Showing papers by "Nora D. Volkow published in 2018"

β-Amyloid accumulation in the human brain after one night of sleep deprivation.

Abstract: The effects of acute sleep deprivation on β-amyloid (Aβ) clearance in the human brain have not been documented. Here we used PET and 18F-florbetaben to measure brain Aβ burden (ABB) in 20 healthy controls tested after a night of rested sleep (baseline) and after a night of sleep deprivation. We show that one night of sleep deprivation, relative to baseline, resulted in a significant increase in Aβ burden in the right hippocampus and thalamus. These increases were associated with mood worsening following sleep deprivation, but were not related to the genetic risk (APOE genotype) for Alzheimer's disease. Additionally, baseline ABB in a range of subcortical regions and the precuneus was inversely associated with reported night sleep hours. APOE genotyping was also linked to subcortical ABB, suggesting that different Alzheimer's disease risk factors might independently affect ABB in nearby brain regions. In summary, our findings show adverse effects of one-night sleep deprivation on brain ABB and expand on prior findings of higher Aβ accumulation with chronic less sleep.

Suicide: A Silent Contributor to Opioid-Overdose Deaths

Abstract: A Silent Contributor to Opioid-Overdose Deaths Most strategies for reducing opioid-overdose deaths don’t include screening for suicide risk or address tailoring of interventions for suicidal persons. And the inaccuracy of data on the proportion of opioid deaths that are suicides hinders appropriate prevention.

Use and Misuse of Opioids in Chronic Pain

Abstract: The prescribing of opioid analgesics for pain management-particularly for management of chronic noncancer pain (CNCP)-has increased more than fourfold in the United States since the mid-1990s. Yet there is mounting evidence that opioids have only limited effectiveness in the management of CNCP, and the increased availability of prescribed opioids has contributed to upsurges in opioid-related addiction cases and overdose deaths. These concerns have led to critical revisiting and modification of prior pain management practices (e.g., guidelines from the Centers for Disease Control and Prevention), but the much-needed changes in clinical practice will be facilitated by a better understanding of the pharmacology and behavioral effects of opioids that underlie both their therapeutic effects (analgesia) and their adverse effects (addiction and overdose). With these goals in mind, this review first presents an overview of the contemporary problems associated with opioid management of CNCP and the related public health issues of opioid diversion, overdose, and addiction. It then discusses the pharmacology underlying the therapeutic and main adverse effects of opioids and its implications for clinical management of CNCP within the framework of recent clinical guidelines for prescribing opioids in the management of CNCP.

Cannabis Addiction and the Brain: a Review.

Abstract: Cannabis is the most commonly used substance of abuse in the United States after alcohol and tobacco. With a recent increase in the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the addictive potential of cannabis. Here we evaluate cannabis use through the neurobiological model of addiction proposed by Koob and Volkow. The model proposes that repeated substance abuse drives neurobiological changes in the brain that can be separated into three distinct stages, each of which perpetuates the cycle of addiction. Here we review previous research on the acute and long-term effects of cannabis use on the brain and behavior, and find that the three-stage framework of addiction applies to CUD in a manner similar to other drugs of abuse, albeit with some slight differences. These findings highlight the urgent need to conduct research that elucidates specific neurobiological changes associated with CUD in humans.

Neuroscience of Addiction: Relevance to Prevention and Treatment

Abstract: Addiction, the most severe form of substance use disorder, is a chronic brain disorder molded by strong biosocial factors that has devastating consequences to individuals and to society. Our understanding of substance use disorder has advanced significantly over the last 3 decades in part due to major progress in genetics and neuroscience research and to the development of new technologies, including tools to interrogate molecular changes in specific neuronal populations in animal models of substance use disorder, as well as brain imaging devices to assess brain function and neurochemistry in humans. These advances have illuminated the neurobiological processes through which biological and sociocultural factors contribute to resilience against or vulnerability for drug use and addiction. The delineation of the neurocircuitry disrupted in addiction, which includes circuits that mediate reward and motivation, executive control, and emotional processing, has given us an understanding of the aberrant behavior...

Helping to End Addiction Over the Long-term: The Research Plan for the NIH HEAL Initiative.

Abstract: Extraordinary focus by all segments of society is required to respond to the nation’s opioid crisis. Now is the time to channel the efforts of the scientific community to deliver effective—and sustainable—solutions to this formidable public health challenge. Recognizing this opportunity, Congress added $500 million to the base appropriation of the National Institutes of Health (NIH), starting in fiscal year 2018.1 The NIH will invest these much-needed resources to support science that advances national priorities for addiction and pain research2 with a bold new trans-NIH initiative called Helping to End Addiction Long-term (HEAL).3 In this Viewpoint, we outline the initial components of this cross-cutting, interdisciplinary program. More than 25 million US adults are affected by daily pain.4 More than 2 million individuals in the United States have an opioid use disorder (OUD), most starting with opioid analgesics prescribed to them or procured from diverted medications, but once addicted, often shifting to illicit heroin or synthetic opioids.5 The scope of this crisis is staggering, but scientific advances offer strategies that can help the nation overcome it. At the National Rx Drug Abuse and Heroin Summit in April 2018, leaders from both the public and private sectors affirmed that research is essential to the effort to end this public health crisis. It will take “all hands on deck” to make this happen, which is why HEAL seeks to foster innovative partnerships with other government agencies, academic institutions, industry, communities, and patient advocates. Through a year-long series of engagements with individuals from these groups, the NIH has developed an innovative, action-oriented research plan for HEAL that is focused on 2 primary areas: improving treatments for opioid misuse and addiction as well as enhancing strategies for pain management (Table). Although there are effective medications for OUD (methadone,buprenorphine,andnaltrexone),onlyasmall percentage of individuals in the United States who would benefit receive these medications. Even among those who have initiated these medications, about half will relapse within 6 months. Research to reformulate these medications to improve adherence, as well as to develop new, more flexible therapies, is needed to help those who have OUD. Similarly, although the opioid antagonist naloxone can effectively reverse opioid overdose, its relatively short half-life compared with those of synthetic opioids (fentanyl and its analogues) frequently requires multiple doses to reverse respiratory arrest, and its effectiveness declines when opioids are combined with other drugs (alcohol, benzodiazepines). HEAL will catalyze the development of extended-release formulations of existing medications to treat OUD, longer-acting formulations of opioid antagonists or partial agonists, new therapies to counter opioid-induced respiratory depression, and novel medications and immunotherapies to treat OUD and prevent and reverse overdoses. HEAL will also support services and implementation researchtodevelopnewmodelsofcareforOUDwithinthe health care and criminal justice settings that can expand access to medications and improve treatment retention. For example, HEAL will test how integrated evidencebased interventions can improve OUD outcomes through the multisite HEALing Communities Study. This study will be developed in close collaboration with the Substance Abuse and Mental Health Services Administration and other federal partners to avoid duplication and leverage complementary ongoing efforts. HEALing Communities will measure the effect of integrated implementation of a comprehensivesetofevidence-basedstrategiesacrossthe OUD cascade of prevention, screening and detection, linkagetocare,initiationofmedication-assistedtreatment,and long-term retention in treatment. The NIH will encourage applications from researchers with linkages to health care and justice systems, fire and police departments, and state and local governments in rural and urban areas highly affectedbytheopioidcrisis.Thewealthofdataandevidence VIEWPOINT

Food addiction: A common neurobiological mechanism with drug abuse.

Abstract: Drugs and food both exert a rewarding effect through the firing of dopamine neurons in the ventral tegmental area, resulting in the release of dopamine into the nucleus accumbens and effects on the mesolimbic pathway. Here, we review the neuroimaging literature to consider the validity of food addiction and the common neurobiological mechanisms that overlap in food and drug addiction. This review paper focuses on findings from Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI) and structural imaging studies, as well as evidence from neuroimaging studies of bariatric surgery and pharmacological interventions on obese individuals. We examine not only functional and structural changes in the mesolimbic pathways, but also in other frontal areas shown to be involved in drug addiction, including the prefrontal cortex, orbitofrontal cortex and anterior cingulate cortex, as well as changes in neurotransmitter systems beyond dopaminergic systems.

Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A2A-Dopamine D2 Receptor Heterotetramers and Adenylyl Cyclase

Abstract: The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating "Go" responses upon exposure to reward-related stimuli and "NoGo" responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson's disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons.

Impact of sugar on the body, brain, and behavior.

Abstract: Sugar is highly palatable and rewarding, both in its taste and nutritive input. Excessive sugar consumption, however, may trigger neuroadaptations in the reward system that decouple eating behavior from caloric needs and leads to compulsive overeating. Excessive sugar intake is in turn associated with adverse health conditions, including obesity, metabolic syndrome, and inflammatory diseases. This review aims to use recent evidence to connect sugar's impact on the body, brain, and behavior to elucidate how and why sugar consumption has been implicated in addictive behaviors and poor health outcomes.

Bariatric surgery in obese patients reduced resting connectivity of brain regions involved with self-referential processing.

Abstract: Obese individuals exhibit brain alterations of resting-state functional connectivity (RSFC) integrity of resting-state networks (RSNs) related to food intake. Bariatric surgery is currently the most effective treatment for combating morbid obesity. How bariatric surgery influences neurocircuitry is mostly unknown. Functional connectivity density (FCD) mapping was employed to calculate local (lFCD)/global (gFCD) voxelwise connectivity metrics in 22 obese participants who underwent functional magnetic resonance imaging before and 1 month after sleeve gastrectomy (SG), and in 19 obese controls (Ctr) without surgery but tested twice (baseline and 1-month later). Two factor (group, time) repeated measures ANOVA was used to assess main and interaction effects in lFCD/gFCD; regions of interest were identified for subsequent seed to voxel connectivity analyses to assess resting-state functional connectivity and to examine association with weight loss. Bariatric surgery significantly decreased lFCD in VMPFC, posterior cingulate cortex (PCC)/precuneus, and dorsal anterior cingulate cortex (dACC)/dorsomedial prefrontal cortex (DMPFC) and decreased gFCD in VMPFC, right dorsolateral prefrontal cortex (DLPFC) and right insula (pFWE < .05). lFCD decreased in VMPFC and PCC/precuneus correlated with reduction in BMI after surgery. Seed to voxel connectivity analyses showed the VMPFC had stronger connectivity with left DLPFC and weaker connectivity with hippocampus/parahippocampus, and PCC/precuneus had stronger connectivity with right caudate and left DLPFC after surgery. Bariatric surgery significantly decreased FCD in regions involved in self-referential processing (VMPFC, DMPFC, dACC, and precuneus), and interoception (insula), and changes in VMPFC/precuneus were associated with reduction in BMI suggesting a role in improving control of eating behaviors following surgery.

Overdose Prevention Through Medical Treatment of Opioid Use Disorders

Abstract: In their article, Larochelle and colleagues provided convincing evidence of the benefits of methadone and buprenorphine in preventing opioid-related deaths in patients with a history of nonfatal op...

Medication development in opioid addiction: Meaningful clinical end points.

Abstract: The FDA’s “abstinence” outcome measure for approval of new medications to treat opioid-use disorders has been difficult to achieve; developing and validating alternative meaningful outcomes could facilitate drug development.

Methylation of the dopamine transporter gene in blood is associated with striatal dopamine transporter availability in ADHD: A preliminary study.

Abstract: Dopamine transporters (DAT) are implicated in the pathogenesis and treatment of attention-deficit hyperactivity disorder (ADHD) and are upregulated by chronic treatment with methylphenidate, commonly prescribed for ADHD. Methylation of the DAT1 gene in brain and blood has been associated with DAT expression in rodents' brains. Here we tested the association between methylation of the DAT1 promoter derived from blood and DAT availability in the striatum of unmedicated ADHD adult participants and in that of healthy age-matched controls (HC) using Positron Emission Tomography (PET) and [11 C]cocaine. Results showed no between-group differences in DAT1 promoter methylation or striatal DAT availability. However, the degree of methylation in the promoter region of DAT1 correlated negatively with DAT availability in caudate in ADHD participants only. DAT availability in VS correlated with inattention scores in ADHD participants. We verified in a postmortem cohort with ADHD diagnosis and without, that DAT1 promoter methylation in peripheral blood correlated positively with DAT1 promoter methylation extracted from substantia nigra (SN) in both groups. In the cohort without ADHD diagnosis, DAT1 gene expression in SN further correlated positively with DAT protein expression in caudate; however, the sample size of the cohort with ADHD was insufficient to investigate DAT1 and DAT expression levels. Overall, these findings suggest that peripheral DAT1 promoter methylation may be predictive of striatal DAT availability in adults with ADHD. Due to the small sample size, more work is needed to validate whether DAT1 methylation in blood predicts DAT1 methylation in SN in ADHD and controls.

Emotion Recognition Biases in Alcohol Use Disorder.

Abstract: Background Alcohol use disorder (AUD) has been associated with impairments in cognitive and emotional function, including difficulty identifying emotional facial expressions. However, it is unclear whether these deficits are associated with alcohol consumption or related anxious and depressive symptoms. Methods We compared the recognition of emotional faces expressing happiness, surprise, sadness, fear, anger, and disgust in 19 AUD participants and 19 healthy volunteers using the Cambridge Neuropsychological Test Automated Battery Emotion Recognition Task. We analyzed group differences in response latency, accuracy, and misidentification patterns (as defined by the tendency to mislabel facial expressions as exhibiting specific emotions). To assess whether misidentification patterns were associated with drinking severity, we also examined associations with alcohol consumption over the past 90 days. Results There were no differences in response latency or accuracy between groups. However, there were group differences in misidentification patterns. While controls tended to misidentify emotional expressions as happy, those with AUD tended to misidentify expressions as angry or disgusted. In AUD participants, the degree to which individuals were biased toward anger or disgust was positively correlated with the number of drinks they consumed in the past 90 days but was not associated with depression or anxiety scores. Conclusions Our findings suggest that individuals with AUD have a bias toward misidentifying emotional facial expressions as hostile, which is not mediated by associated mood changes. This provides further evidence of disrupted social cognition in AUD.

Association of genetic ancestry with striatal dopamine D2/D3 receptor availability.

Abstract: Despite ethnic differences in allele frequencies of variants in dopaminergic genes associated with dopamine D2/D3 receptor availability (D2R), no study to date has investigated the relationship between genetic ancestry and striatal D2R. Here, we show that ancestry-informative markers significantly predict dorsal striatal D2R in 117 healthy ethnically diverse residents of the New York metropolitan area using Positron Emission Tomography (PET) with [11C]raclopride (P<0.0001), while correcting for age, sex, BMI, education, smoking status, and estimated socioeconomic status (ZIP codes). Effects of ethnicity on D2R were not driven by variation in dopaminergic candidate genes. Instead, candidate gene associations with striatal D2R were diminished when correcting for ancestry. These findings imply that future studies investigating D2 receptor genes should covary for genetic ancestry or study homogeneous populations. Moreover, ancestry studies on human neurobiology should control for socioeconomic differences between ethnic groups.

Does glucagon-like peptide-1 (GLP-1) receptor agonist stimulation reduce alcohol intake in patients with alcohol dependence: study protocol of a randomised, double-blinded, placebo-controlled clinical trial

Abstract: Introduction Alcohol dependence is a major public health problem. It is underdiagnosed and undertreated. Even when treated, more than 2/3 of patients in abstinence-oriented treatment will relapse within the first year. Thus, there is an urgent need for efficacious medical treatment of alcohol dependence. Glucagon-like peptide-1 (GLP-1) receptor stimulation has proven to reduce alcohol consumption in preclinical experiments. However, the effect of GLP-1 receptor agonists in humans has to our knowledge, not yet been investigated. Methods and analysis Design, participants and intervention: The effect of the once-weekly GLP-1-receptor-agonist exenatide will be investigated in a double-blinded, placebo-controlled, randomised clinical trial. 114 outpatients will be recruited and randomised to treatment with either placebo or exenatide once weekly for 26 weeks as a supplement to cognitive–behavioural therapy. The primary endpoint is reduction in number of ‘heavy drinking days’. The secondary endpoints include changes in total alcohol consumption, days without consumption, changes in brain activity and function, smoking status, cognition, measures of quality of life and changes in phosphatidylethanol as a biomarker of alcohol consumption from baseline to follow-up at week 26. Status: Currently recruiting patients. Ethics and dissemination Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study results will be disseminated by peer-review publications and conference presentations and has the potential to reveal a completely new medical treatment of alcohol dependence.

Ketogenic Diet Suppresses Alcohol Withdrawal Syndrome in Rats.

Abstract: Background Alcohol use disorder is underdiagnosed and undertreated, and up to 50% of alcohol-abstinent patients diagnosed with alcohol dependence relapse within the first year of treatment. Current treatments for the maintenance of alcohol abstinence in patients with alcohol use disorder have limited efficacy, and there is an urgent need for novel treatment strategies. Decreased cerebral glucose metabolism and increased brain uptake of acetate were recently reported in heavy drinkers, relative to controls. Given the switch of metabolic fuel from glucose to acetate in the alcohol-dependent brain, we investigated the potential therapeutic benefit of a ketogenic diet in managing alcohol withdrawal symptoms during detoxification. Methods Male Sprague Dawley rats fed either ketogenic or regular diet were administered ethanol or water orally, twice daily for 6 days while the diet conditions were maintained. Abstinence symptoms were rated 6, 24, 48, and 72 hours after the last alcohol administration. Results Maintenance on a ketogenic diet caused a significant decrease in the alcohol withdrawal symptoms' “rigidity” and “irritability.” Conclusions Our preclinical pilot study suggests that a ketogenic diet may be a novel approach for treating alcohol withdrawal symptoms in humans.

An Autonomic Network: Synchrony Between Slow Rhythms of Pulse and Brain Resting State Is Associated with Personality and Emotions

Abstract: The sympathetic system’s role in modulating vasculature and its influence on emotions and personality led us to test the hypothesis that interactions between brain resting-state networks (RSNs) and pulse amplitude (indexing sympathetic activity) would be associated with emotions and personality. In 203 participants, we characterized RSN spatiotemporal characteristics, and phase–amplitude associations of RSN fluctuations with pulse and respiratory recordings. We found that RSNs are spatially reproducible within participants and were temporally associated with low frequencies (LFs < 0.1 Hz) in physiological signals. LF fluctuations in pulse amplitude were not related to cardiac electrical activity and preceded LF fluctuations in RSNs, while LF respiratory amplitude fluctuations followed LF fluctuations in RSNs. LF phase dispersion (PD) (lack of synchrony) between RSNs and pulse (PDpulse) (not respiratory) correlated with the common variability in measures of personality and emotions, with more synchrony being associated with more positive temperamental characteristics. Voxel-level PDpulse mapping revealed an “autonomic brain network,” including sensory cortices and dorsal attention stream, with significant interactions with peripheral signals. Here, we uncover associations between pulse signal amplitude (presumably of sympathetic origin) and brain resting state, suggesting that interactions between central and autonomic nervous systems are important for characterizing personality and emotions.

Intrathecal morphine administration reduces postoperative pain and peripheral endocannabinoid levels in total knee arthroplasty patients: a randomized clinical trial.

Abstract: The primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain. The secondary goal was to determine the effect of intrathecal morphine upon circulating levels of the weakly analgesic endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the related lipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Forty two total knee arthroplasty (TKA) patients were enrolled in a prospective, double-blinded, randomized study. The intervention consisted of intrathecal morphine (200 μg) or placebo administered at the time of the spinal anesthesia. Postoperative pain was measured during the first 4 h after surgery while serum levels of AEA, 2-AG, PEA, OEA, and cortisol were measured at baseline and 4 h after surgery. Administration of intrathecal morphine reduced postoperative pain 4 h after TKA surgery compared to placebo (p = 0.005) and reduced postoperative systemic opioid consumption (p = 0.001). At baseline, intrathecal morphine led to a significant reduction in AEA, 2-AG, and OEA levels but did not affect PEA or cortisol levels. In patients administered intrathecal placebo, 2-AG levels were elevated 4 h after surgery; whereas patients receiving intrathecal morphine showed reductions in AEA, PEA, and OEA when compared to placebo. At 4 h after TKA surgery cortisol levels were significantly elevated in the placebo group and reduced in those receiving morphine. These results indicate that intrathecal morphine reduces postoperative pain in TKA patients. Furthermore, activation of central opioid receptors negatively modulates the endocannabinoid tone, suggesting that potent analgesics may reduce the stimulus for production of peripheral endocannabinoids. This study is the first to document the existence of rapid communication between the central opioid and peripheral endocannabinoid systems in humans. This trial was registered retrospectively. Trial registry: NCT02620631 . Study to Examine Pain Relief With Supplemental Intrathecal Morphine in TKA Patients, NCT02620631 , 12/03/2015.

Disrupted topological organization of the frontal-mesolimbic network in obese patients

Abstract: Neuroimaging studies have revealed brain functional abnormalities in frontal-mesolimbic regions in obesity. However, the effects of obesity on brain network topology remains largely unknown. In the current study, we employed resting-state functional magnetic resonance imaging and graph theory methods to investigate obesity-related changes in brain network topology in 26 obese patients and 28 normal weight subjects. Results revealed that the whole-brain networks of the two groups exhibited typical features of small-world topology. Obese patients showed significantly increased shortest path length (Lp) and decreased global efficiency (Eglob). Moreover, decreased nodal-degree/efficiency was found in frontal (medial orbitofrontal cortex-mOFC, rostral anterior cingulate cortex-rACC), striatal (caudate/nucleus accumbens) and limbic regions (insula, amygdala, hippocampus/parahippocampal gyrus) and thalamus in obese patients. Network-based statistics showed that a sub-network, composed of 31 nodes and 30 edges, was significantly disrupted in obese patients; 29 out of 30 connections were associated with the right rACC. In the obese group, Lp and Eglob were negatively correlated with body mass index (BMI, P < 0.005), and BMI was negatively correlated with nodal-degree/efficiency of the mOFC (P < 0.001). Findings suggest disruption of the small-world organization and a global reduction of integration of functional brain networks involving the right rACC in obesity and implicating the mOFC in mediating severity.

Preclinical Evaluation of the First Adenosine A1 Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

Abstract: Central adenosine A1 receptor (A1R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A1R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A1R during the sleep–awake cycle. Although several human A1R PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored non-nucleoside (3,5-dicyanopyridine and 5-cyanopyrimidine) templates for developing an agonist A1R PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxyphenyl)-6-(2-(6-methylpyridin-2-yl)ethyl)pyridine-3,5-dicarbonitrile (MMPD, 22b), a partial A1R agonist of sub-nanomolar affinity. [11C]22b showed suitable blood–brain barrier (BBB) permeability and test–retest reproducibility. Regional brain uptake of [11C]22b was consistent with known brain A1R...

Neuroethics for the National Institutes of Health BRAIN Initiative.

Abstract: ### Background on the National Institutes of Health BRAIN Initiative and neuroethics The National Institutes of Health (NIH) works tirelessly to support the best science and ensure that its funded research adheres to the highest ethical standards. From its inception, the NIH Brain Research through