The Brain on Drugs: From Reward to Addiction.

Advances in neuroscience identified addiction as a chronic brain disease with strong genetic, neurodevelopmental, and sociocultural components. We here discuss the circuit- and cell-level mechanisms of this condition and its co-option of pathways regulating reward, self-control, and affect. Drugs of abuse exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors. Repeated drug administration triggers neuroplastic changes in glutamatergic inputs to the striatum and midbrain dopamine neurons, enhancing the brain's reactivity to drug cues, reducing the sensitivity to non-drug rewards, weakening self-regulation, and increasing the sensitivity to stressful stimuli and dysphoria. Drug-induced impairments are long lasting; thus, interventions designed to mitigate or even reverse them would be beneficial for the treatment of addiction.

The Neuroscience of Drug Reward and Addiction.

Drug consumption is driven by a drug's pharmacological effects, which are experienced as rewarding, and is influenced by genetic, developmental, and psychosocial factors that mediate drug accessibility, norms, and social support systems or lack thereof. The reinforcing effects of drugs mostly depend on dopamine signaling in the nucleus accumbens, and chronic drug exposure triggers glutamatergic-mediated neuroadaptations in dopamine striato-thalamo-cortical (predominantly in prefrontal cortical regions including orbitofrontal cortex and anterior cingulate cortex) and limbic pathways (amygdala and hippocampus) that, in vulnerable individuals, can result in addiction. In parallel, changes in the extended amygdala result in negative emotional states that perpetuate drug taking as an attempt to temporarily alleviate them. Counterintuitively, in the addicted person, the actual drug consumption is associated with an attenuated dopamine increase in brain reward regions, which might contribute to drug-taking behavior to compensate for the difference between the magnitude of the expected reward triggered by the conditioning to drug cues and the actual experience of it. Combined, these effects result in an enhanced motivation to "seek the drug" (energized by dopamine increases triggered by drug cues) and an impaired prefrontal top-down self-regulation that favors compulsive drug-taking against the backdrop of negative emotionality and an enhanced interoceptive awareness of "drug hunger." Treatment interventions intended to reverse these neuroadaptations show promise as therapeutic approaches for addiction.

Examining the role of dopamine in methylphenidate's effects on resting brain function.

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.

Astrocytes modulate cerebral blood flow and neuronal response to cocaine in prefrontal cortex.

Cocaine affects both cerebral blood vessels and neuronal activity in brain. Cocaine can also disrupt astrocytes, which modulate neurovascular coupling-a process that regulates cerebral hemodynamics in response to neuronal activation. However, separating neuronal and astrocytic effects from cocaine's direct vasoactive effects has been challenging, partially due to limitations of neuroimaging techniques able to differentiate vascular from neuronal and glial effects at high temporal and spatial resolutions. Here, we used a newly-developed multi-channel fluorescence and optical coherence Doppler microscope (fl-ODM) that allows for simultaneous measurements of neuronal and astrocytic activities (reflected by the intracellular calcium changes in neurons Ca2+N and astrocytes Ca2+A, respectively) alongside their vascular interactions in vivo to address this challenge. Using green and red genetically-encoded Ca2+ indicators differentially expressed in astrocytes and neurons, fl-ODM enabled concomitant imaging of large-scale astrocytic and neuronal Ca2+ fluorescence and 3D cerebral blood flow velocity (CBFv) in vascular networks in the mouse cortex. We assessed cocaine's effects in the prefrontal cortex (PFC) and found that the CBFv changes triggered by cocaine were temporally correlated with astrocytic Ca2+A activity. Chemogenetic inhibition of astrocytes during the baseline state resulted in blood vessel dilation and CBFv increases but did not affect neuronal activity, suggesting modulation of spontaneous blood vessel's vascular tone by astrocytes. Chemogenetic inhibition of astrocytes during a cocaine challenge prevented its vasoconstricting effects alongside the CBFv decreases, but it also attenuated the neuronal Ca2+N increases triggered by cocaine. These results document a role of astrocytes both in regulating vascular tone and consequently blood flow, at baseline and for modulating the vasoconstricting and neuronal activation responses to cocaine in the PFC. Strategies to inhibit astrocytic activity could offer promise for ameliorating vascular and neuronal toxicity from cocaine misuse.

Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study.

Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide's potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42-0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46-0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29-0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42-1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.

Disparities in sleep duration among American children: effects of race and ethnicity, income, age, and sex.

Children in the United States sleep less than the recommended amount and sleep deficiencies may be worse among disadvantaged children. Prior studies that compared sleep time in children of different race/ethnic groups mostly relied on questionnaires or were limited to small sample sizes. Our study takes advantage of the Adolescent Brain Cognitive Development study to compare total sleep time using a week of actigraphy data among American children (n = 4,207, 9 to 13 y old) of different racial/ethnic and income groups. We also assessed the effects of neighborhood deprivation, experience of discrimination, parent's age at child's birth, body mass index (BMI), and time the child fell asleep on sleep times. Daily total sleep time for the sample was 7.45 h and race/ethnicity, income, sex, age, BMI, were all significant predictors of total sleep time. Black children slept less than White children (∼34 min; Cohen's d = 0.95), children from lower income families slept less than those from higher incomes (∼16 min; Cohen's d = 0.44), boys slept less than girls (∼7 min; Cohen's d = 0.18), and older children slept less than younger ones (∼32 min; Cohen's d = 0.91); mostly due to later sleep times. Children with higher BMI also had shorter sleep times. Neither area deprivation index, experience of discrimination, or parent's age at child's birth significantly contributed to sleep time. Our findings indicate that children in the United States sleep significantly less than the recommended amount for healthy development and identifies significant racial and income disparities. Interventions to improve sleep hygiene in children will help improve health and ameliorate racial disparities in health outcomes.

Seasonality in regional brain glucose metabolism.

BACKGROUND: Daylength and the rates of changes in daylength have been associated with seasonal fluctuations in psychiatric symptoms and in cognition and mood in healthy adults. However, variations in human brain glucose metabolism in concordance with seasonal changes remain under explored. METHODS: In this cross-sectional study, we examined seasonal effects on brain glucose metabolism, which we measured using 18F-fluorodeoxyglucose-PET in 97 healthy participants. To maximize the sensitivity of regional effects, we computed relative metabolic measures by normalizing the regional measures to white matter metabolism. Additionally, we explored the role of rest-activity rhythms/sleep-wake activity measured with actigraphy in the seasonal variations of regional brain metabolic activity. RESULTS: We found that seasonal variations of cerebral glucose metabolism differed across brain regions. Glucose metabolism in prefrontal regions increased with longer daylength and with greater day-to-day increases in daylength. The cuneus and olfactory bulb had the maximum and minimum metabolic values around the summer and winter solstice respectively (positively associated with daylength), whereas the temporal lobe, brainstem, and postcentral cortex showed maximum and minimum metabolic values around the spring and autumn equinoxes, respectively (positively associated with faster daylength gain). Longer daylength was associated with greater amplitude and robustness of diurnal activity rhythms suggesting circadian involvement. CONCLUSIONS: The current findings advance our knowledge of seasonal patterns in a key indicator of brain function relevant for mood and cognition. These data could inform treatment interventions for psychiatric symptoms that peak at specific times of the year.

Preterm birth associated alterations in brain structure, cognitive functioning and behavior in children from the ABCD dataset.

BACKGROUND: Preterm birth is a global health problem and associated with increased risk of long-term developmental impairments, but findings on the adverse outcomes of prematurity have been inconsistent. METHODS: Data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development (ABCD) Study. We identified 1706 preterm children and 1865 matched individuals as Control group and compared brain structure (MRI data), cognitive function and mental health symptoms. RESULTS: Results showed that preterm children had higher psychopathological risk and lower cognitive function scores compared to controls. Structural MRI analysis indicated that preterm children had higher cortical thickness in the medial orbitofrontal cortex, parahippocampal gyrus, temporal and occipital gyrus; smaller volumes in the temporal and parietal gyrus, cerebellum, insula and thalamus; and smaller fiber tract volumes in the fornix and parahippocampal-cingulum bundle. Partial correlation analyses showed that gestational age and birth weight were associated with ADHD symptoms, picvocab, flanker, reading, fluid cognition composite, crystallized cognition composite and total cognition composite scores, and measures of brain structure in regions involved with emotional regulation, attention and cognition. CONCLUSIONS: These findings suggest a complex interplay between psychopathological risk and cognitive deficits in preterm children that is associated with changes in regional brain volumes, cortical thickness, and structural connectivity among cortical and limbic brain regions critical for cognition and emotional well-being.

Effects of family income on brain functional connectivity in US children: associations with cognition.

Higher family income (FI) is associated with larger cortical gray matter volume and improved cognitive performance in children. However, little is known about the effects of FI on brain functional and structural connectivity. This cross-sectional study investigates the effects of FI on brain connectivity and cognitive performance in 9- to 11-years old children (n = 8739) from the Adolescent Brain Cognitive Development (ABCD) study. Lower FI was associated with decreased global functional connectivity density (gFCD) in the default-mode network (DMN), inferior and superior parietal cortices and in posterior cerebellum, and increased gFCD in motor, auditory, and extrastriate visual areas, and in subcortical regions both for girls and boys. Findings demonstrated high reproducibility in Discovery and Reproducibility samples. Cognitive performance partially mediated the association between FI and DMN connectivity, whereas DMN connectivity did not mediate the association between FI and cognitive performance. In contrast, there was no significant association between FI and structural connectivity. Findings suggest that poor cognitive performance, which likely reflects multiple factors (genetic, nutritional, the level and quality of parental interactions, and educational exposure [1]), contributes to reduced DMN functional connectivity in children from low-income families. Follow-up studies are needed to help clarify if this leads to reductions in structural connectivity as these children age.

Association of COVID-19 with endocarditis in patients with cocaine or opioid use disorders in the US.

The incidence of endocarditis in the US is increasing, driven in part by the rise in intravenous drug use, mostly opioids and stimulant drugs (cocaine and methamphetamine). Recent reports have documented that individuals with COVID-19 are at increased risk for cardiovascular diseases. However, it is unknown whether COVID-19 is associated with increased risk for endocarditis in patients with opioid or stimulant use disorders. This is a retrospective cohort study based on a nationwide database of electronic health records (EHRs) of 109 million patients in the US, including 736,502 patients with a diagnosis of opioid use disorder (OUD) and 379,623 patients with a diagnosis of cocaine use disorder (CocaineUD). Since Metamphetamine use disorder is not coded we could not analyze it. We show that the incidence rate of endocarditis among patients with OUD or CocaineUD significantly increased from 2011 to 2022 with acceleration during 2021-2022. COVID-19 was associated with increased risk of new diagnosis of endocarditis among patients with OUD (HR: 2.23, 95% CI: 1.92-2.60) and with CocaineUD (HR: 2.24, 95% CI: 1.79-2.80). Clinically diagnosed COVID-19 was associated with higher risk of endocarditis than lab-test confirmed COVID-19 without clinical diagnosis. Hospitalization within 2 weeks following COVID-19 infection was associated with increased risk of new diagnosis of endocarditis. The risk for endocarditis did not differ between patients with and without EHR-recorded vaccination. There were significant racial and ethnic differences in the risk for COVID-19 associated endocarditis, lower in blacks than in whites and lower in Hispanics than in non-Hispanics. Among patients with OUD or CocaineUD, the 180-day hospitalization risk following endocarditis was 67.5% in patients with COVID-19, compared to 58.7% in matched patients without COVID-19 (HR: 1.21, 95% CI: 1.07-1.35). The 180-day mortality risk following the new diagnosis of endocarditis was 9.2% in patients with COVID-19, compared to 8.0% in matched patients without COVID-19 (HR: 1.16, 95% CI: 0.83-1.61). This study shows that COVID-19 is associated with significantly increased risk for endocarditis in patients with opioid or cocaine use disorders. These results highlight the need for endocarditis screening and for linkage to infectious disease and addiction treatment in patients with opioid or cocaine use disorders who contracted COVID-19. Future studies are needed to understand how COVID-19 damages the heart and the vascular endothelium among people who misuse opioids or cocaine (presumably also methamphetamines).

Brain functional and structural magnetic resonance imaging of obesity and weight loss interventions.

Obesity has tripled over the past 40 years to become a major public health issue, as it is linked with increased mortality and elevated risk for various physical and neuropsychiatric illnesses. Accumulating evidence from neuroimaging studies suggests that obesity negatively affects brain function and structure, especially within fronto-mesolimbic circuitry. Obese individuals show abnormal neural responses to food cues, taste and smell, resting-state activity and functional connectivity, and cognitive tasks including decision-making, inhibitory-control, learning/memory, and attention. In addition, obesity is associated with altered cortical morphometry, a lowered gray/white matter volume, and impaired white matter integrity. Various interventions and treatments including bariatric surgery, the most effective treatment for obesity in clinical practice, as well as dietary, exercise, pharmacological, and neuromodulation interventions such as transcranial direct current stimulation, transcranial magnetic stimulation and neurofeedback have been employed and achieved promising outcomes. These interventions and treatments appear to normalize hyper- and hypoactivations of brain regions involved with reward processing, food-intake control, and cognitive function, and also promote recovery of brain structural abnormalities. This paper provides a comprehensive literature review of the recent neuroimaging advances on the underlying neural mechanisms of both obesity and interventions, in the hope of guiding development of novel and effective treatments.

IUPHAR Review: New strategies for medications to treat substance use disorders.

Substance use disorders (SUDs) and drug overdose are a public health emergency and safe and effective treatments are urgently needed. Developing new medications to treat them is expensive, time-consuming, and the probability of a compound progressing to clinical trials and obtaining FDA-approval is low. The small number of FDA-approved medications for SUDs reflects the low interest of pharmaceutical companies to invest in this area due to market forces, characteristics of the population (e.g., stigma, and socio-economic and legal disadvantages), and the high bar regulatory agencies set for new medication approval. In consequence, most research on medications is funded by government agencies, such as the National Institute on Drug Abuse (NIDA). Multiple scientific opportunities are emerging that can accelerate the discovery and development of new medications for SUDs. These include fast and efficient tools to screen new molecules, discover new medication targets, use of big data to explore large clinical data sets and artificial intelligence (AI) applications to make predictions, and precision medicine tools to individualize and optimize treatments. This review provides a general description of these new research strategies for the development of medications to treat SUDs with emphasis on the gaps and scientific opportunities. It includes a brief overview of the rising public health toll of SUDs; the justification, challenges, and opportunities to develop new medications; and a discussion of medications and treatment endpoints that are being evaluated with support from NIDA.

Treatment for Opioid Use Disorder: Population Estimates - United States, 2022.

In 2022, 81,806 opioid-involved overdose deaths were reported in the United States, more than in any previous year. Medications for opioid use disorder (OUD), particularly buprenorphine and methadone, substantially reduce overdose-related and overall mortality. However, only a small proportion of persons with OUD receive these medications. Data from the 2022 National Survey on Drug Use and Health were applied to a cascade of care framework to estimate and characterize U.S. adult populations who need OUD treatment, receive any OUD treatment, and receive medications for OUD. In 2022, 3.7% of U.S. adults aged ≥18 years needed OUD treatment. Among these, only 25.1% received medications for OUD. Most adults who needed OUD treatment either did not perceive that they needed it (42.7%) or received OUD treatment without medications for OUD (30.0%). Compared with non-Hispanic Black or African American and Hispanic or Latino adults, higher percentages of non-Hispanic White adults received any OUD treatment. Higher percentages of men and adults aged 35-49 years received medications for OUD than did women and younger or older adults. Expanded communication about the effectiveness of medications for OUD is needed. Increased efforts to engage persons with OUD in treatment that includes medications are essential. Clinicians and other treatment providers should offer or arrange evidence-based treatment, including medications, for patients with OUD. Pharmacists and payors can work to make these medications available without delays.

Activation of brain arousal networks coincident with eye blinks during resting state.

Eye-blinking has been implicated in arousal and attention. Here we test the hypothesis that blinking-moments represent arousal surges associated with activation of the ascending arousal network (AAN) and its thalamic projections. For this purpose, we explored the temporal relationship between eye-blinks and fMRI BOLD activity in AAN and thalamic nuclei, as well as whole brain cluster corrected activations during eyes-open, resting-state fMRI scanning. We show that BOLD activations in the AAN nuclei peaked prior to the eye blinks and in thalamic nuclei peaked prior to and during the blink, consistent with the role of eye blinking in arousal surges. Additionally, we showed visual cortex peak activation prior to the eye blinks, providing further evidence of the visual cortex's role in arousal, and document cerebellar peak activation post eye blinks, which might reflect downstream engagement from arousal surges.

Associations between body mass index, sleep-disordered breathing, brain structure, and behavior in healthy children.

Pediatric overweight/obesity can lead to sleep-disordered breathing (SDB), abnormal neurological and cognitive development, and psychiatric problems, but the associations and interactions between these factors have not been fully explored. Therefore, we investigated the associations between body mass index (BMI), SDB, psychiatric and cognitive measures, and brain morphometry in 8484 children 9-11 years old using the Adolescent Brain Cognitive Development dataset. BMI was positively associated with SDB, and both were negatively correlated with cortical thickness in lingual gyrus and lateral orbitofrontal cortex, and cortical volumes in postcentral gyrus, precentral gyrus, precuneus, superior parietal lobule, and insula. Mediation analysis showed that SDB partially mediated the effect of overweight/obesity on these brain regions. Dimensional psychopathology (including aggressive behavior and externalizing problem) and cognitive function were correlated with BMI and SDB. SDB and cortical volumes in precentral gyrus and insula mediated the correlations between BMI and externalizing problem and matrix reasoning ability. Comparisons by sex showed that obesity and SDB had a greater impact on brain measures, cognitive function, and mental health in girls than in boys. These findings suggest that preventing childhood obesity will help decrease SDB symptom burden, abnormal neurological and cognitive development, and psychiatric problems.

Associations among body mass index, working memory performance, gray matter volume, and brain activation in healthy children.

To investigate the neural mechanisms underlying the association between poorer working memory performance and higher body mass index (BMI) in children. We employed structural-(sMRI) and functional magnetic resonance imaging (fMRI) with a 2-back working memory task to examine brain abnormalities and their associations with BMI and working memory performance in 232 children with overweight/obesity (OW/OB) and 244 normal weight children (NW) from the Adolescent Brain Cognitive Development dataset. OW/OB had lower working memory accuracy, which was associated with higher BMI. They showed smaller gray matter (GM) volumes in the left superior frontal gyrus (SFG_L), dorsal anterior cingulate cortex, medial orbital frontal cortex, and medial superior frontal gyrus, which were associated with lower working memory accuracy. During the working memory task, OW/OB relative to NW showed weaker activation in the left superior temporal pole, amygdala, insula, and bilateral caudate. In addition, caudate activation mediated the relationship between higher BMI and lower working memory accuracy. Higher BMI is associated with smaller GM volumes and weaker brain activation in regions involved with working memory. Task-related caudate dysfunction may account for lower working memory accuracy in children with higher BMI.

Obesity is associated with decreased gray matter volume in children: a longitudinal study.

Childhood obesity has become a global health problem. Previous studies showed that childhood obesity is associated with brain structural differences relative to controls. However, few studies have been performed with longitudinal evaluations of brain structural developmental trajectories in childhood obesity. We employed voxel-based morphometry (VBM) analysis to assess gray matter (GM) volume at baseline and 2-year follow-up in 258 obese children (OB) and 265 normal weight children (NW), recruited as part of the National Institutes of Health Adolescent Brain and Cognitive Development study. Significant group × time effects on GM volume were observed in the prefrontal lobe, thalamus, right precentral gyrus, caudate, and parahippocampal gyrus/amygdala. OB compared with NW had greater reductions in GM volume in these regions over the 2-year period. Body mass index (BMI) was negatively correlated with GM volume in prefrontal lobe and with matrix reasoning ability at baseline and 2-year follow-up. In OB, Picture Test was positively correlated with GM volume in the left orbital region of the inferior frontal gyrus (OFCinf_L) at baseline and was negatively correlated with reductions in OFCinf_L volume (2-year follow-up vs. baseline). These findings indicate that childhood obesity is associated with GM volume reduction in regions involved with reward evaluation, executive function, and cognitive performance.

Habenular connectivity predict weight loss and negative emotional-related eating behavior after laparoscopic sleeve gastrectomy.

Habenular (Hb) processes negative emotions that may drive compulsive food-intake. Its functional changes were reported following laparoscopic-sleeve-gastrectomy (LSG). However, structural connectivity (SC) of Hb-homeostatic/hedonic circuits after LSG remains unclear. We selected regions implicated in homeostatic/hedonic regulation that have anatomical connections with Hb as regions-of-interest (ROIs), and used diffusion-tensor-imaging with probabilistic tractography to calculate SC between Hb and these ROIs in 30 obese participants before LSG (PreLSG) and at 12-month post-LSG (PostLSG12) and 30 normal-weight controls. Three-factor-eating-questionnaire (TFEQ) and Dutch-eating-behavior-questionnaire (DEBQ) were used to assess eating behaviors. LSG significantly decreased weight, negative emotion, and improved self-reported eating behavior. LSG increased SC between the Hb and homeostatic/hedonic regions including hypothalamus (Hy), bilateral superior frontal gyri (SFG), left amygdala (AMY), and orbitofrontal cortex (OFC). TFEQ-hunger negatively correlated with SC of Hb-Hy at PostLSG12; and increased SC of Hb-Hy correlated with reduced depression and DEBQ-external eating. TFEQ-disinhibition negatively correlated with SC of Hb-bilateral SFG at PreLSG. Increased SC of Hb-left AMY correlated with reduced DEBQ-emotional eating. Higher percentage of total weight-loss negatively correlated with SC of Hb-left OFC at PreLSG. Enhanced SC of Hb-homeostatic/hedonic regulatory regions post-LSG may contribute to its beneficial effects in improving eating behaviors including negative emotional eating, and long-term weight-loss.

The NIDA Avenir award in genetics or epigenetics of substance use disorders.

NIDA's Avenir Program in the Genetics or Epigenetics of Substance Use Disorders (SUDs) was launched to support early stage investigators who propose innovative, high risk, but potentially high impact research and who show promise of being tomorrow's leaders in this scientific field. Since 2015, NIDA has supported 30 Avenir Investigators with unique expertise and creative ideas. This special issue showcases how some of these ideas have germinated, flourished, and borne fruit. In this perspective article we briefly describe the purpose and implementation of the Avenir award and provide a high altitude overview of the awardees and their scientific projects to date.

Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences.

The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized the magnitude and duration of respiratory depression, the leading cause of death in opioid overdose cases, induced by heroin or fentanyl and the development of tolerance in male and female rats. We used whole-body plethysmography to first establish dose-response curves by recording breathing for 60 minutes post-intravenous opioid injection. We then tested the development of respiratory tolerance to acute heroin or fentanyl over several weeks and to chronic fentanyl with acute fentanyl or heroin challenge. Heroin and fentanyl each provoked dose-dependent respiratory depression. Heroin caused prolonged (45-60 minute) respiratory depression in female and male rats, characterized by decreased frequency, tidal volume, and minute ventilation and increased inspiratory time and apneic pause. Fentanyl produced similar changes with a shorter duration (10-15 minutes). High-dose heroin or fentanyl produced robust respiratory depression that was slightly more severe in females and, when given intermittently (acute doses 2 to 3 weeks apart), did not lead to tolerance. In contrast, chronic fentanyl delivered with an osmotic minipump resulted in tolerance to acute fentanyl and heroin, characterized by a shorter duration of respiratory depression. This effect persisted during withdrawal in males only. Our model and experimental design will allow for investigation of the neurobiology of opioid-induced respiratory depression and for testing potential therapeutics to reverse respiratory depression or stimulate breathing. SIGNIFICANCE STATEMENT: Fentanyl was more potent and had shorter duration in producing respiratory depression than heroin in both sexes, whereas female rats were more sensitive than males to heroin-induced respiratory depression. Tolerance/cross-tolerance develops in chronic fentanyl administration but is minimized with long interadministration intervals.