Irina Esterlis

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.

The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [11C]PBR28 PET study

Depression is associated with systemic inflammation. In animals, systemic inflammation can induce neuroinflammation and activation of microglia; however, postmortem studies have not convincingly shown that there is neuroinflammation in depression. The purpose of this study was to use positron emission tomography (PET) with [¹¹C]PBR28, which binds to the neuroinflammation marker translocator protein 18 kDa (TSPO), to compare the level of TSPO between individuals with depression and control subjects. Ten individuals who were in an acute episode of major depression and 10 control subjects matched for TSPO genotype and other characteristics had a PET scan with arterial input function to quantify levels of TSPO in brain regions of interest (ROIs). Total volume of distribution (VT) of [¹¹C]PBR28 was used as a measure of total ligand binding. The primary outcome was the difference in VT between the two groups; this was assessed using a linear mixed model with group as a between-subject factor and region as a within-subject factor. There was no statistically significant difference in [¹¹C]PBR28 binding (VT) between the two groups. In fact, 7 of 10 individuals with depression had lower [¹¹C]PBR28 binding in all ROIs compared to their respective genotype-matched control subjects. Future studies are needed to determine whether individuals with mild-to-moderate depression have lower TSPO levels and to assess whether individuals with severe depression and/or with elevated levels of systemic inflammation might have higher TSPO levels than control subjects.

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.

KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS.

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid‐acting antidepressant medications. The N‐methyl‐d‐aspartate receptor (NMDA‐R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment‐resistant depression. Animal and human research suggest that ketamines antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid‐acting antidepressant effects of ketamine. This review discusses stress‐related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamines mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.

In Vivo Ketamine-Induced Changes in [11C]ABP688 Binding to Metabotropic Glutamate Receptor Subtype 5

BACKGROUND At subanesthetic doses, ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, increases glutamate release. We imaged the acute effect of ketamine on brain metabotropic glutamatergic receptor subtype 5 with a high-affinity positron emission tomography (PET) ligand [(11)C]ABP688 (E)-3-[2-(6-methyl-2-pyridinyl)ethynyl]-2-cyclohexen-1-one-O-(methyl-11C)oxime, a negative allosteric modulator of the metabotropic glutamatergic receptor subtype 5. METHODS Two [(11)C]ABP688 PET scans were performed in 10 healthy nonsmoking human volunteers (34 ± 13 years old); the two PET scans were performed on the same day-before (scan 1) and during intravenous ketamine administration (.23 mg/kg over 1 min, then .58 mg/kg over 1 hour; scan 2). The PET data were acquired for 90 min immediately after [(11)C]ABP688 bolus injection. Input functions were obtained through arterial blood sampling with metabolite analysis. RESULTS A significant reduction in [(11)C]ABP688 volume of distribution was observed in scan 2 relative to scan 1 of 21.3% ± 21.4%, on average, in the anterior cingulate, medial prefrontal cortex, orbital prefrontal cortex, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus. There was a significant increase in measurements of dissociative state after ketamine initiation (p < .05), which resolved after completion of the scan. CONCLUSIONS This study provides first evidence that ketamine administration decreases [(11)C]ABP688 binding in vivo in human subjects. The results suggest that [(11)C]ABP688 binding is sensitive to ketamine-induced effects, although the high individual variation in ketamine response requires further examination.

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.

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.

Imaging Changes in Synaptic Acetylcholine Availability in Living Human Subjects

In vivo estimation of β2-nicotinic acetylcholine receptor availability with molecular neuroimaging is complicated by competition between the endogenous neurotransmitter acetylcholine and the radioligand 123I-3-[2(S)-2-azetidinylmethoxy]pyridine (123I-5-IA). We examined whether binding of 123I-5-IA is sensitive to increases in extracellular levels of acetylcholine in humans, as suggested in nonhuman primates. Methods: Six healthy subjects (31 ± 4 y) participated in a 123I-5-IA SPECT study. After baseline scans, physostigmine (1–1.5 mg) was administered intravenously over 60 min, and 9 additional scans were obtained. Results: We observed a significant reduction in the total volume of distribution after physostigmine administration (29% ± 17% in the cortex, 19% ± 15% in the thalamus, 19% ± 15% in the striatum, and 36% ± 30% in the cerebellum; P < 0.05). This reduction reflected a combination of a region-specific 7%–16% decrease in tissue concentration of tracer and a 9% increase in plasma parent concentration. Conclusion: These data suggest that increases in acetylcholine compete with 123I-5-IA for binding to β2-nicotinic acetylcholine receptor. Additional validation of this paradigm is warranted, but it may be used to interrogate changes in extracellular acetylcholine.