Lower dorsal putamen D2/3 receptor availability and amphetamine-induced dopamine release are related to poorer cognitive function in recently abstinent people who smoke and healthy controls.

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 cognitbie deficits. The dorsal striatum and dlPFC are structurally and functionally connected and are the 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. The goal of this study was to examine the same brain-behavior relationship in the dorsal striatum. METHODS: Twenty-nine (18 males) recently abstinent people who smoke and twenty-nine sex-matched healthy controls participated in two 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=0.022). People who smoke perform worse on immediate (p=0.035) and delayed (p=0.011) recall than healthy controls. In all people, lower dorsal putamen BPND was associated with worse immediate (p=0.006) and delayed recall (p=0.049), and lower %ΔBPND was related to worse delayed recall (p=0.022). CONCLUSION: 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 role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

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.

Psychometric properties of the Persian version of the cognitive emotion regulation questionnaire-short (CERQ-P-short): Reliability, validity, factor structure, treatment sensitivity, and measurement invariance.

AIMS: This study aimed to examine the psychometric properties of a widely-used measure of emotion regulation, the short version of the Cognitive Emotion Regulation Questionnaire (CERQ-short), in the Persian language (CERQ-P-short) among Iranian populations. METHODS: The CERQ-P-short was administered to 1825 participants (female = 974) including 436 adolescents, 834 adults from the general population, 45 patients each with generalized anxiety and obsessive-compulsive disorders, an additional 30 patients each with generalized anxiety and obsessive-compulsive disorders receiving treatment, 45 patients with substance use disorders (SUDs) and an additional 360 adult psychiatric patients. We tested reliability, factor structure, measurement invariance, convergent and discriminant validity, and treatment sensitivity (i.e., intervention response) by age, sex, and diagnostic group. The Depression Anxiety Stress Scale-21 was also administered. RESULTS: Cronbach's alpha coefficient and test-retest coefficients suggested good reliability. Fit indices suggested that the 9-factor CERQ-P-Short model was good across groups. The CERQ-P-Short showed good measurement invariance in all four models (configural, metric, scalar, and strict) in all groups. Both adaptive and maladaptive cognitive emotion-regulation strategies demonstrated convergent and discriminant validity. Finally, treatment sensitivity of the CERQ-P-Short scale before and after the completion of treatment sessions was suggested for patients with generalized anxiety and obsessive-compulsive disorders. CONCLUSIONS: While the present study has some limitations, it represents a significant contribution because it supports CERQ-P-Short scales usefulness, validity, and reliability in the general population and among psychiatric patients. The results of the current study can be beneficial to the both clinicians and researchers.

Diagnostic group differences and exploratory sex differences in intrinsic connectivity during fMRI Stroop in individuals with and without cocaine use disorder.

BACKGROUND: Sex-/gender-related differences in cognitive control and how they relate to addictions may inform novel treatment options. Cognitive control, including Stroop performance, has been linked to addictions and treatment outcomes. The extent to which women and men with cocaine use disorder (CUD) show brain and behavioral differences relating to Stroop performance has not been previously studied. We examined sex-related differences in Stroop-related brain connectivity in female and male CUD and healthy-comparison (HC) subjects. METHODS: 40 individuals with CUD (20 female) and 40 HC (20 female) subjects matched on age, race, and ethnicity completed an fMRI Stroop task. Intrinsic connectivity distribution (ICD) and mean-adjusted ICD analyses were conducted to identify differences related to sex and diagnostic group. Stroop task performance was also considered. RESULTS: Behavioral results confirmed a Stroop effect. A main effect of diagnostic group indicated that the CUD versus HC group showed lower connectivity in the prefrontal cortex, frontal gyrus, cingulate gyrus, precuneus, cerebellum, and somatosensory, visual, and auditory areas. An exploratory main effect of sex suggested that males may show relatively lower connectivity than females in the cerebellum and brainstem, although connectivity was largely similar across sexes. CONCLUSIONS: Intrinsic connectivity during cognitive control varied by diagnostic group and possibly by sex. The findings suggest that interventions targeting cognitive control in CUD should consider sex.

Developing Researchers with Expertise in Sex as a Biological Variable through SCORE Career Enhancement Core Center Programs.

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.

Sex steroid hormone levels associated with dopamine D2/3 receptor availability in people who smoke cigarettes.

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 D2/3 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 [11C]FLB457 positron emission tomography scans, one before and one after amphetamine administration. D2R availability (BPND) 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 BPND. Discussion/conclusion: This study demonstrated that lower estradiol levels are associated with lower dlPFC D2R availability in women which may underlie difficulty resisting smoking.

Liquor consumption is associated with other medical conditions in females who consume alcohol.

Background: Our group previously identified that females with AUD and females engaging in heavy or extreme binge drinking were more likely to report cancers and other medical conditions compared to their male counterparts. This analysis aimed to extend our previous findings to examine relationships between sex and consumption of alcohol by type on past year medical condition diagnoses. Methods: Data from the U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III; n = 36,309) was used to evaluate associations between sex (female vs. male) and alcohol type (liquor, wine, beer, coolers) on past year self-reported doctor-confirmed medical conditions, controlling for frequency of alcohol consumption. Results: A significant interaction demonstrated that females who consumed liquor were more likely to have other medical conditions (OR=1.95) compared to males who consumed liquor. Females who consumed wine in the past year were less likely to have cardiovascular conditions (OR=0.81) compared to males who consumed wine. Those who consumed liquor had increased odds of pain, respiratory, and other conditions (OR=1.11 - 1.21). Females were 1.5 times more likely to have cancers or pain, respiratory, and other medical conditions compared to males (OR=1.36 - 1.81). Conclusions: Results identify that consumption of higher alcohol content drinks (i.e., liquor) is associated with past year self-reported doctor- or health-professional confirmed medical conditions in females compared to males consuming the same high alcohol content beverage. Not only should AUD status and risky drinking be considered in the clinical care of individuals with poorer health but also alcohol type, especially higher alcohol content beverages.

Lower Dopamine D2/3 Receptor Availability is Associated With Worse Verbal Learning and Memory in People Who Smoke Cigarettes.

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.

Systemic inflammation enhances stimulant-induced striatal dopamine elevation in tobacco smokers.

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 [11C]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 [11C]raclopride binding potential (ΔBPND) 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.

Licit and illicit drug use across trimesters in pregnant women endorsing past-year substance use: Results from National Survey on Drug Use and Health (2009-2019).

PURPOSE: Given the health consequences, perinatal substance use is a significant public health concern, especially as substance use rates increase among women; ongoing data regarding the rates of substance use across trimesters of pregnancy is needed. METHODS: The present study utilized cross-sectional population-based data from the National Survey of Drug Use and Health (NSDUH) between 2009 and 2019. We aimed to explore both licit and illicit substance use assessed within each trimester among women endorsing past-year substance use. The NSDUH sample included 8,530 pregnant women. RESULTS: Perinatal substance use was less prevalent among women in later trimesters; however, past-month substance use was observed for all substances across trimesters. The prevalence of past-month licit substance use among pregnant women ranged from 5.77 to 22.50% and past-month illicit substance use ranged from 4.67 to 14.81%. In the second trimester, lower odds of past-month substance use were observed across tobacco, alcohol, and marijuana (odds ratios [ORs] ranging from 0.29 to 0.47), when compared to the first trimester. A similar lower rate of past-month substance use was observed in the third trimester compared to the first trimester, across tobacco, alcohol, and marijuana use, as well as cocaine, prescription pain medication, and tranquilizer use (ORs ranging from 0.02 to 0.42). The likelihood of polysubstance use was lower among women in the second and third trimesters compared to the first trimester (ORs ranging from 0.09 to 0.46). CONCLUSION: Findings indicate that a minority of women continue to use substances across all trimesters. This is especially true among women using licit substances and marijuana. These results highlight the need for improved interventions and improved access to treatment for these women.

Harmonization of [11C]raclopride brain PET images from the HR+ and HRRT: method development and validation in human subjects.

BACKGROUND: There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [11C]raclopride with older data. This typically means harmonizing data across different scanners. Previous harmonization studies have utilized either phantoms or human subjects, but the use of both phantoms and humans in one harmonization study is not common. The purpose herein was (1) to use phantom images to develop an inter-scanner harmonization technique and (2) to test the harmonization technique in human subjects. METHODS: To develop the harmonization technique (Experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on the two scanners in question (HRRT, HR+, Siemens/CTI). Phantom images were used to determine the optimal isotropic Gaussian filter to harmonize HRRT and HR+ images. To evaluate the harmonization on human images (Experiment 2), inter-scanner variability was calculated using [11C]raclopride scans of 3 human subjects on both the HRRT and HR+ using percent difference (PD) in striatal non-displaceable binding potential (BPND) between HR+ and HRRT (with and without Gaussian smoothing). Finally, (Experiment 3), PDT/RT was calculated for test-retest (T/RT) variability of striatal BPND for 8 human subjects scanned twice on the HR+. RESULTS: Experiment 1 identified the optimal filter as a Gaussian with a 4.5 mm FWHM. Experiment 2 resulted in 13.9% PD for unfiltered HRRT and 3.71% for HRRT filtered with 4.5 mm. Experiment 3 yielded 5.24% PDT/RT for HR+. CONCLUSIONS: The PD results show that the variability of harmonized HRRT is less than the T/RT variability of the HR+. The harmonization technique makes it possible for BPND estimates from the HRRT to be compared to (and/or combined with) those from the HR+ without adding to overall variability. Our approach is applicable to all pairs of scanners still in service.

Using machine learning to predict heavy drinking during outpatient alcohol treatment.

BACKGROUND: Accurate clinical prediction supports the effective treatment of alcohol use disorder (AUD) and other psychiatric disorders. Traditional statistical techniques have identified patient characteristics associated with treatment outcomes. However, less work has focused on systematically leveraging these associations to create optimal predictive models. The current study demonstrates how machine learning can be used to predict clinical outcomes in people completing outpatient AUD treatment. METHOD: We used data from the COMBINE multisite clinical trial (n = 1383) to develop and test predictive models. We identified three priority prediction targets, including (1) heavy drinking during the first month of treatment, (2) heavy drinking during the last month of treatment, and (3) heavy drinking between weekly/bi-weekly sessions. Models were generated using the random forest algorithm. We used "leave sites out" partitioning to externally validate the models in trial sites that were not included in the model training. Stratified model development was used to test for sex differences in the relative importance of predictive features. RESULTS: Models predicting heavy alcohol use during the first and last months of treatment showed internal cross-validation area under the curve (AUC) scores ranging from 0.67 to 0.74. AUC was comparable in the external validation using data from held-out sites (AUC range = 0.69 to 0.72). The model predicting between-session heavy drinking showed strong classification accuracy in internal cross-validation (AUC = 0.89) and external test samples (AUC range = 0.80 to 0.87). Stratified analyses showed substantial sex differences in optimal feature sets. CONCLUSION: Machine learning techniques can predict alcohol treatment outcomes using routinely collected clinical data. This technique has the potential to greatly improve clinical prediction accuracy without requiring expensive or invasive assessment methods. More research is needed to understand how best to deploy these models.

Nicotine Patch Alters Patterns of Cigarette Smoking-Induced Dopamine Release: Patterns Relate to Biomarkers Associated With Treatment Response.

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.

Sex Differences across Retrospective Transitions in Posttraumatic Stress and Substance Use Disorders.

Objectives: Concurrent substance use disorder (SUD) and posttraumatic stress disorder (PTSD) occur at high rates and are typically associated with poor treatment outcomes in both sexes. However, women have a propensity to cope with increased negative affect via substance use in comparison to men; thus, it is important to elucidate the sex-specific bidirectional relationships between SUD and PTSD to improve our understanding of concurrent SUD/PTSD in men and women. Methods: Using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-Wave 3; n = 36,309), the present study evaluated the impact of sex on the relationship between past-year SUDs (new, remitted, ongoing), including alcohol and drug use, and retrospective transitions in new vs. absent and ongoing vs. remitted diagnoses of PTSD. Additionally, the impact of sex was explored in models examining past year PTSD (new, remitted, ongoing) and retrospective transitions in new vs. absent and ongoing vs. remitted diagnosis of SUDs. Diagnostic transitions were based on retrospective reporting. Results: Results indicated that new, remitted, and ongoing SUDs increase the likelihood of new PTSD diagnoses (OR range = 2.53-8.11; p < 0.05). Among individuals with ongoing drug use disorders (DUD), there were greater odds of ongoing PTSD (OR = 2.10, p < 0.01). When examining the relationship reciprocally, new, remitted, and ongoing PTSD increased the likelihood of new SUDs (OR range = 2.50-8.22; p < 0.05), and ongoing PTSD increased the likelihood of ongoing SUD and DUD (OR = 1.40, 1.70, respectively; p < 0.05). Sex-specific analyses revealed that the relationship between PTSD and SUDs varies between sexes, particularly among women. For instance, women with new PTSD had higher odds of SUDs, and women with ongoing PTSD were almost 2.5 times more likely to have an ongoing DUD. Women with a new PTSD diagnosis were more likely to be diagnosed with a new SUD (OR = 3.27) and an ongoing DUD (OR = 3.08). Conclusions: Results indicate a bidirectional relationship between PTSD and SUD that is in many instances larger in women. Thus, illustrating potential sex-specific differences in underlying mechanisms implicated in SUD/PTSD, warranting additional research.

Prospective Associations of Pain Intensity and Substance Use in the United States Population: A Cross-Lagged Panel Analysis.

OBJECTIVE: Pain is associated with increased risk for harmful substance use. Substance use also may increase levels of pain, suggesting that these two factors may reciprocally increase risk. The current study examined the reciprocal association between pain and substance use outcomes (i.e., alcohol, cannabis, and painkillers/sedatives/tranquilizers [PSTs]) longitudinally in a nationally representative cohort of non-incarcerated U.S. citizens. METHOD: Adult (≥18 years old) survey data from Waves 2-4 of the Population Assessment of Tobacco and Health (PATH) study were used. The PATH is a nationally representative multiwave cohort survey (Wave 2: October 2014-October 2015, Wave 3: October 2015-October 2016, Wave 4: December 2016-January 2018). Cross-lagged panel models were used to estimate the reciprocal effects of pain intensity and substance use on subsequent changes in both variables. Substance use outcomes were substance use problems and greater-than-weekly use for cannabis and PSTs, total past-month drinks, and alcohol use exceeding moderate drinking guidelines. All models controlled for autoregressive effects and demographic covariates. RESULTS: Pain intensity showed a positive prospective association with all substance use outcomes. All cannabis and PST use were positively associated with subsequent pain intensity. Alcohol use problems also predicted higher levels of pain intensity. Neither total past-month drinks nor exceeding moderate drinking guidelines predicted subsequent pain intensity. CONCLUSIONS: Pain and substance use show a reciprocal association and may act in a positive feedback loop to worsen both conditions over time in people with a history of use.

Risk drinking levels and sex are associated with cancer and liver, respiratory, and other medical conditions.

Background: Heavy alcohol use is associated with increased risk of alcohol-related health consequences. Alcohol consumption has increased in females in the last fifteen years and females are more likely to experience exacerbated health risks due to drinking. Our group identified that females with AUD were more likely to report respiratory conditions or cancers compared to their male counterparts. This analysis sought to further examine relationships between sex and alcohol use on medical conditions by using the new 2020 U.S. Dietary Guidelines risk drinking levels. Methods: Data from the U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III; n = 36,309) was used to evaluate associations between sex (female vs. male) and alcohol risk drinking levels (abstainer, binge, heavy, extreme binge vs. moderate drinking) on past year self-reported doctor-confirmed medical conditions). Results: Females were 1.5 to 2 times more likely to have pain, respiratory, or other medical conditions in the past year (odds ratio [OR]=1.46-2.11) vs. males. Significant interactions demonstrated that heavy drinking females or extreme binge drinking females were 2 to 3 times more likely to have cancers or other conditions (OR=1.95-2.69) vs. males at the same risk drinking level. Female abstainers were more likely than male abstainers to have other medical conditions (OR=1.77). Conclusions: Consistent with our previous findings, results identify that higher risk drinking levels are associated with the presence of past year self-reported doctor-confirmed medical conditions spanning organ systems, particularly in females. Treatment for high-risk drinking should be considered in the clinical care of individuals with significant medical conditions.

Sex and the dopaminergic system: Insights from addiction 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.

Sex differences in amphetamine-induced dopamine release in the dorsolateral prefrontal cortex of tobacco smokers.

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 D2/3-type receptor (D2R) 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 [11C]FLB457 positron emission tomography (PET) scans before and 3-hours after amphetamine administration (0.4-0.5 mg/kg, PO). D2R availability (non-displaceable binding potential; BPND) was measured pre- and post-amphetamine. The percent fractional change in BPND (%ΔBPND) between pre- and post-amphetamine, an index of DA release, was compared between male and female smokers and nonsmokers. Smokers showed significantly lower dlPFC D2R availability (BPND = 0.77 ± 0.05) than nonsmokers (BPND = 0.92 ± 0.04), p = 0.016, driven by males. Female smokers showed significantly less amphetamine-induced DA release in dlPFC (%ΔBPND = 1.9 ± 3.0%) than male smokers (%ΔBPND = 14.0 ± 4.3%), p < 0.005, and female nonsmokers (%ΔBPND = 9.3 ± 3.3%), p < 0.005. This study shows that in the prefrontal cortex, smokers have lower D2R 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.

Toward whole-brain dopamine movies: a critical review of PET imaging of dopamine transmission in the striatum and cortex.

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.