Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

临床精神神经内分泌学和神经精神药理学（CPN）

• 批准号: 10699667
• 负责人: Lorenzo Leggio
• 金额: $ 253.54万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699667
• 关键词: Addictive Behavior; Address; Affinity; Alcohol consumption; Alcohol dependence; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Aldosterone; Amino Acid Substitution; Amygdaloid structure; Animal Model; Arrestins; Attention; Autopsy; Beds; Behavior; Binding; Biological; Biological Assay; Biological Factors; Brain; Brain imaging; Butyric Acids; California; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cocaine; Cohort Studies; Collaborations; Complex; Cues; Data; Data Analyses; Data Collection; Development; Disease; Disulfiram; Dopamine; Dose; Drug Kinetics; Electrophysiology (science); Elements; Endorphins; Environmental Risk Factor; Enzymes; Etiology; Euphoria; Exposure to; Feeling; Functional Magnetic Resonance Imaging; GHS-R1a; Genetic Variation; Genetic study; Glutamates; Heavy Drinking; Hippocampus (Brain); Human; Individual; Injections; Inositol; Inpatients; Institutes; Intake; Intervention; Intramuscular; Investigation; Joints; Knock-out; Laboratories; Lead; Leptin; Light; Liver; Messenger RNA; Mineralocorticoid Receptor; Mineralocorticoids; Mus; Naltrexone; Names; National Institute of Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurosecretory Systems; Neurotransmitters; Nucleus Accumbens; Oral; Outcome; Outpatients; Oxycodone; Oxytocin; Parents; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phase; Physiological; Play; Positron-Emission Tomography; Preparation; Procedures; Psychiatry; Psychoneuroendocrinology; Rattus; Reducing Agents; Reporting; Research; Research Institute; Rewards; Rodent; Role; Route; Scientist; Self Administration; Series; Serotonin; Severities; Signal Pathway; Spironolactone; Substance Use Disorder; Surveys; System; Tablets; Techniques; Testing; United States Food and Drug Administration; United States National Institutes of Health; Work; acamprosate; addiction; alcohol craving; alcohol misuse; alcohol seeking behavior; alcohol use disorder; analog; antagonist; bariatric surgery; behavioral pharmacology; binge drinking; dopaminergic neuron; drinking; drinking behavior; drug seeking behavior; experimental study; feeding; food craving; ghrelin; glucagon-like peptide 1; gut microbiome; gut microbiota; gut-brain axis; high dimensionality; high throughput screening; imaging genetics; improved; inhibitor; innovation; interest; microbiota-gut-brain axis; neuropsychopharmacology; novel; optogenetics; pleasure; pre-clinical; primary care setting; psychosocial; radioligand; receptor; recruit; response; safety assessment; safety testing; secondary analysis; substance use treatment; translational study; transmission process; vapor

The joint NIDA-NIAAA CPN Section conducts translational and clinical studies to identify possible novel medications for addiction. We are particularly interested in understanding the role of the gut-liver-brain axis and other peripheral-central mechanisms underlying alcohol use and their potential role as novel pharmacotherapeutic targets. This report summarizes work conducted in the CPN section, including collaborative efforts with many other scientists in the NIDA IRP, other NIH Institutes, as well as with academic centers. The ghrelin system might represent a novel pharmacological target for AUD treatment. To test whether GHS-R1a blockade may represent a pharmacotherapy for AUD, we developed a translational project to assess the effect of a GHS-R1a blocker, PF-5190457. In addition to safety assessments and pharmacokinetic characterization in rodents, we conducted a Phase 1b clinical study and showed that PF-5190457, co-administered with alcohol, is safe, tolerable and does not affect alcohol pharmacokinetics (Lee et al., Mol Psychiatry 2020). We also completed a Phase 2a clinical study to assess the efficacy of this compound in reducing alcohol craving and its potential effects on food craving/choices in patients with AUD (data analysis ongoing). By using a reverse translational bed-to-bench approach, we discovered a major metabolite of PF-5190457, named PF-6870961 (Adusumalli et al., Drug Metab Dispos. 2019). We further evaluated potential off-target binding of PF-6870961 through a radioligand binding high-throughput screen; no off-target binding of PF-6870961 was shown for any of the 84 targets evaluated. We also found that PF-6870961 binds to GHS-R1a, albeit with weaker affinity than the parent compound. Dose-dependent inhibition of the GOAT enzyme was not observed for either PF-6870961 or PF-5190457. Finally, the inhibition potency of PF-6870961 and PF-5190457 were evaluated using inositol trisphosphate (IP3) and -arrestin mobilization assays. PF-5190457 and PF-6870961 inhibit IP3 mobilization, with higher EC50 values than LEAP-2 (a recently discovered endogenous ghrelin antagonist) for both constitutive GHS-R1a and ghrelin-activated receptor activity. For -arrestin assays, the opposite was observed, with PF-5190457 and PF-6870961 having lower EC50 values than LEAP-2, suggesting improved activity through this signaling pathway (Deschaine et al., under review). As a way of targeting the ghrelin system with a different approach, we also started another clinical protocol to test the safety and efficacy of a GOAT inhibitor in non-treatment-seeking individuals with (recruitment ongoing). Beyond alcohol, we recently showed that acquisition of either cocaine or oxycodone self-administration in rats is associated with increased peripheral ghrelin levels and with upregulated GHS-R1a mRNA levels in dopamine neurons in the VTA. Additionally, systemic injections of the GHS-R1a antagonist JMV2959 decreased both cocaine and oxycodone self-administration in wild-type, but not GHS-R1a knock-out, rats. We also found that JMV2959 injection decreases cue-induced reinstatement of oxycodone and cocaine seeking, and brain stimulation reward, maintained by optogenetic stimulation of VTA dopamine neurons, or enhancement of this effect by cocaine (You et al., Neuropsychopharmacology 2021; Mol Psychiatry 2022). We are also investigating other gut-brain and peripheral-central neuroendocrine pathways in relation to alcohol use and addictive behaviors. Following on our early work (Suchankova et al., Transl Psychiatry 2015), we conducted an imaging-genetics study and found that genetic variation at the GLP-1R, i.e., two missense SNPs that result in amino-acid substitutions and putative changes in the GLP-1R were differentially associated with within-network brain functional connectivity among individuals with high versus low severity of alcohol use (Farokhnia, Fede et al., Sci Rep 2022). We also performed a series of secondary analyses and found that alcohol intake, with different doses and routes of administration (oral and IV) reduced peripheral GLP-1 levels in heavy-drinking individuals with AUD. In a human postmortem brain study, fold change of GLP-1R mRNA in hippocampus was significantly higher in individuals with AUD, compared to controls, and a less robust effect, but in the same direction, was found in PFC (Farokhnia et al., Addict Biol 2022). These data, along with previous rodent work, suggest that targeting the GLP-1 system may represent a novel pharmacotherapy for AUD. Following our previous work testing long-acting GLP-1 analogues in animal models of alcohol use (Marty, Farokhnia, et al., Front Neurosci 2020), we conducted a set of experiments and found that semaglutide dose-dependently decreased alcohol binge drinking (drinking-in-the dark) in mice and reduced operant alcohol self-administration in both alcohol-dependent and non-dependent rats. In collaboration with Scripps Research Institute, we have also conducted electrophysiology work to shed light on the effects semaglutide on GABA transmission in the central amygdala and infralimbic cortex of nave and alcohol-dependent rodents (Chuong, Farokhnia, Khom, et al., in preparation). Following up on our early translational work showing that the aldosterone/mineralocorticoid system is involved in alcohol seeking and related outcomes (Aoun et al., Mol Psychiatry 2018), we have started to investigate this neuroendocrine system as a potential pharmacotherapeutic target for AUD. In collaboration with Kaiser Permanente North California, we conducted a retrospective high-dimensional propensity score-matched cohort study showing that dispensation of the MR antagonist spironolactone was associated with significant reduction in weekly alcohol use, with a significant dose-response (Palzes et al., Neuropsychopharmacology 2021). In a series of rodent experiments, we demonstrated that spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in mice (drinking-in-the-dark) and suppressed operant alcohol self-administration in dependent and nondependent rats (vapor exposure). In a second and much larger/longer pharmacoepidemiologic cohort study, we found a greater reduction in AUDIT-C scores among those who received spironolactone (for at least 60 days), compared to propensity-score matched controls. The largest effects were among those who reported hazardous alcohol consumption at baseline (AUDIT-C 8) and those exposed to 50 mg/day of spironolactone (Farokhnia, Rentsch, Chuong, McGinn et al., Mol Psychiatry 2022). We have also continued our work on non-pharmacological elements of the gut-brain axis in relation to alcohol use, including a recently completed clinical protocol (17-AA-0093) on gut microbiome in AUD (data analysis ongoing) and a nationwide survey study aimed at understanding the role and correlates of bariatric surgery in relation to AUD and other addictive behaviors (data collection ongoing).

NIDA-NIAAA联合CPN部分进行转化和临床研究，以确定可能成瘾的新药物。我们特别有兴趣了解肠道脑轴和其他饮酒的其他中央中心机制的作用及其作为新型药物治疗靶标的潜在作用。该报告总结了CPN部分进行的工作，包括与NIDA IRP的许多其他科学家，其他NIH机构以及学术中心的合作努力。 生长素蛋白系统可能代表了AUD治疗的新型药理学靶标。为了测试GHS-R1A封锁是否代表AUD的药物治疗，我们开发了一个转化项目，以评估GHS-R1A阻滞剂PF-5190457的效果。除了在啮齿动物中的安全评估和药代动力学表征外，我们还进行了1B期临床研究，并表明PF-5190457与酒精共同管理，是安全的，可容忍的，并且不影响酒精药代动力学（Lee等人，Mol。，Mol Chepth.2020）。我们还完成了一项2A期临床研究，以评估该化合物在减少酒精渴望及其对AUD患者食品渴望/选择的潜在影响（正在进行的数据分析）中的潜在影响。 通过使用反向翻译床到台式方法，我们发现了PF-5190457的主要代谢物，称为PF-6870961（Adusumalli等人，Drug MetabDispos。2019）。我们进一步评估了PF-6870961通过放射性结合的高通量屏幕的潜在靶向结合；对于评估的84个目标中的任何一个，尚未显示PF-6870961的靶向脱靶结合。我们还发现，PF-6870961与GHS-R1A结合，尽管亲和力弱于母体化合物。对于PF-6870961或PF-5190457，均未观察到剂量依赖性山羊酶的抑制作用。最后，使用肌醇三磷酸（IP3）和-Arrestin动员测定法对PF-6870961和PF-5190457的抑制作用进行了评估。 PF-5190457和PF-6870961抑制IP3动员，EC50值高于LEAP-2（最近发现的内源性生长素蛋白拮抗剂），用于组成型GHS-R1A和GHRELIN激活的受体活性。对于-arrestin分析，观察到相反的情况，PF-5190457和PF-6870961的EC50值低于LEAP-2，这表明通过此信号传导途径改善了活性（Deschaine等人，综述）。 作为针对生长素蛋白系统采用不同方法的一种方式，我们还启动了另一种临床方案，以测试山羊抑制剂在非治疗的寻求治疗的人（正在进行的招募）中的安全性和功效。 除了酒精之外，我们最近表明，大鼠中可卡因或羟考酮自我给药的获取与VTA中多巴胺神经元中的外周生长素水平增加以及上调的GHS-R1A mRNA水平有关。此外，对GHS-R1A拮抗剂JMV2959的全身注射降低了可卡因和羟考酮在野生型中的自我给药，但不降低GHS-R1A敲除大鼠。我们还发现，JMV2959的注射降低了提示诱导的羟考酮和可卡因寻求的恢复原状，以及通过光遗传学刺激VTA多巴胺神经元维持的脑刺激奖励，或可卡因对这种作用增强这种作用（You等，Neuropsyperopsyperpopharmacologology 20221; Mol Psicty20222222222）。 我们还研究了与酒精使用和成瘾行为有关的其他肠道和外围中心神经内分泌途径。 Following on our early work (Suchankova et al., Transl Psychiatry 2015), we conducted an imaging-genetics study and found that genetic variation at the GLP-1R, i.e., two missense SNPs that result in amino-acid substitutions and putative changes in the GLP-1R were differentially associated with within-network brain functional connectivity among individuals with high versus low severity of alcohol use (Farokhnia, Fede et al., Sci Rep 2022）。我们还进行了一系列二次分析，发现酒精摄入量不同，剂量和给药途径（口服和IV）降低了饮用AUD的人的外围GLP-1水平。在人类术后脑研究中，与对照组相比，AUD的个体中，海马中GLP-1R mRNA的折叠变化明显更高，并且在PFC中发现了较不强大的效果，但在同一方向上发现了PFC（Farokhnia等人，AddictBiol。20222222）。这些数据以及先前的啮齿动物工作表明，针对GLP-1系统可能代表了AUD的新药物疗法。在我们先前的工作测试酒精使用模型（Marty，Farokhnia等，前神经洛西2020）中的长效GLP-1类似物之后，我们进行了一组实验，发现Semaglutide剂量依赖性地降低了酒精暴饮暴食（黑暗中的酒精饮酒（深色饮酒），在小鼠中饮酒和饮酒中的饮酒依赖性依赖性依赖性依赖性依赖性rate。与Scripps研究所合作，我们还进行了电生理学工作，以阐明semaglutide对中央杏仁核中心和依赖酒精依赖啮齿动物的Infralimbic Cortex（Chuong，Chuong，Farokhn，Farokhn，Khom，Khom等）的影响。 跟进我们的早期翻译工作，表明醛固酮/矿物皮质激素系统参与了酒精和相关结果（Aoun等，Mol Psychiatry 2018），我们已经开始研究该神经内分泌系统，作为AUD的潜在药物治疗靶标。与Kaiser Permanente North California合作，我们进行了回顾性的高维得分匹配的队列研究，表明MR拮抗剂螺内酯的分配与每周酒精使用的显着降低相关，并具有显着的剂量反应（Palzes等人，神经性心理吸气学2021）。在一系列的啮齿动物实验中，我们证明了螺内酯剂量依赖性地降低了小鼠（在黑暗中饮酒）中的甜或未加糖的酒精溶液的摄入，并抑制了依赖和非依赖性大鼠（蒸气暴露）中的作战剂饮酒自我给药。在第二次和更大/更长/更长的药物ePidemiologic COHORT研究中，与倾向得分匹配的对照相比，接受螺内酯的人（至少60天）的审计-C分数降低了。最大的影响是在基线时报告危险饮酒（审计-C 8）和暴露于50 mg/天的螺内酯（Farokhnia，Rentsch，Chuong，Chuong，McGinn等人，Mol Psychiatry 2022）的人中。 我们还继续研究与饮酒有关的肠脑轴的非药理元素，包括最近在AUD（正在进行的数据分析）和一项旨在了解Bariatric Hervery与Aud to Aud conteriate and Auding Cantict and Data Canditive Candive Activative Candies（数据分析）中（正在进行的数据分析）对肠道微生物组的最近完成的临床方案（17-AA-0093）。