Subjects were adults (mean±SD age, 36.6±11.8 years; 8 men, 3 women) who smoked 22.2±2.8 (mean±SD) regular cigarettes per day and had been smoking for a mean±SD of 17.5±10.5 years. Six subjects were African American, 4 subjects were white, and 1 subject was Asian American. One participant's longest previous quit period was 2 years, while the others had longest quit periods ranging from a few days to 1 year. Mean±SD total scores for the Fagerström Test for Nicotine Dependence (5.9±2.2) and the Beck Depression Inventory (3.1±2.5) and mean±SD per item scores for the Spielberger State-Trait Anxiety Index (1.8 ± 0.5) and the Shiffman-Jarvik Withdrawal Scale (4.2±0.7) indicated that subjects were moderately dependent on tobacco and had low levels of depression and anxiety during the study. At the time of screening, subjects had exhaled CO levels consistent with tobacco dependence (mean±SD, 18.1±5.7 ppm), while at the time of scanning, subjects had low exhaled CO levels (mean±SD, 1.9±1.0 ppm), consistent with their compliance with the abstinence protocol of the study. For all subjects, venous plasma nicotine levels were lower than the level of detection of the laboratory for this study (<1 ng/mL) prior to the smoking break in scanning and were the highest in the first sample after smoking, with a half-life of 145 minutes.
Time-activity curves for the control (no-smoking) scans ( and ) demonstrate that the distribution of radioligand reached a near equilibrium state 3.5 hours after initiation of 2-FA administration, with tissue concentrations maintained in a near steady state for the remainder of the scanning sessions. The percentage change per hour in the no-smoking group was calculated by determining the difference in average radioactivity for each region of interest between the period at which 2-FA reached an approximate steady state (180-240 minutes after infusion initiation) and the final 70 minutes of scanning (395-480 minutes after infusion initiation, including a 15-minute break) and dividing by the number of hours (3.8) between the midpoint of these 2 periods. This calculation resulted in average increases in radioactivity for the thalamus, brainstem, and cerebellum of 12%, 12%, and 10%, respectively (3.2%, 3.2%, and 2.6% per hour, respectively). For the last 70 minutes of scanning (last 85 minutes of the scanning session, including a 15-minute break), an almost complete steady state (indicating equilibrium between plasma and brain tissue) was reached, with change in radioactivity in the thalamus, brainstem, and cerebellum of only 0.0±1.0% (mean±SE), 1.0±1.0%(mean±SE), and 1.0±1.0%(±mean±SE), respectively (determined by linear regression).
For the scans with cigarette smoking, decreases in total radioactivity for the 3 studied brain regions with the highest radioactivity accumulation (thalamus, brainstem, and cerebellum) were clearly dose dependent ( and ). A single puff of a cigarette was the only amount of smoking that was followed by recovery of receptor availability within the 3-hour 50-minute time frame after smoking (), while the medium to high levels of smoking (one quarter of a cigarette to satiety) resulted in new steady-state conditions at 3 hours after smoking ( and ). Smoking to satiety resulted in a profound decrease of radioactivity in all brain regions studied (). The dose-response curves for displacement of total and specifically bound radioactivities are shown in .
The mean±SE effective dose of a cigarette required to occupy 50% of receptors (ED50
) for the 3 primary regions of interest at 3.1 hours after smoking was 0.19±0.05 (). After correcting for the imperfect steady state found in the control group that did not smoke (by multiplying the prebreak mean total radioactivities for the thalamus, brainstem, and cerebellum by 1.12, 1.12, and 1.10, respectively), ED50
was calculated to be 0.13±0.03 (mean±SE) of a cigarette (). The mean±SE venous plasma nicotine concentration associated with 50% occupancy of receptors (EC50
) was determined from the dose response curve () to be 0.87±0.16 ng/mL (5.3±1.0 nM) (). Apparent binding potential (BP*) values for the thalamus () were similar to those in another published report using 2-FA.29
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
The mean receptor fractional occupancies at 3.1 hours after smoking 1 puff, 3 puffs, 1 full cigarette, and to satiety were 33%, 75%, 88%, and 95%, respectively () (). Earlier than 3.1 hours after smoking, we would hypothesize that the fractional occupancy of nAChRs would be even higher. For example, assuming a t1/2
(half-life) of venous plasma nicotine of 2.5 hours,27
we would expect that smoking 1 cigarette would result in venous plasma nicotine levels at 1 and 2.5 hours after smoking to be roughly 1.8 and 1.2 times higher than the levels at 3.1 hours. These higher nicotine levels would lead to estimated receptor occupancies at 1 and 2.5 hours of 93% and 90%, respectively.
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
Craving was only alleviated with higher smoking levels (1 full cigarette or satiety). For the 5 smoking levels (none, 1 puff, 3 puffs, 1 cigarette, and satiety), changes in mean±SD Urge to Smoke Scale scores (0- to 6-point scale) from before to after smoking were –0.8 ± 0.7, 0.2 ± 0.2, 0.1 ± 0.4, –4.6 ± 1.2, and –4.8 ± 1.1, respectively. Craving relief was temporary and elevated craving levels returned later during the scanning session. For example, a mean ± SD change of –2.3 ± 1.6 in Urge to Smoke Scale score was found from before to 2.5 hours after smoking for the group that smoked 1 full cigarette.