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BACKGROUND: The use of pejorative or stigmatizing language surrounding individuals with alcohol and substance use disorders adversely affects treatment seeking, quality of care, and treatment outcomes. In 2015, the International Society of Addiction Journal Editors released terminology guidelines that recommended against the use of words that contribute to stigma against individuals with an addictive disorder. This study examined the use of stigmatizing language in NIH-funded research and reviews published by the journal, Alcoholism: Clinical and Experimental Research (ACER) from 2010-2020, with the goal of sharing the results with the alcohol research community to enhance awareness. METHODS: The search for stigmatizing language in ACER was limited to NIH-funded articles made publicly available on PubMed Central (PMC). Though ACER is not an open access journal, original research and reviews directly funded by NIH are published to PMC for open access to the public as required by the conditons of NIH funding. ACER articles published on PMC were searched from 2010-2020 with specific queries for individual terms of interest including those considered pejorative (“alcoholic,” “addict,” “abuser”) and outdated (“alcohol dependent,” “alcohol abuse,” “alcoholism”). The number of articles containing a term of interest for a given year were divided by the total number of articles published in that year to determine the percent use of each term per year. RESULTS: Our search of research and reviews (n=1903) published in ACER on PMC determined that although the use of pejorative and outdated terminology has decreased over time, there is continued use of the term “alcoholic” over the last decade. Specifically, over 40% of articles searched for in PMC still included “alcoholic” in the year 2020. The results of a separate manual search (n=110) on Wiley Online Database suggested that approximately 30% of articles used the term “alcoholic” in a stigmatizing manner. CONCLUSIONS: Stigmatizing language can perpetuate negative biases against people with alcohol use disorder. We encourage researchers to shift away from language that maintains discriminatory conceptions of alcohol use disorder. Reducing stigma has the potential to increase rates of treatment seeking, and improve treatment outcomes for individuals managing alcohol use disorder.

Acetylcholine (ACh) has distinct functional roles in striatum compared with cortex, and imbalance between these systems may contribute to neuropsychiatric disease. Preclinical studies indicate markedly higher ACh concentrations in the striatum. The goal of this work was to leverage positron emission tomography (PET) imaging estimates of drug occupancy at cholinergic receptors to explore ACh variation across the human brain, because these measures can be influenced by competition with endogenous neurotransmitter. PET scans were analyzed from healthy human volunteers (n = 4) and nonhuman primates (n = 2) scanned with the M1-selective radiotracer [11C]LSN3172176 in the presence of muscarinic antagonist scopolamine, and human volunteers (n = 10) scanned with the α4β2* nicotinic ligand (−)-[18F]flubatine during nicotine challenge. In all cases, occupancy estimates within striatal regions were consistently lower (M1/scopolamine human scans, 31 ± 3.4% occupancy in striatum, 43 ± 2.9% in extrastriatal regions, p = 0.0094; nonhuman primate scans, 42 ± 26% vs. 69 ± 28%, p

Psychiatric and neurologic disorders are often characterized by both neuroinflammation and cognitive dysfunction. To date, however, the relationship between neuroinflammation and cognitive dysfunction remains understudied in humans. Preclinical research indicates that experimental induction of neuroinflammation reliably impairs memory processes. In this paradigm development study, we translated those robust preclinical findings to humans using positron emission tomography (PET) imaging with [11C]PBR28, a marker of microglia, and lipopolysaccharide (LPS), a potent neuroimmune stimulus. In a sample of 18 healthy adults, we extended our previous findings that LPS administration increased whole-brain [11C]PBR28 availability by 31-50%, demonstrating a robust neuroimmune response (Cohen's ds > 1.6). We now show that LPS specifically impaired verbal learning and recall, hippocampal memory processes, by 11% and 22%, respectively (Cohen's ds > 0.9), but did not alter attention, motor, or executive processes. The LPS-induced increase in [11C]PBR28 binding was correlated with significantly greater decrements in verbal learning performance in the hippocampus (r = -0.52, p = .028), putamen (r = -0.50, p = .04), and thalamus (r = -0.55, p = .02). This experimental paradigm may be useful in investigating mechanistic relationships between neuroinflammatory signaling and cognitive dysfunction in psychiatric and neurologic disorders. It may also provide a direct approach to evaluate medications designed to rescue cognitive deficits associated with neuroinflammatory dysfunction.

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [

BACKGROUND: People recovering from alcohol use disorder (AUD) show altered resting brain connectivity. The metabotropic glutamate 5 (mGlu5) receptor is an important regulator of synaptic plasticity potentially linked with synchronized brain activity, and is also a target of interest in treating AUD. The goal of this work was to assess potential relationships of brain connectivity at rest with mGlu5 receptor availability in people with AUD at two time points early in abstinence. METHODS: A total of 48 image data sets were acquired with a multimodal neuroimaging battery including resting state functional magnetic resonance imaging (fMRI) and mGlu5 receptor positron emission tomography (PET) with the radiotracer [(18)F]FPEB. Participants with AUD (n=14) were scanned twice, at approximately one week and four weeks after beginning supervised abstinence. [(18)F]FPEB PET results were published previously. Primary comparisons of fMRI outcomes were performed between the AUD group and healthy controls (HCs; n=23), and assessed changes over time within the AUD group. Relationships between resting state connectivity measures and mGlu5 receptor availability were explored within groups. RESULTS: Compared to HCs, global functional connectivity of the orbitofrontal cortex was higher in the AUD group at 4 weeks abstinence (p = 0.003), while network-level functional connectivity within the default mode network (DMN) was lower (p < 0.04). Exploratory multimodal analyses found that mGlu5 receptor availability was correlated with global connectivity across all brain regions (HCs, r = 0.41; AUD group 1 week abstinence, r = 0.50 and 4 weeks, r = 0.46; all p < 0.0001). Furthermore, a component of cortical and striatal mGlu5 availability was correlated with connectivity between DMN and salience networks in HCs (r = 0.60, p = 0.003) but not in the AUD group (p > 0.3). CONCLUSIONS: These preliminary findings of altered global and network connectivity during the first month of abstinence from drinking may reflect loss of efficient network function, while exploratory relationships with mGlu5 receptor availability suggest a potential glutamatergic relationship with network coherence.

Chronic alcohol use has important effects on the glutamate system. The metabotropic glutamate 5 (mGlu5) receptor has shown promise in preclinical models as a target to reduce drinking-related behaviors and cue-induced reinstatement, motivating human studies of mGlu5 receptor negative allosteric modulators. The goal of this work was to measure levels of mGlu5 receptor availability with positron emission tomography (PET) imaging using the mGlu5 receptor-specific radiotracer [(18)F]FPEB during early and extended alcohol abstinence. Subjects who met DSM-5 criteria for alcohol use disorder (AUD; n = 17) were admitted inpatient for the study duration. [(18)F]FPEB PET scans were acquired first during early abstinence (6 ± 4 days after last drink) and a second time during extended abstinence (n = 13; 27 ± 6 days after last drink). A single scan was acquired in healthy controls matched for sex and smoking status (n = 20). [(18)F]FPEB total volumes of distribution (V(T)) corrected for partial volume effects were measured using equilibrium analysis throughout the brain. A linear mixed model controlling for smoking status and sex identified significantly higher [(18)F]FPEB V(T) in AUD subjects at early abstinence compared to controls (F((1,32)) = 7.23, p = 0.011). Post-hoc analyses revealed this effect to occur in cortical brain regions. No evidence for significant changes in [(18)F]FPEB V(T) over time were established. These findings provide human evidence consistent with a robust preclinical literature supporting mGlu5 receptor drugs as pharmacotherapies for AUD.

Over the last 10 years, rates of alcohol use disorder (AUD) have increased in women by 84% relative to a 35% increase in men. Rates of alcohol use and high-risk drinking have also increased in women by 16% and 58% relative to a 7% and 16% increase in men, respectively, over the last decade. This robust increase in drinking among women highlights the critical need to identify underlying neural mechanisms that may contribute to problematic alcohol consumption across sex/gender (SG), especially given that many neuroimaging studies are underpowered to detect main or interactive effects of SG on imaging outcomes. This narrative review aims to explore the recent neuroimaging literature on SG differences in brain function and structure as it pertains to alcohol across positron emission tomography (PET), magnetic resonance imaging (MRI), and functional magnetic resonance imaging (fMRI) modalities in humans. Additional work using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and event-related potentials (ERPs) to examine SG differences in AUD will be covered. Overall, current research neuroimaging AUD, alcohol consumption, or risk of AUD is limited, and findings are mixed regarding the effect of SG on neurochemical, structural, and functional mechanisms associated with AUD. We address SG disparities in the neuroimaging of AUD and propose a call to action to include women in brain imaging research. Future studies are crucial to our understanding of the neurobiological underpinnings of AUD across neural systems and the vulnerability for AUD among women and men.

Social factors are associated with psychiatric outcomes and brain function. Relationships between local population data obtained from Social Explorer analyses of the American Community Survey (2014–2018) and dopamine D(2/3) receptor (D(2/3)R) availability were explored in this retrospective analysis of [(11)C]PHNO positron emission tomography (PET) imaging data (n=70). Larger local population size and lower percentage of the population with a bachelor’s degree or higher were significantly associated with higher striatal D(2/3)R availability, suggesting that living in a populous area with fewer educational resources may be accompanied by stressors with concomitant dopaminergic changes. Future prospective, collaborative studies are needed to better understand the precise etiology of the observed relationships.

Introduction Chronic nicotine exposure desensitizes dopamine responses in animals, but it is not known if this occurs in human tobacco smokers. Deficits in dopamine function are likely to make smoking cessation difficult. We used positron emission tomography (PET) brain imaging with the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO to determine if abstinent smokers exhibit less amphetamine-induced dopamine release in the ventral striatum than nonsmokers, and whether this was associated with clinical correlates of smoking cessation. Methods Baseline [11C]-(+)-PHNO scans were acquired from smokers (n = 22, 7 female, abstinent 11 ± 9 days) and nonsmokers (n = 20, 7 female). A subset of thirty-seven participants (18 smokers) received oral amphetamine (0.5 mg/kg) three hours before a second [11C]-(+)-PHNO scan. Binding potential (BPND) (i.e., D2/3 receptor availability) was estimated at baseline and postamphetamine in the ventral striatum. Amphetamine-induced percent change in BPND was calculated to reflect dopamine release. Subjects also completed the Center for Epidemiologic Studies Depression Scale (CES-D). Results There were no group differences in baseline BPND. Amphetamine-induced percent change in BPND in the ventral striatum was significantly lower in abstinent smokers compared to nonsmokers (p=0.019; d=0.82). Higher CES-D scores were significantly associated with lower ventral striatal percent change in BPND for abstinent smokers (rs=-0.627, p=0.025). Conclusions In conclusion, abstinent smokers exhibited significantly less amphetamine-induced dopamine release in the ventral striatum than nonsmokers. In abstinent smokers, worse mood was significantly associated with less striatal dopamine release. Our findings highlight a potential neural mechanism that may underlie negative mood symptoms during early abstinence. Implications This study combined quantitative PET imaging and an amphetamine challenge to examine striatal dopamine function during early smoking cessation attempts. The findings demonstrate that recently abstinent tobacco smokers exhibit significant, mood-associated striatal dopamine dysfunction compared to nonsmokers. This study advances our knowledge of the neurobiology underlying early quit attempts, and bridges novel neural findings with clinically relevant symptoms of smoking cessation. These results may explain the challenge of maintaining long-term abstinence from smoking, and can lend insight into the development of treatment strategies for smoking cessation.

OBJECTIVE: PET studies have demonstrated less dopamine D(2/3) receptor availability and blunted psychostimulant-induced dopamine release in cocaine dependent subjects (CDS). No studies in CDS have reported the in vivo status of D(2/3) and dopamine release in the cortex. Basic and functional imaging studies suggest a role for prefrontal cortical dopaminergic abnormalities in impaired executive function and relapse in cocaine dependence. Here, we used [(11)C]FLB 457 PET and amphetamine to measure cortical D(2/3) receptors and dopamine release in CDS. METHODS: [(11)C]FLB 457 and PET were used to measure D(2/3) receptor binding potential in cortical regions of interest (ROIs) in recently abstinent (n = 24) CDS and healthy control subjects (n = 36) both before and after 0.5 mg kg(−1) of oral d-amphetamine. Binding potential relative to non-displaceable uptake (BP(ND)) and total plasma concentration (BP(P)) were derived using an arterial input function-based kinetic analysis. Cortical dopamine release in ROIs was measured as the change (D) in BP(ND) and BP(P) after amphetamine. RESULTS: Baseline D(2/3) receptor availability (BP(P) and BP(ND)) and amphetamine-induced dopamine release (ΔBP(ND) and ΔBP(P)) were significantly lower in the cortical regions in CDS compared to HC. Less D(2/3) receptors and dopamine release in CDS were not associated with performance on a working memory and attention tasks. CONCLUSIONS: The results of this study suggest that deficits in dopamine D(2/3) transmission involve the cortex in cocaine dependence. Further studies to understand the clinical relevance of these findings are warranted.

BACKGROUND: Dopaminergic mechanisms that may underlie cannabis’ reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D(2/3) receptor antagonist [(11)C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample. METHODS: PET emission data were acquired from regular cannabis users (n=14; 7M/7F; 19-32 years old) over 90 minutes immediately after [(11)C]raclopride administration (584±95 MBq) as bolus followed by constant infusion (K(bol)=105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 minutes after scan start. Plasma concentrations of Δ(9)-THC and metabolites and ratings of subjective “high” were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [(11)C]raclopride binding, linearized-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region). RESULTS: Cannabis smoking increased plasma Δ(9)-THC levels (peak: 0-10 minutes) and subjective high (peak: 0-30 minutes). Significant clusters (>16 voxels) modeled by transient reductions in [(11)C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans. CONCLUSIONS: These preliminary data support the sensitivity of [(11)C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.

Introduction Tobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively. Aims and Methods To better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate. Results Dopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers. Conclusions These findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations. Implications This is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation.

Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods [11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies. Electronic supplementary material The online version of this article (10.1007/s00259-019-04403-7) contains supplementary material, which is available to authorized users.

The prevalence of cardiovascular diseases (CVD) is increased in subjects with post-traumatic stress disorder (PTSD). Vascular inflammation mediates CVD and may be assessed by(18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging. In this pilot study, we investigated whether subjects with PTSD have enhanced vascular and systemic inflammation compared to healthy controls, as assessed by FDG PET imaging. METHODS: A prospective group of 16 subjects (9 PTSD and 7 controls, age 34±7) without prior history of CVD underwent FDG PET/CT imaging. The presence of PTSD symptoms at the time of the study was confirmed using PTSD checklist for DSM-5 (PCL5) questionnaire. Blood samples were collected to determine blood glucose, lipid and inflammatory biomarkers (tumor necrosis factor α, interleukin-1β, and interleukin-6) levels. FDG signal in the ascending aorta, amygdala, spleen and bone marrow was quantified. RESULTS: The two groups matched closely with regards to cardiovascular risk factors. The inflammatory biomarkers were all within the normal range. There was no significant difference in FDG signal in the aorta (target to background ratio: 2.40±0.29 and 2.34±0.29 for control and PTSD subjects, difference −0.6, 95% confidence interval of difference −0.38 – 0.26), spleen, bone marrow, or amygdala between control and PTSD subjects. There was no significant correlation between aortic and amygdala FDG signal. However, a significant positive correlation existed between amygdala, splenic, and bone marrow FDG signal. CONCLUSION: This pilot, small study did not reveal any difference in vascular or systemic inflammation as assessed by FDG PET imaging between PTSD and healthy control subjects. Because of the small number of subjects, a modest increase in vascular inflammation, which requires larger scale studies to establish, cannot be excluded. The correlation between FDG signal in amygdala, spleen and bone marrow may reflect a link between amygdala activity and systemic inflammation.

BACKGROUND: Investigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used positron emission tomography (PET) to image 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD. METHODS: Sixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [(18)F]AS2471907, a radioligand for 11β-HSD1. RESULTS: Prefrontal-limbic 11β-HSD1 availability, estimated as [(18)F]AS2471907 volume of distribution (V(T)), was significantly higher in the PTSD group compared with the TC group (β = 1.16, P = 0.0057). Lower prefrontal-limbic 11β-HSD1 availability was related to greater overall PTSD severity (R(2) = 0.27, P = 0.038) in the PTSD group. 11β-HSD1 availability was not related to plasma cortisol levels (R(2) = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11β-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (β = 4.40, P = 0.039). CONCLUSION: Higher brain cortisol–producing 11β-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11β-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD. FUNDING: Brain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.

Sex differences are present in psychiatric disorders associated with disrupted dopamine function, and thus, sex differences in dopamine neurobiology may underlie these clinical disparities. In this chapter, we review sex differences in the dopaminergic system with a focus on substance use disorders, especially tobacco smoking, as our exemplar disorder. This chapter is organized into five sections describing sex differences in the dopaminergic system: (1) neurobiology, (2) role of sex hormones, (3) genetic underpinnings, (4) cognitive function, and (5) influence on addiction. In each section, we provide an overview of the topic area, summarize sex differences identified to date, highlight addiction research, especially clinical neuroimaging studies, and suggest avenues for future research.

Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals—with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology., Neuroinflammation has been proposed to accompany the peripheral inflammation observed in PTSD. Here, authors find lower in vivo and postmortem levels of neuroimmune marker TSPO (translocator protein) in PTSD, in association with greater PTSD severity and higher plasma CRP.

CONTEXT: Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer’s disease phenotypes. The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo. OBJECTIVE: We analyzed positron emission tomography (PET) scans with an 11β-HSD1 inhibitor radioligand in twenty-eight individuals (23M/5F): 10 lean, 13 overweight and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of (11)C-AS2471907 (n=17) or (18)F-AS2471907 (n=11). Injected activity and mass doses were 246±130 MBq and 0.036±0.039 μg, respectively, for (11)C-AS2471907, and 92±15 MBq and 0.001±0.001 μg for (18)F-AS2471907. Correlations of mean whole brain and regional Distribution Volume (V(T)) with body mass index (BMI) and age were performed with a linear regression model. RESULTS: Significant correlations of whole brain mean V(T) with BMI and age (V(T) = 15.23 – 0.63xBMI + 0.27xAge, p=0.001) were revealed. Age-adjusted mean whole brain V(T) values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean V(T) values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe and putamen also showed lower V(T) value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm(3) per decade was seen in BMI-corrected mean whole brain V(T) values. CONCLUSIONS: In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain, and correlation of increased 11β-HSD1 levels in the brain with advancing age.

The PET ligand (11)C-PBR28 (N-((2-(methoxy-(11)C)-phenyl)methyl)-N-(6-phenoxy-3-pyridinyl)acetamide) binds to the 18-kDa translocator protein (TSPO), a biomarker of glia. In clinical studies of TSPO, the ligand total distribution volume, V(T), is frequently the reported outcome measure. Since V(T) is the sum of the ligand-specific distribution volume (V(S)) and the nondisplaceable-binding distribution volume (V(ND)), differences in V(ND) across subjects and groups will have an impact on V(T). Methods: Here, we used a recently developed method for simultaneous estimation of V(ND) (SIME) to disentangle contributions from V(ND) and V(S). Data from 4 previously published (11)C-PBR28 PET studies were included: before and after a lipopolysaccharide challenge (8 subjects), in alcohol use disorder (14 patients, 15 controls), in first-episode psychosis (16 patients, 16 controls), and in Parkinson disease (16 patients, 16 controls). In each dataset, regional V(T) estimates were obtained with a standard 2-tissue-compartment model, and brain-wide V(ND) was estimated with SIME. V(S) was then calculated as V(T) − V(ND). V(ND) and V(S) were then compared across groups, within each dataset. Results: A lower V(ND) was found for individuals with alcohol-use disorder (34%, P = 0.00084) and Parkinson disease (34%, P = 0.0032) than in their corresponding controls. We found no difference in V(ND) between first-episode psychosis patients and their controls, and the administration of lipopolysaccharide did not change V(ND). Conclusion: Our findings suggest that in TSPO PET studies, nondisplaceable binding can differ between patient groups and conditions and should therefore be considered.

The mesocorticolimbic dopamine (DA) circuit, comprising the mesolimbic and mesocortical DA pathways, plays a crucial role in reward, cognitive control, and motivation. The positron emission tomography (PET) radiotracer, [C-11]raclopride, has been used widely to image DA receptors and DA changes in the mesolimbic pathway before and after pharmacological and behavioral challenges. In certain circumstances, properties of traditional kinetic models—used to analyze dynamic PET data—are not well-suited to describing the effects of stimulus-induced DA release. To combat model shortcomings, the authors have advanced a suite of models that characterizes PET data in the presence of time-varying DA release. We review select [C-11]raclopride studies of the striatum during cigarette smoking to illustrate the advantages of such models. DA receptors occur in lower density in the cortex than the striatum. This, as well as higher relative background signal, poses a serious challenge to quantitative PET of DA changes in the mesocortical system. Novel high affinity radioligands [F-18]fallypride and [C-11]FLB457 have been used to image mesocortical DA transmission. Models with time-varying terms may also hold the key to optimizing sensitivity to changes in mesocortical DA. As an illustration, we compare recent PET studies of the effect of stress on cortical DA release. Finally, we consider some challenges and strategies for further optimization of sensitivity of PET to stimulus-induced DA changes throughout the whole brain. Electronic supplementary material The online version of this article (10.1007/s11682-017-9779-7) contains supplementary material, which is available to authorized users.

BACKGROUND: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain β(2)*-nicotinic acetylcholine receptors (β(2)*-nAChR) and how this relates to the behavioral effects and nicotine delivery from cigarettes. METHODS: Seven nicotine users participated in positron emission tomography (PET) studies with (-)-[18F]Flubatine before and after nicotine challenge with 0, 8, and 36 mg/ml nicotine in a 3.3 Volt, 1.5 Ohm EC or a standard tobacco cigarette. Craving was evaluated before and after product use. RESULTS: Average β(2)*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average β(2)*-nAChR occupancy after tobacco cigarette smoking was 68 ± 18% and was not different compared with 8 mg/ml (64 ± 17%,) or 36 mg/ml (84 ± 3%) nicotine in EC users. Area under the curve (AUC) of blood nicotine level was higher in the cigarette smoking group compared with the 8mg/ml group (p = 0.03), but similar compared with the 36 mg/ml EC (p = 0.29). Drug craving was reduced after use of the tobacco cigarette, 8 mg/ml EC, and 36 mg/ml EC. CONCLUSIONS: In this novel investigation of EC effects at β(2)*-nAChRs, we show that average β(2)*-nAChR occupancy was higher after 36 mg/ml EC challenge compared with 8 mg/ml EC. Receptor occupancy and arterial blood nicotine levels after cigarette smoking were similar to 36 mg/ml EC use under controlled conditions. These findings suggest that the ECs studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers. IMPLICATIONS: This is the first study to directly determine the neurologic effects of electronic cigarettes on human brain beta-2 nicotinic acetylcholine receptors using PET neuroimaging with (-)-[18F]Flubatine, a novel radiotracer. Our findings suggest that the e-cigarettes studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers.

The positron emission tomography (PET) radioligand (−)-[18F]flubatine is specific to α4β2∗ nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4β2∗ nAChR quantification with bolus plus constant infusion (B/I) (−)-[18F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n = 8) or B/I (n = 4) administration of (−)-[18F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n = 6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5 mg over 60 min beginning 5 min prior to radiotracer injection); 2. A single scan B/I paradigm (n = 7) lasting up to 240 min with 1.5 mg physostigmine administered over 60 min beginning at 125 min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8 ± 3.3 mL/cm3 in thalamus, 12.9 ± 1.6 mL/cm3 in cerebellum, and ranged from 9.8 to 12.5 mL/cm3 in other gray matter regions. The B/I paradigm with equilibrium analysis at 120 min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means

The effects of tobacco smoking on the immune system of the brain are not well elucidated. Although nicotine is immunosuppressive, other constituents in tobacco smoke have inflammatory effects. PET imaging of the 18-kDa translocator protein (TSPO) provides a biomarker for microglia, the primary immunocompetent cells of the brain. This work compared brain TSPO levels in 20 tobacco smokers (abstinent for at least 2 h) and 20 nonsmokers using a fully quantitative modeling approach for the first time, to our knowledge. Methods: (11)C-PBR28 (N-((2-(methoxy-(11)C)-phenyl)methyl)-N-(6-phenoxy-3-pyridinyl)acetamide) PET scans were acquired with arterial blood sampling to estimate the metabolite-corrected input function. (11)C-PBR28 volumes of distribution were estimated throughout the brain with multilinear analysis. Results: Statistical analyses revealed no evidence of significant differences in regional (11)C-PBR28 volumes of distribution between smokers and nonsmokers (whole-brain Cohen d = 0.09) despite adequate power to detect medium effect sizes. Conclusion: These findings inform previous PET studies reporting lower TSPO radiotracer concentrations in the brain (measured as SUV) for tobacco smokers than for nonsmokers by demonstrating the importance of accounting for radiotracer concentrations in plasma. These findings suggest that nonsmokers and smokers have comparable TSPO levels in the brain. Additional work with other biomarkers is needed to fully characterize the effects of tobacco smoking on the brain immune system.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes enzymatic conversion of cortisone into the stress hormone cortisol. This first-in-human brain imaging study characterizes the kinetic modeling and test–retest reproducibility of [(18)F]AS2471907, a novel PET radiotracer for 11β-HSD1. Eight individuals underwent one 180-min (n = 4) or two 240-min (n = 4) [(18)F]AS2471907 PET brain scans (12 total) acquired on the high-resolution research tomograph (HRRT) scanner with arterial blood sampling. Imaging data were modeled with 1-tissue (1T) and 2-tissue (2T) compartment models and with multilinear analysis (MA1) to estimate [(18)F]AS2471907 availability (V(T)). [(18)F]AS2471907 demonstrated high, heterogeneous uptake throughout the brain. Of the compartment models, 2T best described [(18)F]AS2471907 data. Estimates of V(T) were highly correlated between 2T and MA1 (t* = 30 min) with MA1 yielding V(T) values ranging from 3.2 ± 1.0 mL/cm(3) in the caudate to 15.7 ± 4.2 mL/cm(3) in the occipital cortex. The median absolute test–retest variability of 16 ± 5% and high intraclass correlation coefficient (ICC) values of 0.67–0.97 across regions indicate fair test–retest reliability but large intersubject variability. V(T) estimates using 180 min were within 10% of estimates using full acquisition time. In summary, [(18)F]AS2471907 exhibits reasonable kinetic properties for imaging 11β-HSD1 in human brain.

Sex differences exist in the neurochemical mechanisms underlying tobacco smoking and smoking-related behaviors. Men tend to smoke for the reinforcing effects of nicotine, whereas women tend to smoke for stress and mood regulation, and have a harder time maintaining long-term abstinence. The mesolimbic dopamine (DA) system drives the reinforcing effects of tobacco smoking, whereas the mesocortical DA system—including the dorsolateral prefrontal cortex (dlPFC)—is critical for stress-related cognitive functioning and inhibitory control. This study is the first to investigate dlPFC D(2/3)-type receptor (D(2)R) availability and amphetamine-induced cortical DA release in smokers and nonsmokers. Forty-nine subjects (24 tobacco smokers (12 females) and 25 sex- and age-matched nonsmokers) participated in two same-day [(11)C]FLB457 positron emission tomography (PET) scans before and 3-hours after amphetamine administration (0.4–0.5 mg/kg, PO). D(2)R availability (non-displaceable binding potential; BP(ND)) was measured pre- and post-amphetamine. The percent fractional change in BP(ND) (%ΔBP(ND)) between pre- and post-amphetamine, an index of DA release, was compared between male and female smokers and nonsmokers. Smokers showed significantly lower dlPFC D(2)R availability (BP(ND) = 0.77 ± 0.05) than nonsmokers (BP(ND) = 0.92 ± 0.04), p = 0.016, driven by males. Female smokers showed significantly less amphetamine-induced DA release in dlPFC (%ΔBP(ND) = 1.9 ± 3.0%) than male smokers (%ΔBP(ND) = 14.0 ± 4.3%), p

Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'

Objective Previous imaging studies with positron emission tomography (PET) have reliably demonstrated an age-associated decline in the dopamine system. Most of these studies have focused on the densities of dopamine receptor subtypes D 2/3 R (D 2 R family) in the striatum using antagonist radiotracers that are largely nonselective for D 2 R vs. D 3 R subtypes. Therefore, less is known about any possible age effects in D 3 -rich extrastriatal areas such as the substantia nigra/ventral tegmental area (SN/VTA) and hypothalamus. This study sought to investigate whether the receptor availability measured with [ 11 C](+)PHNO, a D 3 R-preferring agonist radiotracer, also declines with age. Methods Forty-two healthy control subjects (9 females, 33 males; age range 19–55 years) were scanned with [ 11 C](+)PHNO using a High Resolution Research Tomograph (HRRT). Parametric images were computed using the simplified reference tissue model (SRTM2) with cerebellum as the reference region. Binding potentials ( BP ND ) were calculated for the amygdala, caudate, hypothalamus, pallidum, putamen, SN/VTA, thalamus, and ventral striatum and then confirmed at the voxel level with whole-brain parametric images. Results Regional [ 11 C](+)PHNO BP ND displayed a negative correlation between receptor availability and age in the caudate ( r = − 0.56, corrected p = 0.0008) and putamen ( r = − 0.45, corrected p = 0.02) in healthy subjects (respectively 8% and 5% lower per decade). No significant correlations with age were found between age and other regions (including the hypothalamus and SN/VTA). Secondary whole-brain voxel-wise analysis confirmed these ROI findings of negative associations and further identified a positive correlation in midbrain (SN/VTA) regions. Conclusion In accordance with previous studies, the striatum (an area rich in D 2 R) is associated with age-related declines of the dopamine system. We did not initially find evidence of changes with age in the SN/VTA and hypothalamus, areas previously found to have a predominantly D 3 R signal as measured with [ 11 C](+)PHNO. A secondary analysis did find a significant positive correlation in midbrain (SN/VTA) regions, indicating that there may be differential effects of aging, whereby D 2 R receptor availability decreases with age while D 3 R availability stays unchanged or is increased.

Introduction Cigarette smokers report using electronic cigarettes (e-cigarettes) to reduce or quit smoking, but findings are mixed regarding the benefit and risk of e-cigarettes in this population, and effects of gender are unknown. Methods The Population Assessment of Tobacco and Health (PATH; waves 1 and 2; adult interviews) was used to evaluate relationships among wave 1 e-cigarette use (daily, nondaily, never) and gender and their association with transitions (quit vs. current; relapse vs. former) in cigarette smoking status across waves 1 and 2 of the PATH study. Results Daily e-cigarette users had higher odds of quitting smoking (odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.12 to 2.18) compared with never e-cigarette users. Conversely, daily and nondaily e-cigarette users were at greater risk of smoking relapse (OR = 1.84, 95% CI = 1.15 to 2.94 and OR = 1.85, 95% CI = 0.99 to 3.46, respectively) compared with never e-cigarette users. Women were less likely to quit smoking compared with men independent of e-cigarette use (OR = 0.76, 95% CI = 0.59 to 0.99). In stratified analyses, daily or nondaily e-cigarette use did not increase the likelihood of quitting or relapse in women. In men, daily and nondaily e-cigarette users were at greater risk of smoking relapse (OR = 2.96, 95% CI = 1.49 to 5.86 and OR = 3.05, 95% CI = 1.29 to 7.17, respectively) compared with men who were never e-cigarette users. Conclusions Findings identify e-cigarettes as a potential aid for smoking cessation but also as a potential risk for smoking relapse in men only. Overall, women were less likely to quit smoking, and e-cigarette use did not impact their ability to quit or to stay quit. Implications Cigarette smokers report using e-cigarettes to reduce or quit smoking, but findings are mixed regarding the benefit and risk of e-cigarettes in this population. Using data from the newly available PATH (waves 1 and 2; adult interviews), our findings identify e-cigarettes as a potential aid for smoking cessation but also identify e-cigarettes as a potential risk for smoking relapse in men only. These findings may have implications for the regulation of e-cigarettes by the Food and Drug Administration and the benefit-cost ratio of e-cigarette use in smokers.

Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [11C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min [11C]PBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second [11C]PBR28 scan. LPS administration significantly increased [11C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [11C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.

Introduction The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α 4 β 2 receptor radiotracer [ 18 F]-(-)-NCFHEB ([ 18 F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo . Methods [ 18 F]-(-)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N -Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC. Results [ 18 F]-(-)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was > 98% and the mean specific radioactivity was 97.3 ± 16.1 GBq/μmol (n = 6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98-100% of [ 18 F]-(-)-NCFHEB specific binding, and the non-displaceable distribution volume ( V ND ) was estimated at 5.9 ± 1.0 mL/cm 3 (n = 2), or 6.6 ± 1.1 mL/cm 3 after normalization by the plasma free fraction f P . Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [ 18 F]-(-)-NCFHEB can yield robust regional binding potential ( BP ND ) values (thalamus = 4.1 ± 1.5, frontal cortex = 1.2 ± 0.2, putamen = 0.96 ± 0.45, and cerebellum = 0.10 ± 0.29). Conclusion An efficient microfluidic synthetic method was developed for preparation of [ 18 F]-(-)-NCFHEB. PET examination in rhesus monkeys showed that [ 18 F]-(-)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α 4 β 2 receptors. Estimated non-displaceable binding potential ( BP ND ) values in brain regions were better than those of [ 18 F]2-FA and comparable to [ 18 F]AZAN. These results confirm previous findings and support further examination of [ 18 F]-(-)-NCFHEB in humans.

Introduction To determine the effect of ovarian hormones on smoking, we conducted a systematic review of menstrual cycle effects on smoking (i.e., ad lib smoking, smoking topography, and subjective effects) and cessation-related behaviors (i.e., cessation, withdrawal, tonic craving, and cue-induced craving). Methods Thirty-six papers were identified on MEDLINE that included a menstrual-related search term (e.g., menstrual cycle, ovarian hormones), a smoking-related search term (e.g., smoking, nicotine), and met all inclusion criteria. Thirty-two studies examined menstrual phase, 1 study measured hormone levels, and 3 studies administered progesterone. Results Sufficient data were available to conduct meta-analyses for only 2 of the 7 variables: withdrawal and tonic craving. Women reported greater withdrawal during the luteal phase than during the follicular phase, and there was a nonsignificant trend for greater tonic craving in the luteal phase. Progesterone administration was associated with decreased positive and increased negative subjective effects of nicotine. Studies of menstrual phase effects on the other outcome variables were either small in number or yielded mixed outcomes. Conclusions The impact of menstrual cycle phase on smoking behavior and cessation is complicated, and insufficient research is available upon which to conduct meta-analyses on most smoking outcomes. Future progress will require collecting ovarian hormone levels to more precisely quantify the impact of dynamic changes in hormone levels through the cycle on smoking behavior. Clarifying the relationship between hormones and smoking-particularly related to quitting, relapse, and medication response-could determine the best type and timing of interventions to improve quit rates for women.

Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding—men activating more ventrally than women—is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release (“DA movies”) in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen.

Understanding the effects of tobacco smoking on neuroadaptations in GABAA receptor levels over alcohol withdrawal will provide critical insights for the treatment of comorbid alcohol and nicotine dependence. We conducted parallel studies in human subjects and nonhuman primates to investigate the differential effects of tobacco smoking and nicotine on changes in GABAA receptor availability during acute and prolonged alcohol withdrawal. We report that alcohol withdrawal with or without concurrent tobacco smoking/nicotine consumption resulted in significant and robust elevations in GABAA receptor levels over the first week of withdrawal. Over prolonged withdrawal, GABAA receptors returned to control levels in alcohol-dependent nonsmokers, but alcohol-dependent smokers had significant and sustained elevations in GABAA receptors that were associated with craving for alcohol and cigarettes. In nonhuman primates, GABAA receptor levels normalized by 1 mo of abstinence in both groups--that is, those that consumed alcohol alone or the combination of alcohol and nicotine. These data suggest that constituents in tobacco smoke other than nicotine block the recovery of GABAA receptor systems during sustained alcohol abstinence, contributing to alcohol relapse and the perpetuation of smoking.

Background The goal of this study was to conduct a preliminary network analysis (using graph-theory measures) of intrinsic functional connectivity in adult smokers, with an exploration of sex differences in smokers. Methods Twenty-seven adult smokers (13 males; mean age = 35) and 17 sex and age-matched controls (11 males; mean age = 35) completed a blood oxygen level-dependent resting state functional magnetic resonance imaging experiment. Data analysis involved preprocessing, creation of connectivity matrices using partial correlation, and computation of graph-theory measures using the Brain Connectivity Toolbox. Connector hubs and additional graph-theory measures were examined for differences between smokers and controls and correlations with nicotine dependence. Sex differences were examined in a priori regions of interest based on prior literature. Results Compared to nonsmokers, connector hubs in smokers emerged primarily in limbic (parahippocampus) and salience network (cingulate cortex) regions. In addition, global influence of the right insula and left nucleus accumbens was associated with higher nicotine dependence. These trends were present in male but not female smokers. Conclusions Network communication was altered in smokers, primarily in limbic and salience network regions. Network topology was associated with nicotine dependence in male but not female smokers in regions associated with reinforcement (nucleus accumbens) and craving (insula), consistent with the idea that male smokers are more sensitive to the reinforcing aspects of nicotine than female smokers. Implications Identifying alterations in brain network communication in male and female smokers can help tailor future behavioral and pharmacological smoking interventions. Male smokers showed alterations in brain networks associated with the reinforcing effects of nicotine more so than females, suggesting that pharmacotherapies targeting reinforcement and craving may be more efficacious in male smokers.

We aimed to characterize changes in binding of (−)-[(18)F]Flubatine to α(4)β(2)*-nicotinic acetylcholine receptors (α(4)β(2)*-nAChRs) during a tobacco cigarette smoking challenge. Displacement of (−)-[(18)F] Flubatine throughout the brain was quantified as change in (−)-[(18)F]Flubatine distribution volume (V(T)), with particular emphasis on regions with low V(T). Three tobacco smokers were imaged with positron emission tomography (PET) during a 210 min bolus-plus-constant infusion of (−)-[(18)F]Flubatine. A tobacco cigarette was smoked in the PET scanner ~125 min after the start of (−)-[(18)F] Flubatine injection. Equilibrium analysis was used to estimate V(T) at baseline (90–120 min) and after cigarette challenge (180–210 min), at the time of greatest receptor occupancy by nicotine. Smoking reduced V(T) by 21 ± 9% (average ±SD) in corpus callosum, 17 ± 9% in frontal cortex, 36 ± 11% in cerebellum, and 22 ± 10% in putamen. The finding of displaceable (−)-[(18)F]Flubatine binding throughout the brain is an important consideration for reference region-based quantification approaches with this tracer. We observed displacement of (−)-[(18)F]Flubatine binding to α(4)β(2)*-nicotinic acetylcholine receptors in corpus callosum by a tobacco cigarette challenge. We conclude that reference region approaches utilizing corpus callosum should first perform careful characterization of displaceable (−)-[(18)F]Flubatine binding and nondisplaceable kinetics in this putative reference region.

Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with guanfacine with [(11)C]FLB457, a dopamine D(2)/D(3) receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [(11)C]FLB457 PET scans on the same day, one before and one at 2.5–3 h after amphetamine (0.4–0.5 mg/kg, PO). A subset (n=12) then underwent guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated. [(11)C]FLB457-binding potential (BP(ND)) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BP(ND) after vs before amphetamine (Δ BP(ND)) is an indirect measure of DA release and was compared between the untreated and guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BP(ND) from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [(11)C]FLB457 BP(ND) in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.

One prominent, long-standing view is that individuals with schizophrenia smoke cigarettes more than the general population to “self-medicate” cognitive deficits and other symptoms. This study tested the self-medication hypothesis by examining the effects of smoking abstinence and resumption on cognition in patients with schizophrenia. Nicotine-dependent smokers with schizophrenia (n=26) were trained on a cognitive battery and then hospitalized to achieve and maintain confirmed abstinence from smoking for ~1 week. Cognition was tested while smoking as usual (baseline), one day after smoking cessation (early abstinence), ~1 week later (extended abstinence), and within ~3 weeks of resuming smoking (resumption). The test battery included measures of processing speed, attention, conflict resolution, verbal memory, working memory, verbal fluency, and executive function to evaluate multiple cognitive domains affected by schizophrenia. Positive and negative symptoms of schizophrenia, depressive symptoms, and dyskinesia were also measured at baseline and after prolonged abstinence. There were no significant changes in global cognitive test performance with smoking cessation, abstinence, or resumption. There were small decreases in a measure of processing speed and delayed verbal recall with abstinence, but these findings failed to survive adjustments for multiple comparisons. Surprisingly, in this within subject “On- Off—Off-On” design, there were no significant effects of early or prolonged abstinence from smoking on cognitive and behavioral measures in smokers with schizophrenia. The results of this study challenge the widely held “self-medication” hypothesis of smoking and schizophrenia, question the extent of pro-cognitive effects of smoking and nicotine in schizophrenia, and support encouraging smoking cessation in schizophrenia.

The α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two PET radioligands specific to α7 nAChRs, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to further assess the quantification and test-retest variability of [18F]ASEM in humans.

Background Schizophrenia is associated with very high rates of tobacco smoking. The latter may be related to an attempt to self-medicate symptoms and/or to alterations in function of high-affinity β 2 -subunit-containing nicotinic acetylcholine receptors (β 2 *-nAChRs). Methods Smoking and nonsmoking subjects with schizophrenia ( n = 31) and age-, smoking-, and sex-matched comparison subjects ( n = 31) participated in one [ 123 I]5-IA-85380 single photon emission computed tomography scan to quantify β 2 *-nAChR availability. Psychiatric, cognitive, nicotine craving, and mood assessments were obtained during active smoking, as well as smoking abstinence. Results There were no differences in smoking characteristics between smokers with and without schizophrenia. Subjects with schizophrenia had lower β 2 *-nAChR availability relative to comparison group, and nonsmokers had lower β 2 *-nAChR availability relative to smokers. However, there was no smoking by diagnosis interaction. Relative to nonsmokers with schizophrenia, smokers with schizophrenia had higher β 2 *-nAChR availability in limited brain regions. In smokers with schizophrenia, higher β 2 *-nAChR availability was associated with lower negative symptoms of schizophrenia and better performance on tests of executive control. Chronic exposure to antipsychotic drugs was not associated with changes in β 2 *-nAChR availability in schizophrenia. Conclusions Although subjects with schizophrenia have lower β 2 *-nAChR availability relative to comparison group, smokers with schizophrenia appear to upregulate in the cortical regions. Lower receptor availability in smokers with schizophrenia in the cortical regions is associated with a greater number of negative symptoms and worse performance on tests of executive function, suggesting smoking subjects with schizophrenia who upregulate to a lesser degree may be at risk for poorer outcomes.

Background The cholinergic system is substantially altered in individuals with major depression and is partially restored when depression remits. We quantified the availability of β 2 -subunit-containing nicotinic acetylcholine receptors (β 2 *-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 β 2 *-nAChR V T / f P (total volume of distribution, corrected for individual differences in metabolism and protein binding of the radiotracer). Average V T / f P was compared between groups and correlated with clinical characteristics. Postmortem analysis of β 2 *-nAChRs was conducted using equilibrium binding with [ 125 I]5IA in subjects with bipolar disorder and matched control subjects. Results We showed significantly lower β 2 *-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 β 2 *-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 V T / f P 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.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure.

Preclinical research is fundamental for the advancement of biomedical sciences and enhancing healthcare. Considering sex differences in all studies throughout the entire biomedical research pipeline is necessary to adequately inform clinical research and improve health outcomes. However, there is a paucity of information to date on sex differences in preclinical work. As of 2009, most (about 80 percent) rodent studies across 10 fields of biology were still conducted with only male animals. In 2016, the National Institutes of Health implemented a policy aimed to address this concern by requiring the consideration of sex as a biological variable in preclinical research grant applications. This perspective piece aims to (1) provide a brief history of female inclusion in biomedical research, (2) describe the importance of studying sex differences, (3) explain possible reasons for opposition of female inclusion, and (4) present potential additional solutions to reduce sex bias in preclinical research.

The "linear parametric neurotransmitter PET" (lp-ntPET) model was introduced to capture the time course of transient endogenous neurotransmitter response to drug stimulus from dynamic PET data. We previously used this novel analysis tool to probe the short-lived dopamine (DA) response induced by cigarette smoking in the PET scanner. It allowed us to find a sex difference in the DA signature of cigarette smoking. To make best use of this tool to characterize neurotransmitter response to drug stimulus, the sensitivity of lp-ntPET to detect such responses must be maximized. We designed a series of simulation studies to examine the impact of the following factors on the sensitivity of lp-ntPET using smoking-induced DA release as an example application: tracer delivery protocol, pre-processing for image denoising, timing of the smoking task, duration of the PET scan, and dose of the radiotracer. Our results suggest that a Bolus paradigm could replace a more difficult B/I paradigm without sacrificing the sensitivity of the method. Pre-processing the PET data with the de-noising algorithm HYPR could improve the sensitivity. The optimal timing to start the smoking task is 45min in a 90min scan and 35min in a 75min scan. A mild shortening of the scan time from 90mCi to 75min should be acceptable without loss of sensitivity. We suggest a lower dose limit of a bolus injection at 16mCi to limit underestimation of DA activation. This study established the framework to optimize the experimental design for reaching the full potential of lp-ntPET to detect neurotransmitter responses to drugs or even behavioral tasks.

INTRODUCTION Tobacco smoking leads to increased numbers of β2*-containing nicotinic acetylcholine receptors (β2*-nAChRs) throughout the brain, which return to nonsmoker levels over extended abstinence. The goal of the current study was to determine whether the degree of tobacco smoking-induced changes in β2*-nAChR availability is genetically influenced. METHODS In this study, 113 European Americans participated in one or two [(123)I]5-IA-85380 single photon emission computed tomography (SPECT) brain scans. Smokers (n = 58) participated in one scan at 7-9 days of abstinence and those who remained abstinent (n = 27) were imaged again at 6-8 weeks of abstinence. Age- and sex-matched nonsmokers (n = 55) participated in one scan. Blood samples were collected for DNA analysis and genotyped for single nucleotide polymorphisms (SNPs) in the CHRNA4 and ANKK1 gene loci. β2*-nAChR availability was measured in the thalamus, striatum, cortical regions, and cerebellum. RESULTS The CHRNA4 SNP rs2236196 and ANKK1 SNP rs4938015 were associated with significantly higher cerebellar and cortical β2*-nAChR availability in smokers versus nonsmokers for specific genotypes. There were no significant differences by carrier status in the change in β2*-nAChR availability in smokers from 7-9 days to 6-8 weeks of abstinence. CONCLUSION This study provides evidence for genetic regulation of tobacco smoking-induced changes in β2*-nAChR availability and suggests that β2*-nAChR availability could be an endophenotype mediating influences of CHRNA4 variants on nicotine dependence. These results highlight individual differences in the neurochemistry of nicotine dependence and may suggest the need for individualized programs for smoking cessation. IMPLICATIONS This study demonstrates genetic regulation of smoking-induced changes in β2*-nAChRs throughout the brain and highlights the need for personalized programs for smoking cessation.

Most prior work with positron emission tomography (PET) dopamine subtype 2/3 receptor (D2/3R) non-selective antagonist tracers suggests that obese (OB) individuals exhibit lower D2/3Rs when compared with normal weight (NW) individuals. A D3-preferring D2/3R agonist tracer, [11C](+)PHNO, has demonstrated that body mass index (BMI) was positively associated with D2/3R availability within striatal reward regions. To date, OB individuals have not been studied with [11C](+)PHNO. We assessed D2/3R availability in striatal and extrastriatal reward regions in 14 OB and 14 age- and gender-matched NW individuals with [11C](+)PHNO PET utilizing a high-resolution research tomograph. Additionally, in regions where group D2/3R differences were observed, secondary analyses of 42 individuals that constituted an overweight cohort was done to study the linear association between BMI and D2/3R availability in those respective regions. A group-by-brain region interaction effect (F7, 182=2.08, p=0.047) was observed. Post hoc analyses revealed that OB individuals exhibited higher tracer binding in D3-rich regions: the substantia nigra/ventral tegmental area (SN/VTA) (+20% p=0.02), ventral striatum (VST) (+14% p

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.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.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.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.

This paper reviews evidence suggesting that nicotine and tobacco smoke profoundly modulate the effects of alcohol on γ-aminobutyric acid (GABA) neuronal function, specifically at the GABA(A)-benzodiazepine receptor (GABA(A)-BZR). The focus of this paper is on recent neuroimaging evidence in preclinical models as well as clinical experiments. First, we review findings implicating the role of alcohol at the GABA(A)-BZR and discuss the changes in GABA(A)-BZR availability during acute and prolonged alcohol withdrawal. Second, we discuss preclinical evidence that suggests nicotine affects GABA neuronal function indirectly by a primary action at neuronal nicotinic acetylcholine receptors. Third, we show how this evidence converges in studies that examine GABA levels and GABA(A)-BZRs in alcohol-dependent smokers and nonsmokers, suggesting that tobacco smoking attenuates the chemical changes that occur during alcohol withdrawal. Based on a comprehensive review of literature, we hypothesize that tobacco smoking minimizes the changes in GABA levels that typically occur during the acute cycles of drinking in alcohol-dependent individuals. Thus, during alcohol withdrawal, the continued tobacco smoking decreases the severity of the withdrawal-related changes in GABA chemistry. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on β 2 -containing nicotinic acetylcholine receptor (β 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 6–8 h later under equilibrium conditions. The effect of age on regional β 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 β 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 β 2 -nAChRs in cognitive aging.

Clinical and epidemiologic evidence demonstrates sex differences in the prevalence and course of various psychiatric disorders. Understanding sex-specific brain differences in healthy individuals is a critical first step toward understanding sex-specific expression of psychiatric disorders. Here, we evaluate evidence on sex differences in brain structure, chemistry, and function using imaging methodologies, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), and structural magnetic resonance imaging (MRI) in mentally healthy individuals. MEDLINE searches of English-language literature (1980-November 2006) using the terms sex, gender, PET, SPECT, MRI, fMRI, morphometry, neurochemistry, and neurotransmission were performed to extract relevant sources. The literature suggests that while there are many similarities in brain structure, function, and neurotransmission in healthy men and women, there are important differences that distinguish the male from the female brain. Overall, brain volume is greater in men than women; yet, when controlling for total volume, women have a higher percentage of gray matter and men a higher percentage of white matter. Regional volume differences are less consistent. Global cerebral blood flow is higher in women than in men. Sex-specific differences in dopaminergic, serotonergic, and gamma-aminobutyric acid (GABA)ergic markers indicate that male and female brains are neurochemically distinct. Insight into the etiology of sex differences in the normal living human brain provides an important foundation to delineate the pathophysiological mechanisms underlying sex differences in neuropsychiatric disorders and to guide the development of sex-specific treatments for these devastating brain disorders.