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

This study identifies and characterizes symptoms of caffeine dependence in adolescents. Thirty-six adolescents who consumed caffeine daily and had some features of caffeine dependence on telephone screen were scheduled for outpatient evaluation. Evaluation included the Diagnostic Interview Schedule for Children-IV-Youth Version (DISC-IV) and modified DISC-IV questions that assessed caffeine dependence based on DSM-IV substance dependence criteria. Of 36 subjects, 41.7% (n=15) reported tolerance to caffeine, 77.8% (n=28) described withdrawal symptoms after cessation or reduction of caffeine intake, 38.9% (n=14) reported desire or unsuccessful attempts to control use, and 16.7% (n=6) endorsed use despite knowledge of physical or psychological problems associated with caffeine. There was no significant difference in the amount of caffeine consumed daily by caffeine dependent versus non-dependent teenagers. These findings are important due to the vast number of adolescents who drink caffeinated beverages. [ABSTRACT FROM AUTHOR]

The elucidation of synaptic density changes provides valuable insights into the underlying brain mechanisms of substance use. In preclinical studies, synaptic density markers, like spine density, are altered by substances of abuse (e.g., alcohol, amphetamine, cannabis, cocaine, opioids, nicotine). These changes could be linked to phenomena including behavioral sensitization and drug self-administration in rodents. However, studies have produced heterogeneous results for spine density across substances and brain regions. Identifying patterns will inform translational studies given tools that now exist to measure in vivo synaptic density in humans. We performed a meta-analysis of preclinical studies to identify consistent findings across studies. PubMed, ScienceDirect, Scopus, and EBSCO were searched between September 2022 and September 2023, based on a protocol (PROSPERO: CRD42022354006). We screened 6083 publications and included 70 for meta-analysis. The meta-analysis revealed drug-specific patterns in spine density changes. Hippocampal spine density increased after amphetamine. Amphetamine, cocaine, and nicotine increased spine density in the nucleus accumbens. Alcohol and amphetamine increased, and cannabis reduced, spine density in the prefrontal cortex. There was no convergence of findings for morphine's effects. The effects of cocaine on the prefrontal cortex presented contrasting results compared to human studies, warranting further investigation. Publication bias was small for alcohol or morphine and substantial for the other substances. Heterogeneity was moderate-to-high across all substances. Nonetheless, these findings inform current translational efforts examining spine density in humans with substance use disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [ 11 C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease., Competing Interests: Competing interests statement:J.H.K.: (consultations less than $5,000/y) Aptinyx, Inc., BioXcel, Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Cerevel Pharmaceuticals, Epiodyne, Inc., Esai, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., PsychoGenics, Inc., Sunovion Pharmaceuticals, Inc., Takeda Pharmaceuticals (Stock/Options) Biohaven Pharmaceuticals, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, Inc., EpiVario, Inc., Freedom Biosciences, Neumora Therapeutics, Inc., Response Pharmaceuticals, Rest Therapeutics, Spring Health, Inc., Tempero Bio, Inc., Terran Biosciences, Tetricus Inc. (nonmonetary support, i.e., provision of drug) Cerevel Pharmaceuticals, Novartis. J.H.K. stands to benefit from patents held by Yale University that were licensed to Janssen Pharmaceuticals (ketamine), Biohaven Pharmaceuticals (riluzole), Freedom Biosciences (NMDA-R antagonist plus MTORC inhibitor), and Spring Health (precision medicine strategy).

Introduction: In the dopamine system, the mesolimbic pathway, including the dorsal striatum, underlies the reinforcing properties of tobacco smoking, and the mesocortical pathway, including the dorsolateral prefrontal cortex (dlPFC), is critical for cognitive functioning. Dysregulated dopamine signaling has been linked to drug-seeking behaviors and cognitive deficits. The dorsal striatum and dlPFC are structurally and functionally connected and are key regions for cognitive functioning. We recently showed that people who smoke have lower dlPFC dopamine (D2/3R) receptor availability than people who do not, which is related to poorer cognitive function., Aims and Methods: The goal of this study was to examine the same brain-behavior relationship in the dorsal striatum. Twenty-nine (18 males) recently abstinent people who smoke and 29 sex-matched healthy controls participated in 2 same-day [11C]-(+)-PHNO positron emission tomography scans before and after amphetamine administration to provoke dopamine release. D2/3R availability (binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND) were calculated. Cognition (verbal learning and memory) was assessed with the CogState computerized battery., Results: There were no group differences in baseline BPND. People who smoke have a smaller magnitude %ΔBPND in dorsal putamen than healthy controls (p = .022). People who smoke perform worse on immediate (p = .035) and delayed (p = .011) recall than healthy controls. In all people, lower dorsal putamen BPND was associated with worse immediate (p = .006) and delayed recall (p = .049), and lower %ΔBPND was related to worse delayed recall (p = .022)., Conclusions: Lower dorsal putamen D2/3R availability and function are associated with disruptions in cognitive function that may underlie difficulty with resisting smoking., Implications: This study directly relates dopamine imaging outcomes in the dorsal striatum to cognitive function in recently abstinent people who smoke cigarettes and healthy controls. The current work included a well-characterized subject sample in terms of demographics, smoking characteristics, and a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature relating dopamine imaging outcomes to cognition in recently abstinent people who smoke and people who do not smoke, expanding our understanding of brain-behavior relationships., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The neuroimmune system performs a wide range of functions in the brain and the central nervous system. The microglial translocator protein (TSPO) has an established role as a cell marker in identification of the neuroimmune system. Previously, human studies have shown TSPO differences in neuropsychiatric disorders. Seasonal variability has also been demonstrated in multiple systems of healthy individuals. Therefore, in this study, we attempt to understand whether seasonal changes affect brain TSPO levels using [ 11 C]PBR28 positron emission tomography (PET) imaging., Methods: 46 healthy subjects (mean age ± SD = 32.5 ± 10); sex (M/F) = 32/14)) underwent PET imaging with [ 11 C]PBR28 in a retrospectively conducted analysis. All PET scans were performed on the HRRT scanner. Volume of distribution (V T ) values were generated for cortical and subcortical regions and the cerebellum. Spring/summer months were defined as March to August while fall/winter months were defined as September to February and were compared through 2-tailed t-tests (SciPy library v.1.10.1 and Pinguoin library on Python v.3.8.8). Average daylight hours and temperature in New Haven, CT were obtained online (www.wunderground.com) and compared to V T with Spearman's correlations., Results: There were no significant differences observed between the TSPO levels of spring/summer and fall/winter months in the brain (t = 0.52, p = 0.61). Additional analysis on all individual brain regions also indicated non-significance. Likewise, no significant correlations were found between TSPO levels in the whole brain and brain regions against daylight hours (ρ= 0.05, p = 0.74), temperature (ρ = 0.04, p = 0.81), or month (ρ = 0.08, p = 0.60). Controlling TSPO gene polymorphisms and other variables had no significant effect on the outcome., Conclusion: To the best of our knowledge, this is the first human study to investigate seasonal changes in TSPO expression. Our results can be interpreted as the lack of seasonal variability in the neuroimmune system, but important limitations include high interindividual variability, test-retest variability, specificity of the tracer, and a limited sample size. Limitations notwithstanding, our results conclude that TSPO levels in the brain are not impacted by light and temperature changes in different seasons., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [ 18 F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls., Methods: We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [ 18 F]AS2471907 as a bolus injection and were imaged for 150-180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [ 18 F]AS2471907 volume of distribution ( V T ; mL/cm 3 ). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate., Results: Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [ 18 F]AS2471907 V T was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls ( p  < 0.05). In AUD, vmPFC [ 18 F]AS2471907 V T was associated with drinks per week (r = 0.81, p  = 0.01) and quantity per drinking episode (r = 0.75, p  = 0.02)., Conclusions: This is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

In humans, the negative effects of alcohol are linked to immune dysfunction in both the periphery and the brain. Yet acute effects of alcohol on the neuroimmune system and its relationships with peripheral immune function are not fully understood. To address this gap, immune response to an alcohol challenge was measured with positron emission tomography (PET) using the radiotracer [ 11 C]PBR28, which targets the 18-kDa translocator protein, a marker sensitive to immune challenges. Participants (n = 12; 5 F; 25-45 years) who reported consuming binge levels of alcohol (>3 drinks for females; >4 drinks for males) 1-3 months before scan day were enrolled. Imaging featured a baseline [ 11 C]PBR28 scan followed by an oral laboratory alcohol challenge over 90 min. An hour later, a second [ 11 C]PBR28 scan was acquired. Dynamic PET data were acquired for at least 90 min with arterial blood sampling to measure the metabolite-corrected input function. [ 11 C]PBR28 volume of distributions (V T ) was estimated in the brain using multilinear analysis 1. Subjective effects, blood alcohol levels (BAL), and plasma cytokines were measured during the paradigm. Full completion of the alcohol challenge and data acquisition occurred for n = 8 (2 F) participants. Mean peak BAL was 101 ± 15 mg/dL. Alcohol significantly increased brain [ 11 C]PBR28 V T (n = 8; F (1,49)  = 34.72, p > 0.0001; Cohen's d'=0.8-1.7) throughout brain by 9-16%. Alcohol significantly altered plasma cytokines TNF-α (F (2,22)  = 17.49, p < 0.0001), IL-6 (F (2,22)  = 18.00, p > 0.0001), and MCP-1 (F (2,22)  = 7.02, p = 0.004). Exploratory analyses identified a negative association between the subjective degree of alcohol intoxication and changes in [ 11 C]PBR28 V T . These findings provide, to our knowledge, the first in vivo human evidence for an acute brain immune response to alcohol., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

There is a critical need for interdisciplinary and translational scientists to apply sex as a biological variable (SABV) research to address knowledge gaps in the health of women. In 2018, the Office of Research on Women's Health (ORWH) partnered with several National Institute of Health (NIH) Institutes and Centers to expand the Specialized Centers of Research (SCOR) Excellence (SCORE) Programs (together referred to as SCOR/E) with an important feature-the Career Enhancement Core (CEC). The SCORE CEC mentors early career investigators to become the next generation of biomedical and behavioral researchers focused on SABV and women's health. In this article, we outline our approach at the Yale University SCORE to support early career trajectories through the provision of salary support, educational curricula, translational mentorship, pilot project funding, and professional development. Using the Yale-SCOR/E CEC Programs as instructional models, we highlight critical measures of academic success, namely grant funding and publications, among early career investigators. At Yale University, 12 pilot projects funded by the SCOR/E Programs resulted in 14 extramural grants, amounting to an $80 return on every $1 invested in "seed" funding. So far, our SCOR/E Programs have resulted in 129 publications, 83% of which were first-authored by trainees, and 100% of trainees continued research careers with an emphasis on SABV. Finally, we provide recommendations on how biomedical scientists can apply SABV in their studies of major medical conditions in an interdisciplinary and integrative way.

Introduction: Sex differences exist in tobacco smoking. Women have greater difficulty quitting smoking than men. Tobacco smoking is driven by the reinforcing effects of nicotine, the primary addictive component in cigarettes. Nicotine binds to nicotinic acetylcholine receptors, facilitating dopamine release in striatal and cortical brain regions. Dysregulated dopamine D 2/3 receptor signaling in the dorsolateral prefrontal cortex (dlPFC) is associated with cognitive deficits such as impairments in attention, learning, and inhibitory control that impede quit attempts. Sex steroid hormones, such as estradiol and progesterone, influence drug-taking behaviors, through dopaminergic actions, suggesting that their influence may explain sex differences in tobacco smoking. The goal of this study was to relate dlPFC dopamine metrics to sex steroid hormone levels in people who smoke and healthy controls., Methods: Twenty-four (12 women) people who smoke cigarettes and 25 sex- and age-matched controls participated in two same-day [ 11 C]FLB457 positron emission tomography scans, one before and one after amphetamine administration. D 2 R availability ( BP ND ) at baseline and after amphetamine administration was calculated. On the same day, plasma samples were collected for the analysis of sex steroid hormone levels: estradiol, progesterone, and free testosterone., Results: Women who smoke had trending lower levels of estradiol than their sex-matched counterparts. Men who smoke had higher levels of estradiol and trending higher levels of free testosterone than their sex-matched counterparts. Among women only, lower estradiol levels were significantly associated with lower pre-amphetamine dlPFC BP ND ., Discussion/conclusion: This study demonstrated that lower estradiol levels are associated with lower dlPFC D 2 R availability in women which may underlie difficulty resisting smoking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zakiniaeiz, Gueorguieva, Peltier, Verplaetse, Roberts, McKee and Cosgrove.)

Striatal kappa opioid receptor (KOR) availability in 48 subjects with Alcohol Use Disorder (AUD) was previously found to be associated with degree of drinking following a week of naltrexone treatment (de Laat et al. Biological Psychiatry, 86(11), 864-871, 2019). The purpose of the current study was to determine if spectral clustering applied to previously acquired KOR images (with [11C]LY2795050 PET) could identify meaningful groupings of different responses to naltrexone and to assess the robustness of the finding. Spectral clustering was applied to 6 features (regional volume of distribution values, V T ) per AUD subject to produce 3 classes of subjects with different mean responses to naltrexone. Response to naltrexone was quantified as the difference in drinks consumed in an established lab-based alcohol drinking paradigm (Krishnan-Sarin et al. Biological Psychiatry, 62(6), 694-697, 2007) prior to, and after a week of naltrexone treatment. Clustering was applied exclusively to features of the image data with no a priori knowledge of the subjects' responses. Separation of classes was tested using a 1-way analysis of variance (ANOVA) with drink reduction as the outcome of interest. To assess robustness of the result, the size of the training set was varied by using successively reduced subsets of the data. Clustering resulted in significantly different groupings of drink reduction. The finding was robust to initialization of the spectral clustering procedure and was replicable for different random subsets of training subjects. Finding: Spectral clustering of kappa PET images separates AUD subjects into behaviorally distinct groups expressing distinct responses to naltrexone., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β 2 -subunit containing nicotinic acetylcholine receptor (β 2 *-nAChR) partial agonist radioligand (-)-[ 18 F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[ 18 F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (V T ) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[ 18 F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[ 18 F]flubatine V T , consistent with increased cortical acetylcholine levels reducing the number of β 2 *-nAChR sites available for (-)-[ 18 F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[ 18 F]flubatine V T was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

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 [ 11 C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [ 11 C]raclopride binding potential (ΔBP ND ) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

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., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

Background: The use of pejorative or stigmatizing language to describe individuals with alcohol and drug 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 National Institutes of Health (NIH)-funded research and reviews published by the journal, Alcoholism: Clinical and Experimental Research (ACER) from 2010 to 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 conditions of NIH funding. ACER articles published on PMC were searched from 2010 to 2020 with specific queries for individual terms of interest including those considered pejorative ("alcoholic," "addict," and "abuser") and outdated ("alcohol dependent," "alcohol abuse," and "alcoholism"). The number of articles containing a term of interest for a given year was 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, in 2020, over 40% of articles searched for in PMC still included "alcoholic." The results of a separate manual search (n = 110) on the Wiley Online Database showed 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 with alcohol use disorder., (© 2022 by the Research Society on Alcoholism.)

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 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: Forty-eight image data sets were acquired with a multimodal neuroimaging battery that included 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 1 and 4 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 of abstinence (p = 0.003), while network-level functional connectivity within the default mode network (DMN) was lower (p < 0.04). Exploratory multimodal analyses showed that mGlu5 receptor availability was correlated with global connectivity across all brain regions (HCs, r = 0.41; AUD group at 1 week of abstinence, r = 0.50 and at 4 weeks, r = 0.46; all p < 0.0001). Furthermore, a component of cortical and striatal mGlu5 availability was correlated with connectivity between the 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 the loss of efficient network function, while exploratory relationships with mGlu5 receptor availability suggest a potential glutamatergic relationship with network coherence., (© 2022 by the Research Society on Alcoholism.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

BACKGROUNDInvestigations 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.METHODSSixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [18F]AS2471907, a radioligand for 11β-HSD1.RESULTSPrefrontal-limbic 11β-HSD1 availability, estimated as [18F]AS2471907 volume of distribution (VT), 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 (R2 = 0.27, P = 0.038) in the PTSD group. 11β-HSD1 availability was not related to plasma cortisol levels (R2 = 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).CONCLUSIONHigher 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.FUNDINGBrain 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.

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; 7 M/7 F; 19-32 years old) over 90 min 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 min 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, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region)., Results: Cannabis smoking increased plasma Δ 9 -THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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 < 0.0001; α4β2*/nicotine scans, 67 ± 15% vs. 74 ± 16%, p = 0.0065), indicating higher striatal ACh concentration. Subject-level measures of these concentration differences were estimated, and whole-brain images of regional ACh concentration gradients were generated. These results constitute the first in vivo estimates of regional variation in ACh concentration in the living brain and offer a novel experimental method to assess potential ACh imbalances in clinical populations., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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: - 0.06, 95% confidence interval of difference: - 0.38 to 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.

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.', (Published by Elsevier Ltd.)

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., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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.

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 [ 11 C]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 [ 11 C]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 [ 11 C]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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 the 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, magnetic resonance imaging, and functional magnetic resonance imaging modalities in humans. Additional work using magnetic resonance spectroscopy, diffusion tensor imaging, and event-related potentials to examine SG differences in AUD will be covered. Overall, current research on the neuroimaging of 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., (© 2020 Wiley Periodicals, Inc.)

2-deoxy-2- [ 18 F] fluoro-D-glucose (FDG) PET is commonly used for the assessment of vessel wall inflammation. Guidelines for analysis of arterial wall FDG signal recommend the use of the average of maximal standardized uptake value (mean SUV max ) and target-to-blood (mean TBR max ) ratio. However, these methods have not been validated against a gold standard such as tissue activity ex vivo or net uptake rate of FDG (K i ) obtained using kinetic modeling. We sought to evaluate the accuracy of mean SUV max and mean TBR max for aortic wall FDG signal quantification in comparison with the net uptake rate of FDG., Methods: Dynamic PET data from 13 subjects without prior history of cardiovascular disease who enrolled in a study of vascular inflammation were used for this analysis. Ex vivo measurement of plasma activity was used as the input function and voxel-by-voxel Patlak analysis was performed with t* = 20 minute to obtain the K i image. The FDG signal in the ascending aortic wall was quantified on PET images following recent guidelines for vascular imaging to determine mean SUV max and mean TBR max ., Results: The K i in the ascending aortic wall did not correlate with mean SUV max (r = 0.10, P = NS), but correlated with mean TBR max (r = 0.82, P < 0.001) (Figure 1B). K i and K i&#95;max strongly correlated (R = 0.96, P < 0.0001) and similar to K i , K i&#95;max did not correlate with mean SUV max (r = 0.17, P = NS), but correlated with mean TBR max (r = 0.83, P < 0.001)., Conclusions: Kinetic modeling supports the use of mean TBR max as a surrogate for the net uptake rate of FDG in the arterial wall. These results are relevant to any PET imaging agent, regardless of the biological significance of the tracer uptake in the vessel wall.

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., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [ 11 C]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.

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.

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: [ 11 C]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 η 2 = 0.56-0.89, ps <. 05), whereas SUV and SUVR did not., Conclusion: These findings highlight the importance of incorporating AIF measurements to quantify LPS-TSPO studies.

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., Competing Interests: Conflicts of Interest The authors have no financial or ethical conflicts of interests to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 < 0.005, and female nonsmokers (%ΔBP ND  = 9.3 ± 3.3%), p < 0.005. This study shows that in the prefrontal cortex, smokers have lower D 2 R availability than nonsmokers and that female vs. male smokers have a blunted amphetamine-induced DA release. These findings demonstrate that tobacco smoking differentially affects the mesocortical DA system in men vs. women, suggesting a potential target for gender-specific treatments.

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 [ 11 C]PBR28., Methods: [ 11 C]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 (V T ) 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 V T in the frontal and temporal cortex. BMI showed a significant negative correlation with V T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V T . A subgroup analysis revealed a positive correlation between V T 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.

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., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: The authors have no conflicts of interests to declare.

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.

Rates of alcohol use disorder (AUD) have increased in women by 84% over the past ten years relative to a 35% increase in men. This substantive increase in female drinking is alarming given that women experience greater alcohol-related health consequences compared to men. Stress is strongly associated with all phases of alcohol addiction, including drinking initiation, maintenance, and relapse for both women and men, but plays an especially critical role for women. The purpose of the present narrative review is to highlight what is known about sex differences in the relationship between stress and drinking. The critical role stress reactivity and negative affect play in initiating and maintaining alcohol use in women is addressed, and the available evidence for sex differences in drinking for negative reinforcement as it relates to brain stress systems is presented. This review discusses the critical structures and neurotransmitters that may underlie sex differences in stress-related alcohol use (e.g., prefrontal cortex, amygdala, norepinephrine, corticotropin releasing factor, and dynorphin), the involvement of sex and stress in alcohol-induced neurodegeneration, and the role of ovarian hormones in stress-related drinking. Finally, the potential avenues for the development of sex-appropriate pharmacological and behavioral treatments for AUD are identified. Overall, women are generally more likely to drink to regulate negative affect and stress reactivity. Sex differences in the onset and maintenance of alcohol use begin to develop during adolescence, coinciding with exposure to early life stress. These factors continue to affect alcohol use into adulthood, when reduced responsivity to stress, increased affect-related psychiatric comorbidities and alcohol-induced neurodegeneration contribute to chronic and problematic alcohol use, particularly for women. However, current research is limited regarding the examination of sex in the initiation and maintenance of alcohol use. Probing brain stress systems and associated brain regions is an important future direction for developing sex-appropriate treatments to address the role of stress in AUD.

Converging lines of evidence suggest that men generally smoke for nicotine-related reinforcement, whereas women smoke for non-nicotine factors. Women have more difficulty quitting smoking and are less responsive to nicotine replacement therapies than men, underscoring the importance of examining sex differences in the neurochemical mechanisms underlying nicotine-motivated behavior. We review the recent imaging literature on sex differences in the nicotinic acetylcholine receptor system and in the dopaminergic system in response to nicotine administration and tobacco smoking. We offer an explanation to unify imaging findings related to the dopamine system. We then propose a course of action for future medication development for tobacco smoking addiction., Competing Interests: Declaration of Conflicting Interests: All authors declare that they have no conflicts of interest.

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.

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.

Background: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain β2*-nicotinic acetylcholine receptors (β2*-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 β2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average β2*-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 β2*-nAChRs, we show that average β2*-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.

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., (© 2017 Wiley Periodicals, Inc.)

Background: Stress contributes to the development and maintenance of substance use disorders (SUD), with some research suggesting that the impact of stress on SUD is greater in women. However, this has yet to be evaluated in a national dataset, across major substances of abuse., Methods: Using data from the newly available U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Wave 3; n =36,309) we evaluated relationships among past year stressful life events (0 or 1 vs. 2+ events, range 0-16) and gender, and their association with transitions (new vs. absent cases; ongoing vs. remitted cases) in Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) alcohol use disorder (AUD), tobacco use disorder (TUD), cannabis use disorder (CUD), and nonmedical prescription opioid use disorder (OUD) diagnoses., Results: Having 2 or more stressful life events in the past year increased the odds of having a new AUD, TUD, CUD, and OUD (OR=3.14, 2.15, 5.52, and 3.06, respectively) or ongoing AUD, TUD, and CUD (OR=2.39, 2.62, and 2.95, respectively) compared to 0 or 1 stressful life event. A stress by gender interaction for new vs. absent AUD demonstrated that having 2 or more stressful life events was associated with increased odds of new AUD in men (OR=2.51) and even greater odds of new AUD in women (OR=3.94)., Conclusions: Results highlight that stress is a robust factor in both men and women with new or ongoing substance use disorders, and that effective treatments for substance use should consider the role of stress in addiction etiology and maintenance. There was little evidence for gender differences in the role of stress on transitions in substance use disorders, except for the onset of alcohol use disorders. Given that rates of alcohol use disorders are increasing in women; the impact of stress needs to be considered., Competing Interests: Declaration of conflicting interests Sherry A. McKee has consulted to Cerecor and Embera, has received research support for investigator-initiated studies from Pfizer, Inc. and Cerecor, and has ownership in Lumme, Inc. All other authors declare that there is no conflict of interest.