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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queries for individual terms of interest including those considered pejorative (“alcoholic,” “addict,” “abuser”) and outdated (“alcohol dependent,” “alcohol abuse,” “alcoholism”).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Our search of research and reviews (n=1903) published in ACER on PMC determined that although the use of pejorative and outdated terminology has decreased over time, there is continued use of the term “alcoholic” over the last decade.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.

Post-traumatic stress disorder is a prevalent disorder within the USA and worldwide with a yearly diagnosis rate of 2–4% and affecting women more than men. One of the primary methods for study of this stress disorder relies on animal models as there are few noninvasive methods and few replicated peripheral biomarkers for use in humans. One area of active research in psychiatric neuroscience is the field of epigenetics – how the chemical modifications of the genetic code regulate behavior. The dynamic changes in histone acetylation and deacetylation in the brain are not fully reflected by the study of peripheral biomarker. In this review, we aim to examine the role of histone acetylation and deacetylation in memory formation and fear memory learning. The studies discussed here focus largely on the role of histone deacetylases (HDACs) in animal models of trauma and fear response. Many studies used HDAC inhibitors to elucidate the effects after inhibition of these enzymes after trauma or stress. These studies of memory processing and cued fear extinction in animal can often shed light on human disorders of cued fear responses and memory dysregulation after stress or trauma such as in PTSD. These results provide strong evidence for a role of these enzymes in PTSD in humans. The few clinical studies that exist with HDAC inhibitors also suggest a fundamental role of these enzymes in the neurobiology of the stress response. Further study of these enzymes in both clinical and pre-clinical settings may help elucidate the neurobiology of stress-related pathology like PTSD and provide a foundation for novel therapy to treat these disorders.

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.

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.

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.

Introduction Tobacco smoking is a major public health burden. The mesocortical dopamine system—including the dorsolateral prefrontal cortex (dlPFC)—plays an important role in cognitive function. Dysregulated dopamine signaling in dlPFC is associated with cognitive deficits such as impairments in attention, learning, working memory, and inhibitory control. We recently showed that dlPFC dopamine D2/3-type receptor (D2R) availability was significantly lower in people who smoke than in healthy-controls and that dlPFC amphetamine-induced dopamine release was lower in females who smoke relative to males who smoke and female healthy-controls. However, we did not examine whether the smoking-related dopamine deficits were related to cognitive deficits. Aims and Methods The goal of this study was to relate dopamine metrics to cognitive performance in people who smoke and healthy-controls. In total 24 (12 female) people who smoke cigarettes and 25 sex- and age-matched healthy-controls participated in two same-day [11C]FLB457 positron emission tomography (PET) scans before and after amphetamine administration. Two outcome measures were calculated—D2R availability (non-displaceable binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND). Cognition (verbal learning and memory) was assessed with a computerized test from the CogState battery (International Shopping List). Results People who smoke had significantly worse immediate (p = .04) and delayed (p = .03) recall than healthy-controls. Multiple linear regression revealed that for people who smoke only, lower D2R availability was associated with worse immediate (p = .04) and delayed (p < .001) recall. %ΔBPND was not significantly related to task performance. Conclusion This study demonstrated that lower dlPFC D2R availability in people who smoke is associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. Implications This is the first study to directly relate dopamine metrics in the prefrontal cortex to cognitive function in people who smoke cigarettes compared to healthy-controls. The current work included a well-characterized subject sample with regards to demographic and smoking variables, as well as a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature by relating dopamine metrics to cognition in people who smoke, providing a better understanding of brain-behavior relationships.

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.

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.

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.

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.

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 [18F]AS2471907, a novel PET radiotracer for 11β-HSD1. Eight individuals underwent one 180-min ( n = 4) or two 240-min ( n = 4) [18F]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 [18F]AS2471907 availability ( VT). [18F]AS2471907 demonstrated high, heterogeneous uptake throughout the brain. Of the compartment models, 2T best described [18F]AS2471907 data. Estimates of VT were highly correlated between 2T and MA1 ( t* = 30 min) with MA1 yielding VT values ranging from 3.2 ± 1.0 mL/cm3 in the caudate to 15.7 ± 4.2 mL/cm3 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. VT estimates using 180 min were within 10% of estimates using full acquisition time. In summary, [18F]AS2471907 exhibits reasonable kinetic properties for imaging 11β-HSD1 in human brain.

There is tremendous interest in the role of the neuroimmune system and inflammatory processes in substance use disorders (SUDs). Imaging biomarkers of the neuroimmune system in vivo provide a vital translational bridge between preclinical and clinical research. Herein, we examine two imaging techniques that measure putative indices of the neuroimmune system and review their application among SUDs. Positron emission tomography (PET) imaging of 18 kDa translocator protein availability is a marker associated with microglia. Proton magnetic resonance spectroscopy quantification of myo-inositol levels is a putative glial marker found in astrocytes. Neuroinflammatory responses are initiated and maintained by microglia and astrocytes, and thus represent important imaging markers. The goal of this review is to summarize neuroimaging findings from the substance use literature that report data using these markers and discuss possible mechanisms of action. The extant literature indicates abused substances exert diverse and complex neuroimmune effects. Moreover, drug effects may change across addiction stages, i.e. the neuroimmune effects of acute drug administration may differ from chronic use. This burgeoning field has considerable potential to improve our understanding and treatment of SUDs. Future research is needed to determine how targeting the neuroimmune system may improve treatment outcomes.

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.

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.

Background Lipopolysaccharide (LPS) is a classic immune stimulus. LPS combined with positron emission tomography (PET) 18 kDa translocator protein (TSPO) brain imaging provides a robust human laboratory model to study neuroimmune signaling. To evaluate optimal analysis of these data, this work compared the sensitivity of six quantification approaches. Methods [11C]PBR28 data from healthy volunteers (N = 8) were collected before and 3 h after LPS challenge (1.0 ng/kg IV). Quantification approaches included total volume of distribution estimated with two tissue, and two tissue plus irreversible uptake in whole blood, compartment models (2TCM and 2TCM-1k, respectively) and multilinear analysis-1 (MA-1); binding potential estimated with simultaneous estimation (SIME); standardized uptake values (SUV); and SUV ratio (SUVR). Results The 2TCM, 2TCM-1k, MA-1, and SIME approaches each yielded substantive effect sizes for LPS effects (partial η2 = 0.56–0.89, ps Conclusion These findings highlight the importance of incorporating AIF measurements to quantify LPS-TSPO studies.

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.

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.

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.

Cannabis is the most commonly used illicit substance worldwide. In recent decades, highly concentrated products have flooded the market, and prevalence rates have increased. Gender differences exist in cannabis use, as men have higher prevalence of both cannabis use and cannabis use disorder (CUD), while women progress more rapidly from first use to CUD. This paper reviews findings from preclinical and human studies examining the sex-specific neurobiological underpinnings of cannabis use and CUD and associations with psychiatric symptoms. Sex differences exist in the endocannabinoid system, in cannabis exposure effects on brain structure and function, and in the co-occurrence of cannabis use with symptoms of anxiety, depression, and schizophrenia. In female cannabis users, anxiety symptoms correlate with larger amygdala volume, and social anxiety disorder symptoms correlate with CUD symptoms. Female cannabis users are reported to be especially vulnerable to earlier onset of schizophrenia, and mixed trends emerge in the correlation of depressive symptoms with cannabis exposure in females and males. As the prevalence of cannabis use may continue to increase given the shifting policy landscape regarding marijuana laws, understanding the neurobiological mechanisms of cannabis exposure in females and males is key. Examining these mechanisms may help inform future research on sex-specific pharmacological and behavioral interventions for women and men with high-risk cannabis use, comorbid psychiatric disease, and CUD.

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 [11C]FLB457, a dopamine D2/D3 receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [11C]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. [11C]FLB457-binding potential (BPND) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BPND after vs before amphetamine (Δ BPND) 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 BPND from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [11C]FLB457 BPND 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.

The 18-kDa translocator protein (TSPO) is an important target for assessing neuroimmune function in brain with positron-emission tomography (PET) imaging. The goal of this work was to assess two [11C]PBR28 imaging paradigms for measuring dynamic microglia changes in Macaca mulatta. Dynamic [11C]PBR28 PET imaging data with arterial blood sampling were acquired to quantify TSPO levels as [11C]PBR28 V T. Scans were acquired at three timepoints: baseline, immediately post-drug, and prolonged post-drug. In one animal, a colony-stimulating factor 1 receptor kinase inhibitor, previously shown to deplete brain microglia, reduced [11C]PBR28 V T in brain by 46 ± 3% from baseline, which recovered after 12 days to 7 ± 5% from baseline. In a different animal, acute lipopolysaccharide administration, shown to activate brain microglia, increased [11C]PBR28 V T in brain by 39 ± 9% from baseline, which recovered after 14 days to −11 ± 3% from baseline. These studies provide preliminary evidence of complementary paradigms to assess microglia dynamics via in vivo TSPO imaging.

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.