97 ± 0.22, 18.37 ± 3.41, and 95.71 ± 13.77 cm3, respectively. The expected ratio of specific to nonspecific binding for the thalamus based on a study of nonhuman primates using 2-FA PET was roughly 2:1.29

DERIVATIONS OF RECEPTOR OCCUPANCY PARAMETERS

The total concentration of tissue radioactivity (CT) without smoking can be expressed as follows: CT = CSB + CF + CNB, where CSB is the concentration of specifically bound radioligand, CF is the concentration of free radioligand, and CNB is the concentration of nonspecifically bound radioligand. After smoking, C"T = C"SB + CF + CNB. In subjects who smoked, C"SB<CSB because nicotine, its metabolites, or perhaps other components of tobacco smoke displace some of the specifically bound radiotracer.

At equilibrium conditions and assuming that CF and CNB are unchanged as a result of smoking, the fractional displacement (FD) of radiotracer can be expressed as the following:

Figures

Place holder to copy figure label and caption
Figure 1.

Time-activity curves (mean ± SEM) for the 2 subjects undergoing full (8 hours) scanning with no smoking. The graphs demonstrate that 3 to 4 hours from the beginning of radioligand infusion are needed to reach a near steady state in the primary regions of interest for the bolus/infusion paradigm used herein. The average increase in radioactivity starting 3.5 hours after initiation of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380) administration was 3.2%, 3.2%, and 2.6% per hour for the thalamus, brainstem, and cerebellum, respectively.

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Place holder to copy figure label and caption
Figure 2.

Time-activity curves for the 5 smoking levels for the primary regions of interest. A, Thalamus. B, Brainstem. C, Cerebellum. Radioactivity is expressed as percentage of baseline value (mean radioactivity for the hour before the smoking break ± standard errors of the mean between subjects). 1 indicates 0 cigarettes; 2 indicates 1 puff; 3 indicates 3 puffs; 4 indicates 1 full cigarette; and 5 indicates satiety (2.8 cigarettes). Dotted lines indicate the time of the smoking break. D, Displacement of radioactivity in the whole brain and regions of interest in a subject who smoked to satiety (2.5 cigarettes) during the break (mean ± SE in volume of interest).

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Place holder to copy figure label and caption
Figure 3.

2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380) positron emission tomography (PET) images before (top row) and 3.1 hours after (bottom row) cigarette smoking. Images were obtained by averaging the six 10-minute frames over the 1 hour prior to the smoking break and by averaging the seven 10-minute scans from a mean of 3.1 hours after smoking the cigarette amount listed. The far right column shows a magnetic resonance image (MRI) of the brain and a PET image of nondisplaceable radioactivity distribution (calculated). All PET images were aligned to the level shown on the MRI.

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Place holder to copy figure label and caption
Figure 4.

Effects of variable smoking (number of cigarettes) and venous plasma nicotine levels on radiotracer displacement. A, Percentage of displacement of total radioactivity (Ct) in regions of interest for the range of smoking levels from 0 to 2.8 cigarettes, based on the ratio of displaced Ct by each cigarette dose to prebreak Ct, without correction for the imperfect steady state of the radiotracer found in control scans. B and C, Displacement of specific binding (SB) (a measure that takes into account nondisplaceable radioactivity derived from the asymptotic portion of the saturation curve in part A) by the varying smoking levels without and with correction for the imperfect steady state, respectively. D, Specific binding displacement as a function of venous plasma nicotine levels, corrected.

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Tables

Table Graphic Jump LocationTable 1. Effective Dose of a Cigarette and Effective Concentration of Venous Plasma Nicotine Needed to Occupy 50% of α4β2* nAChRs During Positron Emission Tomography Scanning for the 3 Primary Regions of Interesta
Table Graphic Jump LocationTable 2. Cigarette Dose, Venous Plasma Nicotine Concentration, and Percentage Change in Occupancy of Nicotinic Acetylcholine Receptors in Regions of Interest From Before Smoking to 3.1 Hours After Smokinga

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