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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.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.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).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.

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 [

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.

There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [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 [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% PDThe 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 BP

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.

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.

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

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.

Addiction is a disorder characterized by poorly controlled substance use despite negative health and social consequences. Additionally, the only behavioral addiction recognized in the main text of the DSM-5, gambling disorder, presents similarly to many substance addictions with respect to the underlying neurobiology and poorly controlled gambling despite negative consequences (e.g., financial, familial problems). This review first provides an overview of the diagnostic criteria for addictive disorders—both substance and nonsubstance—and subsequently reviews the extant literature examining epidemiology, including global prevalence and co-occurring disorders, as well as differences in addicted and nonaddicted groups with respect to genotype, brain function, and neurochemical systems. Last, the prognosis, quality of life, and current treatment strategies for addictions are discussed. The review also includes tables and figures to supplement the text, summarizes important points, and provides visual representations of tasks used to study cognitive aspects of addictions and addiction pathophysiology. This review contains 5 figures, 6 tables, and 81 references. Key words: brain function, cognitive function, epidemiology, functional magnetic resonance imaging, genetics, neurochemistry, positron emission tomography, treatment

Addiction is a disorder characterized by poorly controlled substance use despite negative health and social consequences. Additionally, the only behavioral addiction recognized in the main text of the DSM-5, gambling disorder, presents similarly to many substance addictions with respect to the underlying neurobiology and poorly controlled gambling despite negative consequences (e.g., financial, familial problems). This review first provides an overview of the diagnostic criteria for addictive disorders—both substance and nonsubstance—and subsequently reviews the extant literature examining epidemiology, including global prevalence and co-occurring disorders, as well as differences in addicted and nonaddicted groups with respect to genotype, brain function, and neurochemical systems. Last, the prognosis, quality of life, and current treatment strategies for addictions are discussed. The review also includes tables and figures to supplement the text, summarizes important points, and provides visual representations of tasks used to study cognitive aspects of addictions and addiction pathophysiology. This review contains 5 figures, 6 tables, and 81 references. Key words: brain function, cognitive function, epidemiology, functional magnetic resonance imaging, genetics, neurochemistry, positron emission tomography, treatment

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 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.

Men typically report greater substance use and gambling than women, but the gender gap has been closing in recent years. Men and women engage in drug and gambling behaviors for different reasons and respond differently to drugs and gambling. Telescoping — a phenomenon in which women engage in drug use and/or gambling behaviors at a later age but progress faster to disordered engagement — was initially observed in alcohol and later in opioid, cannabinoid, cocaine, and gambling disorders. Biological and sociocultural gender-related factors may impact withdrawal symptoms and treatment responses among men and women. Further investigation of the neurobiological underpinnings of gender-related differences among addiction populations is required.

Background Prenatal cocaine exposure (PCE) is linked to addiction and obesity vulnerability. Neural responses to stressful and appetitive cues in adolescents with PCE versus those without have been differentially linked to substance-use initiation. However, no prior studies have assessed cue-reactivity responses among PCE adolescents using a connectivity-based approach. Methods Twenty-two PCE and 22 non-prenatally drug-exposed (NDE) age-, sex-, IQ- and BMI-matched adolescents participated in individualized guided imagery with appetitive (favorite-food), stressful and neutral-relaxing cue scripts during functional magnetic resonance imaging. Subjective favorite-food craving scores were collected before and after script exposure. A data-driven voxel-wise intrinsic connectivity distribution analysis was used to identify between-group differences and examine relationships with craving scores. Results A group-by-cue interaction effect identified a parietal lobe cluster where PCE versus NDE adolescents showed less connectivity during stressful and more connectivity during neutral-relaxing conditions. Follow-up seed-based connectivity analyses revealed that, among PCE adolescents, the parietal seed was positively connected to inferior parietal and sensory areas and negatively connected to corticolimbic during both stress and neutral-relaxing conditions. For NDE, greater parietal connectivity to parietal, cingulate and sensory areas and lesser parietal connectivity to medial prefrontal areas were found during stress compared to neutral-relaxing cueing. Craving scores inversely correlated with corticolimbic connectivity in PCE, but not NDE adolescents, during the favorite-food condition. Conclusions Findings from this first data-driven intrinsic connectivity analysis of PCE influences on adolescent brain function indicate differences relating to PCE status and craving. These findings provide insight into the developmental impact of in utero drug exposure.

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

Alcohol dependence is a chronic relapsing illness. Alcohol and stress cues have consistently been shown to increase craving and relapse risk in recovering alcohol dependent (AUD) patients. However, differences in functional connectivity in response to these cues have not been studied using data-driven approaches. Here, voxel-wise connectivity is used in a whole-brain investigation of functional connectivity differences associated with alcohol and stress cues and to examine whether these differences are related to subsequent relapse. In Study 1, 45, 4- to 8-week abstinent, recovering AUD patients underwent functional magnetic resonance imaging during individualized imagery of alcohol, stress, and neutral cues. Relapse measures were collected prospectively for 90 days post-discharge from inpatient treatment. AUD patients showed blunted anterior (ACC), mid (MCC) and posterior cingulate cortex (PCC), voxel-wise connectivity responses to stress compared to neutral cues and blunted PCC response to alcohol compared to neutral cues. Using Cox proportional hazard regression, weaker connectivity in ACC and MCC during neutral exposure was associated with longer time to relapse (better recovery outcome). Similarly, greater connectivity in PCC during alcohol-cue compared to stress cue was associated with longer time to relapse. In Study 2, a sub-group of 30 AUD patients were demographically-matched to 30 healthy control (HC) participants for group comparisons. AUD compared to HC participants showed reduced cingulate connectivity during alcohol and stress cues. Using novel data-driven approaches, the cingulate cortex emerged as a key region in the disruption of functional connectivity during alcohol and stress-cue processing in AUD patients and as a marker of subsequent alcohol relapse., Highlights • AUD patients showed blunted cingulate connectivity to alcohol and stress cues. • Cingulate connectivity predicted time to relapse in AUD patients. • Greater PCC connectivity during alcohol cues predicted longer time to relapse. • AUD vs. HC subjects showed less cingulate connectivity to alcohol and stress cues. • The cingulate cortex emerged as a marker of subsequent alcohol relapse.

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

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