Sex-specific differences in GABA(A) -benzodiazepine receptor availability: relationship with sensitivity to pain and tobacco smoking craving.

Sex differences exist in tobacco smoking behaviors. Nicotine, the primary addictive ingredient in tobacco smoke, indirectly affects γ-amino butyric acid (GABA) function. Previous studies reported sex-by-smoking interactions in brain GABA levels. The goal of the present study was to evaluate if there is a sex-by-smoking interaction at the GABA(A)-benzodiazepine receptors (GABA(A)-BZRs), as well as relationships between GABA(A)-BZR availability and behavioral variables before and after 1 week of smoking cessation. Twenty-six women (8 non-smokers, age 36.0 ± 13.4 years; 19 smokers, age 34.6 ± 8.9 years) and 25 men (8 non-smokers, age 37.9 ± 13.8 years; 17 smokers, 34.1 ± 12.4 years) were imaged using [123I]iomazenil and single-photon emission computed tomography. Smokers were imaged at baseline 7 hours after the last cigarette. A significantly great number of men were able to abstain from smoking for 1 week (P = 0.003). There were no significant differences in nicotine dependence and cigarette craving, mood or pain sensitivity between male and female smokers. There was a significant effect of gender across all brain regions (frontal, parietal, anterior cingulate, temporal and occipital cortices, and cerebellum; P < 0.05), with all women (smokers and non-smokers combined) having a higher GABA(A)-BZR availability than all men. There was a negative correlation between GABA(A)-BZR availability and craving (P ≤ 0.02) and pain sensitivity (P = 0.04) in female smokers but not male smokers. This study provides further evidence of a sex-specific regulation of GABA(A)-BZR availability in humans and demonstrates the potential for GABA(A)-BZRs to mediate tobacco smoking craving and pain symptoms differentially in female and male smokers.

Persistent ß2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder.

BACKGROUND: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the ß2 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 ß2-subunit-containing nAChRs (ß2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied ß2*-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 ß2*-nAChRs was quantified as VT/fP. Postmortem analysis of ß2*-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 ß2*-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, ß2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in ß2*-nAChR number between groups in the postmortem study. CONCLUSIONS: Depressed patients have lower ß2*-nAChR availability than do healthy subjects. The difference between ß2*-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 ß2*-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 ß(2) subunit (ß(2)*-nAChRs) may underlie differential nicotine and tobacco smoking effects and related behaviors in women vs men. OBJECTIVES: To examine ß(2)*-nAChR availability in male and female smokers vs nonsmokers and to determine associations among ß(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 ß(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 ß(2)*-nAChR availability than female nonsmokers in any region. In women, ß(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 ß(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.

Assessing the sensitivity of [¹¹C]p943, a novel 5-HT1B radioligand, to endogenous serotonin release.

The main objective of the current study was to determine the sensitivity of the positron emission tomography (PET) radioligand [¹¹C]P943 to fenfluramine-induced changes in endogenous 5-HT in nonhuman primate brain. Fenfluramine-induced changes in 5-HT(1B) occupancy were compared to those obtained by self-block with unlabeled P943. Two baboons and 1 rhesus monkey were given preblocking or displacing doses of fenfluramine (1-5 mg/kg) or preblocking doses of unlabeled P943 (0.2 mg/kg) and imaged with [¹¹C]P943 PET. Receptor occupancy by the low dose of fenfluramine (1 mg/kg) in the baboons was 25 and 29% and by the high dose of fenfluramine (5 mg/kg) in the rhesus macaque was 42%. Receptor occupancy by P943 (0.2 mg/kg) was 68 and 86% in the baboons. PET imaging of 5-HT(1B) receptors with [¹¹C]P943 may be a useful approach for measuring changes in endogenous 5-HT in the living human brain.

Brain ß2*-nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler.

The Nicotrol® (Pfizer, USA) nicotine inhaler reduces craving by mimicking the behavioural component of cigarettes and delivering controlled doses of nicotine, which binds to the beta-2 subunit-containing nicotinic acetylcholine receptors (ß2*-nAChRs). Previous studies examined ß2*-nAChR occupancy after administration of regular and low-nicotine cigarettes. Here, we measured occupancy of ß2*-nAChRs after administration of nicotine via inhaler, and the relationship between occupancy and changes in craving for tobacco smoking and withdrawal symptoms. Tobacco smokers participated in [123I]5-IA-85380 SPECT studies with either a nicotine inhaler (n=9) or tobacco cigarette (n=4) challenge. [123I]5-IA was administered as a bolus plus constant infusion. After equilibrium was achieved, three 30-min baseline scans were collected, and subjects either used the nicotine inhaler or a regular cigarette, and up to six additional scans were obtained. Receptor occupancy was determined based on the Lassen plot method. Craving for tobacco smoking and withdrawal symptoms were evaluated pre- and post-challenge. Use of the nicotine inhaler produced an average 55.9±6.4% occupancy of ß2*-nAChRs 2-5 h post-challenge, whereas use of a cigarette produced significantly higher receptor occupancy (F=10.6, p=0.009) with an average 67.6±14.1% occupancy 1.5-5 h post-challenge. There was a significant decrease in withdrawal symptoms post-nicotine inhaler use (F=6.13, p=0.04). These results demonstrate significant differences in occupancy of ß2*-nAChRs by nicotine after use of the inhaler vs. a cigarette and confirm the ability of the nicotine inhaler to relieve withdrawal symptoms.

Dopamine and serotonin transporter availability in chronic heroin users: a [¹²³I]ß-CIT SPECT imaging study.

Dopamine (DA) and serotonin (5-HT) transporter availability in heroin users and healthy controls was measured using [¹²³I]ß-CIT and SPECT imaging. Heroin users had statistically similar striatal DA and brainstem and diencephalon 5-HT transporter availability compared with controls. No associations between transporter availability and heroin use characteristics were found.

Quantification of smoking-induced occupancy of beta2-nicotinic acetylcholine receptors: estimation of nondisplaceable binding.

UNLABELLED: 5-(123)I-iodo-85380 ((123)I-5-IA) is used to quantitate high-affinity nicotinic acetylcholine receptors (beta(2)-nAChRs) on human SPECT scans. The primary outcome measure is V(T)/f(P), 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 (123)I-5-IA has not been measured in human subjects. Nicotine has high affinity for beta(2)*-nAChRs (nAChRs containing the beta(2)* subunit, for which * represents other subunits that may also be part of the receptor) and displaces specifically bound (123)I-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. (123)I-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 beta(2)*-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. V(T)/f(P) 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 x cm(-3) (range, 15-28 mL x cm(-3)). Thus, in the thalamus, where mean V(T)/f(P) is 93 mL x 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.

SPECT imaging with the serotonin transporter radiotracer [123I]p ZIENT in nonhuman primate brain.

INTRODUCTION: Serotonin dysfunction has been linked to a variety of psychiatric diseases; however, an adequate SPECT radioligand to probe the serotonin transporter system has not been successfully developed. The purpose of this study was to characterize and determine the in vivo selectivity of iodine-123-labeled 2beta-carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane, [(123)I]p ZIENT, in nonhuman primate brain. METHODS: Two ovariohysterectomized female baboons participated in nine studies (one bolus and eight bolus to constant infusion at a ratio of 9.0 h) to evaluate [(123)I]p ZIENT. To evaluate the selectivity of [(123)I]p ZIENT, the serotonin transporter blockers fenfluramine (1.5, 2.5 mg/kg) and citalopram (5 mg/kg), the dopamine transporter blocker methylphenidate (0.5 mg/kg) and the norepinephrine transporter blocker nisoxetine (1 mg/kg) were given at 8 h post-radiotracer injection. RESULTS: In the bolus to constant infusion studies, equilibrium was established by 4-8 h. [(123)I]p ZIENT was 93% and 90% protein bound in the two baboons and there was no detection of lipophilic radiolabeled metabolites entering the brain. In the high-density serotonin transporter regions (diencephalon and brainstem), fenfluramine and citalopram resulted in 35-71% and 129-151% displacement, respectively, whereas methylphenidate and nisoxetine did not produce significant changes (<10%). CONCLUSION: These findings suggest that [(123)I]p ZIENT is a favorable compound for in vivo SPECT imaging of serotonin transporters with negligible binding to norepinephrine and dopamine transporters.

Beta2* nicotinic acetylcholine receptors modulate pain sensitivity in acutely abstinent tobacco smokers.

INTRODUCTION: Nicotine and tobacco smoking administration have demonstrated antinociceptive effects that are mediated by the nicotinic acetylcholine receptor containing the beta2* subunit (beta(2)*-nAChR). In this study, we examined the relationship between beta(2)*-nAChR availability and nociception during acute withdrawal in human tobacco smokers using [(123)I]5-IA-85380 ([(123)I]5-IA) and single photon emission computed tomography (SPECT) brain imaging. METHODS: Tobacco smokers (n = 24, aged 34 +/- 11 years) participated in the cold pressor task during acute withdrawal (up to 3 hr) and a second cold pressor task following 7-13 days of smoking abstinence on the day they were imaged with [(123)I]5-IA SPECT. The cold pressor task is used to measure pain sensitivity (when subjects first feel pain) and pain tolerance (when subjects cannot withstand pain). RESULTS: Following 7-13 days of tobacco smoking abstinence, increased pain sensitivity, for example, shorter time to first feel pain, was significantly associated with higher beta(2)*-nAChR availability in the thalamus (r = -.43), parietal (r = -.50), frontal (r = -.55), anterior cingulate (r = -.44), temporal (r = -.43), and occipital (r = -.48) cortices. The percent change in pain sensitivity from the first to second cold pressor task was significantly correlated with beta(2)*-nAChR availability in the thalamus (r = -.57), cerebellum (r = -.50), striatum (r = -.057), parietal (r = -.46), anterior cingulate (r = -.48), temporal (r = -.55), and occipital (r = -.57) cortices. Similar associations were not observed with pain tolerance. DISCUSSION: This suggests that beta(2)*-nAChRs play a role in pain sensitivity but not pain tolerance during tobacco smoking withdrawal. If individuals are more likely to relapse in response to painful stimuli, lower beta(2)*-nAChR availability during acute abstinence may be protective.

Decreased Beta(2)*-nicotinic acetylcholine receptor availability after chronic ethanol exposure in nonhuman primates.

Ethanol associated behaviors have been linked to the beta(2)-subunit containing nicotinic acetylcholine receptors (beta(2)*-nAChR); however, there is conflicting evidence on ethanol-induced changes in nAChR expression during and after chronic ethanol consumption. In this study, five male animals orally self-administered ethanol for 18 +/- 1 weeks. Animals were scanned with [(123)I]5-IA-85380 and SPECT prior to ethanol self-administration, and at 24 h and 5-13 wks withdrawal. beta(2)*-nAChR availability was not significantly different from baseline at 24 h withdrawal, but was significantly decreased compared to baseline at 5-13 wks withdrawal throughout the cortex and in the thalamus, but not the midbrain. The percent decrease in beta(2)*-nAChR availability from baseline to 5-13 wks withdrawal in the parietal cortex was negatively correlated with total grams of ethanol consumed in lifetime and in the midbrain was negatively correlated with average daily ethanol consumption (g/kg). Prolonged withdrawal from chronic ethanol consumption is associated with a decrease in beta(2)*-nAChR availability. The decrease in beta(2)*-nAChR availability is influenced by alcohol consumption, suggesting the chronicity and severity of alcohol consumption may underlie persistent changes in beta(2)*-nAChR availability.

SPECT imaging of nicotinic acetylcholine receptors in nonsmoking heavy alcohol drinking individuals.

BACKGROUND: The high rate of comorbidity of tobacco smoking with alcohol drinking suggests common neural substrates mediate the two addictive disorders. The beta(2)*-containing nicotinic acetylcholine receptor (beta(2)*-nAChR) has recently emerged as a prime candidate because some alpha and beta subunit genes have been linked to alcohol consumption and alcohol use behaviors. We hypothesized that beta(2)*-nAChR availability would be altered by alcohol in heavy drinking nonsmokers. METHODS: Eleven heavy drinking (mean age 39.6+/-12.1 years) and 11 age and sex-matched control (mean age 40.8+/-14.1 years) nonsmokers were imaged using [(123)I]5-IA-85380 ([(123)I]5-IA) single photon emission computed tomography (SPECT). Heavy alcohol drinkers drank varied amounts of alcohol (70-428/month) to facilitate exploratory linear analyses of the possible effects of alcohol. RESULTS: Heavy drinkers consumed on average 9.1+/-7.3 drinks/occasion; whereas controls drank 1.2+/-0.9 drinks/occasion. Heavy drinkers were imaged 2.0+/-1.6 days after last alcoholic beverage. Overall, there were no significant differences in beta(2)*-nAChR availability between the heavy drinking and control nonsmokers. Exploratory analyses of other factors that may be uniquely regulated by alcohol suggested no effects of age, number of alcohol drinks, years drinking, severity of drinking, craving or withdrawal. CONCLUSIONS: These preliminary analyses do not suggest a decrease in receptor availability in heavy drinking nonsmokers as compared to control nonsmokers. However, a larger study is warranted to explore effects of heavy alcohol drinking on other variables, such as sex, smoking, and genetic make up.

123I-5-IA-85380 SPECT imaging of nicotinic receptors in Alzheimer disease and mild cognitive impairment.

UNLABELLED: Postmortem binding studies have established that the concentration of alpha(4)beta(2)-nicotinic acetylcholine receptors (alpha(4)beta(2)-nAChR) is reduced in advanced Alzheimer disease (AD). However, the status of this receptor in mild or prodromal AD has remained the subject of controversy. METHODS: We compared alpha(4)beta(2)-nAChR availability in 8 brain regions of living human subjects who had AD and mild cognitive impairment (MCI) with that in age-matched healthy control subjects by using the ligand (123)I-5-IA-85380 ((123)I-5-IA) and SPECT. All subjects (n = 32) were nonsmokers; they were administered (123)I-5-IA as a bolus plus a constant infusion and imaged 6-8 h later under equilibrium conditions. The effect of diagnosis on regional alpha(4)beta(2)-nAChR availability (regional brain activity/total parent concentration in plasma, proportional to the binding potential) was analyzed using multivariate analysis of covariance, controlling for the effects of age and sex. RESULTS: Despite a significant overall effect of diagnostic group on mean alpha(4)beta(2)-nAChR availability, univariate analyses revealed no group differences for any brain region analyzed. An exploratory analysis of the relationship between regional alpha(4)beta(2)-nAChR availability and neuropsychologic variables yielded several plausible correlations. However, after Bonferroni adjustment, only the correlation between the anterior cingulate and the Trail Making Test, Part B, in the healthy control subjects remained significant. CONCLUSION: These results are consistent with several postmortem and in vivo studies suggesting the preservation of nAChRs during the prodromal and early stages of AD. They support the interpretation that nAChR and other cholinergic reductions in AD are late-stage phenomena.

Regional distribution and behavioral correlates of 5-HT(2A) receptors in Alzheimer's disease with [(18)F]deuteroaltanserin and PET.

Postmortem studies show reductions in brain serotonin 2A (5-HT(2A)) receptors in Alzheimer's disease (AD). Converging evidence also suggests that serotonergic dysregulation may contribute to behavioral symptoms that frequently occur in AD. This study aimed to define regional reductions in 5-HT(2A) binding in AD patients and to examine their behavioral correlates. Nine patients with probable AD and eight elderly controls were studied using a constant infusion paradigm for equilibrium modeling of [(18)F]deuteroaltanserin with positron emission tomography (PET). Region of interest analyses were performed on PET images coregistered to MRI scans. The outcome measures BP(P) (ratio of specific brain uptake to total plasma parent concentration) and BP(ND) (ratio of specific to nondisplaceable uptake) were obtained for pertinent cortical and subcortical regions. AD patients showed a statistically significant decrease in the anterior cingulate in both BP(P) and BP(ND), but in no other region. Within the AD patient sample, no significant correlations were observed between regional 5-HT(2A) binding and behavioral measures, including depressive and psychotic symptoms. These results confirm a reduction in cortical 5-HT(2A) receptors in AD, specifically in the anterior cingulate. However, in a limited AD patient sample, they fail to demonstrate a relationship between regional 5-HT(2A) binding and major behavioral symptoms.

GABAA-benzodiazepine receptor availability in smokers and nonsmokers: relationship to subsyndromal anxiety and depression.

Many smokers experience subsyndromal anxiety symptoms while smoking and during acute abstinence, which may contribute to relapse. We hypothesized that cortical gamma aminobutyric acid(A)-benzodiazepine receptor (GABA(A)-BZR) availability in smokers and nonsmokers might be related to the expression of subsyndromal anxiety, depressive, and pain symptoms. Cortical GABA(A)-BZRs were imaged in 15 smokers (8 men and 7 women), and 15 healthy age and sex-matched nonsmokers, and 4 abstinent tobacco smokers (3 men; 1 woman) using [(123)I]iomazenil and single photon emission computed tomography (SPECT). Anxiety and depressive symptoms were measured using the Spielberger's State-Trait Anxiety Index (STAI) and the Center for Epidemiology Scale for Depressive Symptoms (CES-D). The cold pressor task was administered to assess pain tolerance and sensitivity. The relationship between cortical GABA(A)-BZR availability, smoking status, and subsyndromal depression and anxiety symptoms, as well as pain tolerance and sensitivity, were evaluated. Surprisingly, there were no statistically significant differences in overall GABA(A)-BZR availability between smokers and nonsmokers or between active and abstinent smokers; however, cortical GABA(A)-BZR availability negatively correlated with subsyndromal state anxiety symptoms in nonsmokers but not in smokers. In nonsmokers, the correlation was seen across many brain areas with state anxiety [parietal (r = -0.47, P = 0.03), frontal (r = -0.46, P = 0.03), anterior cingulate (r = -0.47, P = 0.04), temporal (r = -0.47, P = 0.03), occipital (r = -0.43, P = 0.05) cortices, and cerebellum (r = -0.46, P = 0.04)], trait anxiety [parietal (r = -0.72, P = 0.02), frontal (r = -0.72, P = 0.02), and occipital (r = -0.65, P = 0.04) cortices] and depressive symptoms [parietal (r = -0.68; P = 0.02), frontal (r = -0.65; P = 0.03), anterior cingulate (r = -0.61; P = 0.04), and temporal (r = -0.66; P = 0.02) cortices]. The finding that a similar relationship between GABA(A)-BZR availability and anxiety symptoms was not observed in smokers suggests that there is a difference in GABA(A)-BZR function, but not number, in smokers. Thus, while subsyndromal anxiety and depressive symptoms in nonsmokers may be determined in part by GABA(A)-BZR availability, smoking disrupts this relationship. Aberrant regulation of GABA(A)-BZR function in vulnerable smokers may explain why some smokers experience subsyndromal anxiety and depression.

beta2-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.

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)]beta-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.

Age-related decline in nicotinic receptor availability with [(123)I]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 Pearson's 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.

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.

A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer's Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Abeta1-40 peptide of several of these compounds were in the low-nanomolar range . The lowest K(i) of 9.3nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its (123)I-radiolabeled form ([(123)I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood-brain barrier (BBB) to any significant extent.

beta2 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.

Synthesis, radiolabeling and baboon SPECT imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl)tropane ([(123)I]YP256) as a serotonin transporter radiotracer.

To develop a potential SPECT probe to evaluate the integrity of the serotoninergic system (5-HTT) whose dysfunction is linked to several disease conditions such as Parkinson's disease, Alzheimer's disease and depression, we report the synthesis, radiolabeling and in vivo baboon imaging of 2beta-carbomethoxy-3beta-(3'-[(123)I]iodophenyl) tropane (YP256, 6). The radiolabeling was performed by iododestannylation using sodium [(123)I]iodide and peracetic acid. Although the ligand displayed high selectivity for 5-HTT over dopamine transporter in vitro, SPECT imaging in baboons did not reveal selective 5-HTT accumulation in brain in vivo.