Frederic Bois

β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking

CONTEXT Available levels of nicotinic acetylcholine receptors containing the beta(2) subunit (beta(2)*-nAChR) are higher in recently abstinent tobacco smokers compared with participants who never smoked. Variations in beta(2)*-nAChR availability during 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 beta(2)*-nAChR availability during acute and prolonged abstinence from tobacco smoking and to determine how changes in beta(2)*-nAChR availability were related to clinical features of tobacco smoking. DESIGN Tobacco smokers participated in up to 4 iodide 123-labeled 5-iodo-A-85380 ([(123)I]5-IA) single-photon emission computed tomography (SPECT) scans during abstinence at 1 day (n = 7) and 1 (n = 17), 2 (n = 7), 4 (n = 11), and 6 to 12 (n = 6) weeks. Age-matched nonsmokers participated in a single [(123)I]5-IA SPECT scan. All participants 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 The [(123)I]5-IA SPECT images were converted to distribution volume and were analyzed using regions of interest. RESULTS Compared with nonsmokers, beta(2)*-nAChR availability in the striatum, cortex, and cerebellum of smokers was not different at 1 day of abstinence, was significantly higher at 1 week of abstinence, and was not different at 4 or at 6 to 12 weeks of abstinence. In smokers, beta(2)*-nAChR availability was significantly lower in the cortex and cerebellum at 6 to 12 weeks compared with 1 week of abstinence. In addition, cerebellar beta(2)*-nAChR availability at 4 weeks of abstinence was positively correlated with craving on the day of the SPECT scan. CONCLUSIONS These data suggest that higher beta(2)*-nAChR availability persists up to 1 month of abstinence and normalizes to nonsmoker levels by 6 to 12 weeks of abstinence from tobacco smoking. These marked and persistent changes in beta(2)*-nAChR availability may contribute to difficulties with tobacco cessation.

Persistent β2*-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder

BACKGROUND Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using [123I]5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subjects. METHOD The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one [123I]5-I-A-85380 SPECT scan and an MRI scan. The availability of β2*-nAChRs was quantified as VT/fP. Postmortem analysis of β2*-nAChR binding was conducted with [123I]5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects. RESULTS The β2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, β2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in β2*-nAChR number between groups in the postmortem study. CONCLUSIONS Depressed patients have lower β2*-nAChR availability than do healthy subjects. The difference between β2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.

Sex differences in availability of β2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers

CONTEXT Sex differences exist in the reinforcing effects of nicotine, smoking cessation rates, and response to nicotine therapies. Sex differences in availability of nicotinic acetylcholine receptors containing the β(2) subunit (β(2)*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women vs men. OBJECTIVES To examine β(2)*-nAChR availability in male and female smokers vs nonsmokers and to determine associations among β(2)*-nAChR availability, tobacco smoking characteristics, and female sex steroid hormone levels. DESIGN Male (n = 26) and female (n = 28) tobacco smokers participated in an iodide 123-labeled 5-iodo-A-85380 ([(123)I]5-IA) single-photon emission computed tomography (SPECT) imaging session at 7 to 9 days of abstinence. Age-matched male (n = 26) and female (n = 30) nonsmokers participated in a [(123)I]5-IA SPECT imaging session. All participants completed a magnetic resonance imaging study. SETTING Academic imaging center. PARTICIPANTS Tobacco smokers (n = 54) and age- and sex-matched nonsmokers (n = 56). MAIN OUTCOME MEASURE The [(123)I]5-IA SPECT images were converted to equilibrium distribution volumes and were analyzed using regions of interest. RESULTS The β(2)*-nAChR availability was significantly higher in male smokers compared with male nonsmokers in striatum, cortex, and cerebellum, but female smokers did not have higher β(2)*-nAChR availability than female nonsmokers in any region. In women, β(2)*-nAChR availability in the cortex and cerebellum was negatively and significantly correlated with progesterone level on the SPECT imaging day. In female smokers on imaging day, the progesterone level was positively and significantly correlated with depressive symptoms, craving for a cigarette, and nicotine withdrawal. CONCLUSIONS The regulatory effects of nicotine in the brain (ie, tobacco smoking-induced upregulation of β(2)*-nAChRs) seem to be distinctly different between men and women, and female sex steroid hormones likely have a role in this regulation. These findings suggest an underlying neurochemical mechanism for the reported behavioral sex differences. To treat female smokers more effectively, it is critical that nonnicotinic-mediated medications should be explored.

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) availability in eight brain regions of living human subjects using the ligand [(123)I]5-IA-85380 ([(123)I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N=47) ranging in age from 18 to 85 were administered [(123)I]5-IA using a bolus plus constant infusion paradigm and imaged 6-8h later under equilibrium conditions. The effect of age on regional beta(2)-nAChR availability (V(T), regional brain activity/free plasma parent, a measure proportional to the binding potential) was analyzed using linear regression and Pearsons correlation (r). Age and regional beta(2)-nAChR availability were inversely correlated in seven of the eight brain regions analyzed, with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade. These results in living human subjects corroborate postmortem reports of decline in high affinity nicotine binding with age and may aid in elucidating the role of beta(2)-nAChRs in cognitive aging.

Lower β2*-Nicotinic Acetylcholine Receptor Availability in Smokers With Schizophrenia

OBJECTIVE There is a strong association between cigarette smoking and schizophrenia. Nicotines actions in the brain are mediated through nicotinic acetylcholine receptors. Those containing α(4) and β(2) subunits are the most abundant ones in the brain, have the highest affinity for nicotine, and are critical in mediating nicotines reinforcing properties. Healthy tobacco smokers have significantly higher levels of β(2)*-nicotinic acetylcholine receptors than do nonsmokers. However, in postmortem studies, smokers with schizophrenia do not show these higher levels. The purpose of this study was to measure β(2)*-nicotinic acetylcholine receptors in vivo and to relate levels to concurrent behavioral measures of smoking and schizophrenia. METHOD By using single-photon emission computed tomography with the β(2)*-nicotinic acetylcholine receptor agonist radiotracer [(123)I]5-IA-85380, the availability of receptors was measured in smokers with schizophrenia (11 men) and matched comparison smokers after 1 week of confirmed smoking abstinence. RESULTS Smokers with schizophrenia showed significantly lower (21%-26%) β(2)*-nicotinic acetylcholine receptor availability relative to comparison smokers in the frontal cortex, parietal cortex, and thalamus (in descending order). There was a specific and robust negative correlation between regional β(2)*-nicotinic acetylcholine receptor availability and negative symptoms. CONCLUSIONS These are the first in vivo findings of lower β(2)*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. The relationship between β(2)*-nicotinic acetylcholine receptor availability and negative symptoms may explain the high rates of smoking in schizophrenia and the relationship between smoking and negative symptoms. Findings support the development of medications targeting the β(2)*-nicotinic acetylcholine receptor system for the treatment of negative symptoms.

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

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.

123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Phase

The study of the effects of sex and hormones on brain chemistry and neurotransmission is of increasing importance as evidence emerges of sex differences in behavioral symptoms and treatment response in neuropsychiatric disorders. The nicotinic acetylcholine receptor (nAChR) system has been implicated in a variety of psychiatric disorders, including tobacco smoking, for which there is strong evidence supporting sex differences in behaviors and response to smoking cessation treatments. We examined the availability of nAChR containing the β2 subunit in healthy men and women and the influence of menstrual phase among women. Methods: Ten men and 19 women nonsmokers underwent one 123I-5-IA-85380 (123I-5-IA) SPECT scan and one MRI scan. A subset of 9 women, aged 18–39 y, underwent a second 123I-5-IA scan. These 9 women were scanned during the early follicular (days 4–7 in 8 subjects and day 11 in 1 subject) and mid-luteal (days 19–25) phases of their menstrual cycle. Hormone levels were measured in all women to confirm the phase of the cycle. Results: Regional brain activity (kBq/cm3) was higher (39%–54%) in women than in men nonsmokers. When regional brain activity was normalized to total plasma parent to correct for individual differences in radiotracer metabolism (VT′), differences of 10%–16% were observed, with women greater than men. In contrast, when regional brain activity was normalized to free plasma parent (VT), there was less than a 4% difference by sex in regional brain β2-nAChR availability. These sex differences in kBq/cm3 and VT′ resulted from significantly higher levels of total plasma parent, free fraction (f1), and free plasma parent in women than in men nonsmokers. No differences in plasma measures or brain β2-nAChR availability were observed across the menstrual cycle for any outcome measure. Conclusion: Overall, these findings demonstrate no significant difference in brain β2-nAChR availability between men and women nonsmokers or across the menstrual cycle. Importantly, these findings demonstrate sex differences in radiotracer metabolism and plasma protein binding and highlight the critical need to measure plasma radiotracer levels and f1 in studies that include both sexes.

Dopamine and Serotonin Transporter Availability During Acute Alcohol Withdrawal: Effects of Comorbid Tobacco Smoking

Tobacco smoking is highly comorbid with heavy alcohol drinking, yet the interaction of tobacco smoking and alcohol drinking on brain catecholaminergic synaptic markers is unexplored. Here we evaluate the effects of alcohol drinking alone from comorbid alcohol drinking and tobacco smoking on dopamine (DA) and serotonin (5-HT) transporter availability. A total of 14 heavy alcohol drinking smokers (n=6) and nonsmokers (n=8) and 14 age-matched control smokers (n=6) and nonsmokers (n=8) were imaged with [123]β-CIT single photon emission computed tomography. Alcohol drinking smokers and nonsmokers consumed 134.3±100.3 and 196.5±139.9 drinks, respectively, over the previous month and were imaged during acute withdrawal, eg within 5 days of their last drink. Striatal DA transporter availability was significantly higher (16%, P=0.04) in alcohol drinkers compared to controls. 5-HT transporter availability was also significantly higher in alcohol drinkers vs controls in the brainstem (25%, P=0.001) and the diencephalon (8%, P=0.01). This elevation was restricted to alcohol drinking nonsmokers with higher DA transporter availability in the striatum (26%, P=0.006), and higher 5-HT transporter availability in the diencephalon (26%, P=0.04) and brainstem (42%, P<0.0002). There was a significant positive correlation between days since last drink and 5-HT transporter availability in the diencephalon (r=0.60, P=0.023) and brainstem (r=0.54, P=0.047), in the total group of alcohol drinkers and in the nonsmokers, but not the smokers. During the first week of abstinence, DA and 5-HT transporter availability is higher in alcohol drinking nonsmokers but not in alcohol drinking smokers. Smoking appears to suppress neuroadaptive changes in DA and 5-HT transporters during acute withdrawal from alcohol.

Changes in the Cholinergic System between Bipolar Depression and Euthymia as Measured with [123I]5IA Single Photon Emission Computed Tomography

BACKGROUND The cholinergic system is substantially altered in individuals with major depression and is partially restored when depression remits. We quantified the availability of β2-subunit-containing nicotinic acetylcholine receptors (β2*-nAChR) in subjects with bipolar disorder. METHODS Twenty-five subjects with bipolar disorder (15 depressed, 10 euthymic) and 25 sex- and age-matched control subjects had a [(123)I]5IA-85380 single photon emission computed tomography scan to quantify β2*-nAChR VT/fP (total volume of distribution, corrected for individual differences in metabolism and protein binding of the radiotracer). Average VT/fP was compared between groups and correlated with clinical characteristics. Postmortem analysis of β2*-nAChRs was conducted using equilibrium binding with [(125)I]5IA in subjects with bipolar disorder and matched control subjects. RESULTS We showed significantly lower β2*-nAChR availability (20%-38%) in subjects with bipolar depression compared with euthymic and control subjects across all brain regions assessed (frontal, parietal, temporal, and anterior cingulate cortex, hippocampus, amygdala, thalamus, striatum). The postmortem binding study in which endogenous acetylcholine was washed out did not show a statistically significant difference in β2*-nAChR number in temporal cortex of the bipolar depressed and control groups (15% difference; p = .2). CONCLUSIONS We show that the alteration in the cholinergic system observed during a depressive episode appears to resolve during euthymia. We suggest that lower VT/fP observed in vivo may be due to a combination of higher endogenous acetylcholine levels during depression, which could compete with radiotracer binding to the receptor in vivo, and lower receptor number in bipolar depression. Identification of differences in cholinergic signaling in subjects with bipolar depression may improve our understanding of its etiology and reveal new treatment targets.

β2 Nicotinic acetylcholine receptor availability in post-traumatic stress disorder

Availability of nicotinic acetylcholine receptors containing beta2 subunits (beta2-nAChRs) was studied in unmedicated, symptomatic patients with post-traumatic stress disorder (PTSD) and healthy control subjects, all current non-smokers. A subgroup of participants had a history of smoking. Availability of beta2-nAChRs in the mesiotemporal cortex, prefrontal cortex, thalamus and striatum was determined using the radiotracer [123I]5-IA-85380 ([123I]5-IA) and single-photon emission computed tomography (SPECT). PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS). Never-smoking PTSD patients compared to never-smoking healthy controls showed significantly higher [123I]5-IA binding in the mesiotemporal cortex (ANOVA: F=6.21, d.f.=1, 11, p=0.030). Among all PTSD patients, there was a significant correlation between the re-experiencing symptom cluster and thalamic [123I]5-IA binding (R2=0.66, p=0.019, Bonferroni corrected). These findings not only suggest an involvement of beta2-nAChRs in the pathophysiology of PTSD but also raise the possibility that this receptor may be a novel molecular target for drug development.