Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

临床精神神经内分泌学和神经精神药理学（CPN）

基本信息

批准号：
10253684
负责人：
Lorenzo Leggio
金额：
$ 181.32万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
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/10253684
关键词：
Addictive Behavior Address Agonist Alcohol consumption Alcohol dependence Alcoholic beverage heavy drinker Alcoholism Alcohols Aldosterone Animal Model Animals Antiinflammatory Effect Anxiety Attention Award Beds Behavior Behavioral Biological Biological Factors Biology Blood Brain Brain imaging Brain-Derived Neurotrophic Factor Butyric Acids Cannabis Clinical Clinical Research Clinical Trials Cocaine Cognitive Collaborations Communication Complex Cues Data Analyses Desire for food Development Disease Disulfiram Doctor of Medicine Doctor of Philosophy Dopamine Dose Drug Addiction Endocrine Endorphins Environmental Risk Factor Equipment and supply inventories Etiology Euphoria Feeling Food Foundations Functional Magnetic Resonance Imaging GHS-R1a Glutamates Grant Heavy Drinking Hormones Human Hydrocortisone Individual Inflammatory Inpatients Insulin Intervention Intramuscular Investigation Joints Label Laboratories Lead Leadership Leptin Light Liver Macaca mulatta Metabolism MicroRNAs Mineralocorticoid Receptor Modeling Modification Molecular Naltrexone National Institute of Drug Abuse National Institute on Alcohol Abuse and Alcoholism Nature Neurobiology Neuroimmune system Neuropharmacology Neurosecretory Systems Neurotransmitters Nucleus Accumbens Obsessive compulsive behavior Oral Outcome Outpatients Oxytocin Pancreatic Polypeptide Papio Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Pharmacology Pharmacotherapy Phase Physiological Placebos Play Positron-Emission Tomography Procedures Prolactin Protocols documentation Psychiatry Psychoneuroendocrinology Publishing Rattus Reducing Agents Reporting Research Rewards Rhode Island Ritalin Role Route Safety Sampling Self Administration Serotonin Serum Smoke Substance Use Disorder System Tablets Techniques Testing United States Food and Drug Administration United States National Institutes of Health Universities Vaccines Work acamprosate addiction alcohol craving alcohol misuse alcohol seeking behavior alcohol use disorder bariatric surgery base behavioral pharmacology binge drinking brain research craving drinking drinking behavior drug of abuse drug seeking behavior feeding food craving ghrelin ghrelin receptor glucagon-like peptide 1 gut microbiome gut microbiota hypothalamic-pituitary-adrenal axis improved inflammatory marker innovation interest metabolomics microbiota-gut-brain axis neuropsychiatric disorder neuropsychopharmacology novel pleasure pre-clinical preclinical study primary care setting psychosocial reduced alcohol use response secondary analysis systematic review trait translational study vapor

项目摘要

The joint NIDA-NIAAA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical inpatient and outpatient studies to identify possible novel medications for addiction. Under the leadership of Lorenzo Leggio, M.D., Ph.D., the CPN team is particularly interested in the role of the gut-liver-brain axis in alcohol-seeking behaviors. Both preclinical and human approaches are in progress or under development to shed light on the possible role of the gut-liver-brain axis in alcohol and substance use disorders. Evidence from preclinical and clinical studies suggest that the ghrelin system, might represent a novel pharmacological target for treatment (reviewed in: Zallar et al. 2017; Morris et al., 2018; Farokhnia et al., 2019). Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use has never been tested in humans. To test this hypothesis, the CPN Section developed a translational project to assess the role of a GHS-R1a antagonist manufactured by Pfizer as a novel medication for AUD. This project was developed in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from the University of Rhode Island and was awarded with a NCATS grant award (UH2/UH3 TR000963) to partially support this project. First, a Phase 1b clinical study (protocol 14-AA-0042) was completed and published, indicating that this GHS-R1a inverse agonist is safe and tolerable, when co-administered with alcohol and does not affect alcohol PK. Very preliminary results also suggested that this compound reduces alcohol- and food-cue induced cravings in our bar-lab (Lee et al., Molecular Psychiatry 2020). A secondary analysis from the same study also indicates that this novel compound is safe on endocrine-related outcomes and its effects on some hormone levels suggest potential mechanisms requiring further investigation (Lee et al., Neuropharmacology 2020). Furthermore, by using a reverse translational bed-to-bench approach, we discovered a major metabolite of this novel compound (Adusumalli et al., Drug Metab Dispos. 2019) and additional work on this metabolite is ongoing. Based on these promising findings, we moved to the next phase of the project and completed a Phase 2a clinical study (protocol 16-AA-0080) to assess the efficacy of this novel GHS-R1a inverse agonist in reducing alcohol craving and its potential effects on food craving/choices in treatment-seeking patients with AUD. This study was completed and data analysis is ongoing. We are continuing work on the effects of IV ghrelin on a variety of behavioral and neuroendocrine outcomes in AUD individuals. Consistent with the complex interplay between ghrelin, addiction and the HPA axis (which we reviewed in Morris et al., 2018), we reported that, compared to placebo, IV ghrelin leads to an increase in cortisol and aldosterone blood levels (Haass-Koffler et al., Neuropharmacology 2019). Furthermore, we recently completed a comprehensive neuroendocrine analysis of our IV ghrelin study conducted the the NIH IRP (see Farokhnia et al., Molecular Psychiatr 2018), showing that IV ghrelin, compared to placebo, increased blood levels of glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), cortisol, prolactin, and aldosterone, and decreased blood levels of leptin and insulin in heavy drinking individuals with alcohol dependence who also received IV alcohol (Farokhnia et al., under review). Considering the well-established interplay between the ghrelin system and inflammatory pathways, as well as the role of the neuroimmune system in AUD, we also evaluated the effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals. Results found profound anti-inflammatory effects for IV ghrelin, but effects for ghrelin receptor blockade, confirming the safety of the GHS-R1a inverse agonist compound (Farokhnia et al., Brain Research 2020). Consistent with our increasing interest in the crosstalk between alcohol use and inflammatory pathways, we also acquired and analyzed samples from two previously conducted studies in AUD patients and healthy controls, and found that peripheral proinflammatory markers are upregulated in abstinent alcohol-dependent patients but are not affected by cognitive bias modification (Portelli et al., Drug and Alcohol Dependence 2019). We have also continued our work on oxytocin as another endocrine target involved in addictive behaviors. In collaboration with Dr. Tanda (NIDA IRP MDP), we recently completed a study on the effect of systemically administered oxytocin on dose response for methylphenidate self-administration and mesolimbic dopamine levels (Lee et al., Ann N Y Acad Sci. 2019). In another study, we recently showed, in collaboration with Dr. Kathleen Grant (OHSU), that labeled oxytocin, administered via the intranasal route, reaches the brain in rhesus macaques (Lee et al., Nature Communications 2020). Expanding our work on neuroendocrine correlates of alcohol use, we also conducted, in collaboration with Dr. Dorit Ron (UCSF), a translational study in rats and humans, looking at brain-derived neurotrophic factor (BDNF) in relation to alcohol use. We found that serum BDNF levels are negatively correlated with alcohol intake in both rats with rapid and late onset of heavy alcohol, but increased expression of the micro RNAs targeting BDNF was detected only in the rapid onset rats (Ehinger et al., Addiction Biology 2020). We also found that, among non-treatment-seeking individuals with alcohol dependence and high trait anxiety, serum BDNF concentrations were negatively correlated with average drinks per drinking days and positively correlated with obsessive compulsive drinking scale and state-trait anxiety inventory scores (Portelli, Farokhnia, et al., Alcohol 2020). We have also expanded our focus on psychoneuroendocrinology to other drugs of abuse beyond alcohol. In addition to our previous work on neuroendocrine effects of IV cocaine (Bouhlal et al., Drug and Alcohol Dependence 2017), we recently looked at the effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism. In collaboration with Dr. Marilyn Huestis (NIDA IRP), we found that cannabis administration significantly reduced blood insulin and GLP-1 concentrations (Farokhnia et al., Translational Psychiatry 2020). Finally, in collaboration with Dr. Kim Janda (TSRI), and using a ghrelin vaccine and a GHS-R1a antagonist, we showed that the influence of the ghrelin receptor on cocaine reward is not directly dependent on peripheral acyl-ghrelin (Wenthur et al., Scientific Reports 2019). Increasing evidence suggests a role of the gut microbiota in neuropsychiatric disorders. A systematic review conducted by our team (Temko et al., Alcohol and Alcoholism 2017) indicates that the understanding of the role of the gut microbiota in AUD is very limited and deserves additional investigation. Therefore, the CPN lab developed a translational and clinical project to investigate the role of the gut microbiota in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. This clinical study (17-AA-0093) was completed and data analysis is ongoing. In parallel, we are conducting a study investigating the gut microbiome and metabolomics in a baboon model of binge-drinking -- a model developed by Dr. Elise Weerts at JHU. This project is in fact in collaboration with Dr. Weerts (JHU) and Dr. Fraser (UMB) and analyses are under way.

NIDA NIAAA联合关于临床心理内分泌学和神经心理药理学（CPN）的联合部分进行了转化和临床住院和门诊研究，以识别可能成瘾的新药物。在医学博士Lorenzo Leggio博士的领导下，CPN团队对肠道脑轴在寻求酒精的行为中的作用特别感兴趣。临床前和人类方法都在进行或正在发展，以阐明肠道 - 脑轴在酒精和物质使用障碍中的可能作用。临床前和临床研究的证据表明，生长肽系统可能代表了治疗的新药理靶标（审查：Zallar等人，2017年； Morris等，2018； Farokhnia等，Farokhnia等，2019）。与动物研究相反，关于GHS-R1A拮抗作用的假设导致降低的酒精使用量从未在人类中进行测试。为了检验这一假设，CPN部分开发了一个转化项目，以评估辉瑞制造的GHS-R1A拮抗剂作为AUD的新药物的作用。该项目是与罗德岛大学（University of Rhode Island）的Pharm.D.Fatemeh Akhlaghi合作开发的，并获得了NCATS赠款奖（UH2/UH3 TR000963）的授予，以部分支持该项目。首先，完成并发表了一项1B期临床研究（方案14-AA-0042），表明该GHS-R1A逆激动剂是安全可容忍的，当时与酒精共同管理并且不影响酒精PK。非常初步的结果还表明，这种化合物降低了酒精含量的酒精和食物 - 诱导的渴望（Lee等人，分子精神病学2020年）。同一研究的次要分析还表明，这种新颖的化合物在与内分泌相关的结果上是安全的，其对某些激素水平的影响表明需要进一步研究的潜在机制（Lee等，Neuropharmacology 2020）。此外，通过使用反向翻译的床到台式方法，我们发现了这种新型化合物的主要代谢物（Adusumalli等人，药物MetabDispos。2019），并且对这种代谢产物进行了其他工作。基于这些有希望的发现，我们转到了项目的下一个阶段，并完成了一项2A期临床研究（方案16-AA-0080），以评估这款新型GHS-R1A反向激动剂在减少酒精渴望及其对aud治疗患者中对食物渴望/选择的潜在影响的疗效。这项研究完成了，数据分析正在进行中。我们正在继续研究IV生长素素对AUD个体中各种行为和神经内分泌结果的影响。与生长素蛋白，成瘾和HPA轴之间的复杂相互作用（在Morris等人，2018年进行了回顾），我们报告说，与安慰剂相比，IV ghrelin相比，IV摄氏菌素会导致皮质醇和醛固酮血液水平的升高（Haass-Koffler等人，Haass-Koffler等，Neuropharmopharmanolopology 2019）。 Furthermore, we recently completed a comprehensive neuroendocrine analysis of our IV ghrelin study conducted the the NIH IRP (see Farokhnia et al., Molecular Psychiatr 2018), showing that IV ghrelin, compared to placebo, increased blood levels of glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), cortisol, prolactin, and aldosterone,并降低了饮酒依赖性的瘦饮酒者的血液水平和胰岛素的血液水平，他们也接受了静脉输液（Farokhnia等人，正在审查中）。考虑到生长素蛋白系统与炎症途径之间的良好相互作用，以及神经免疫系统在AUD中的作用，我们还评估了外源性生长素蛋白给药和生长素受体阻断的影响，与酒精结合使用，与酒精相结合，对沉重饮用的个体中外周炎症标记。结果发现，IV生长素素的深刻抗炎作用，但对生长素释放蛋白受体阻断的作用，证实了GHS-R1A逆激动剂化合物的安全性（Farokhnia等人，脑研究2020年）。与我们对酒精使用和炎症途径之间的串扰息息相关的兴趣不断增强，我们还从先前在AUD患者和健康对照组中进行的两项研究的研究中获取并分析了样本，发现外周促炎标记物在戒酒依赖性的酒精依赖性患者中受到上调，但未受到认知偏见的影响（Portelli Etelli Et e等。我们还继续研究催产素，作为成瘾行为涉及的另一个内分泌靶标。与Tanda博士（NIDA IRP MDP）合作，我们最近完成了一项研究，研究了系统施用的催产素对哌醋甲酯自我给药和中羟胺多巴胺水平的剂量反应的影响（Lee等人，Ann N Y AcadSci。2019）。在另一项研究中，我们最近与凯瑟琳·格兰特（Kathleen Grant）（OHSU）的合作表明，通过鼻内途径给药的催产素标记为催产素，该途径在恒河猴中到达大脑（Lee等人，自然通讯2020）。扩大了我们在饮酒的神经内分泌相关性方面的研究，我们还与Dorit Ron博士（UCSF）合作，这是一项针对大鼠和人类的转化研究，研究与酒精使用有关的脑源性神经营养因子（BDNF）。我们发现，两只大鼠的血清BDNF水平与酒精的快速发作和较晚的饮酒均与酒精摄入负相关，但是仅在快速发作大鼠中检测到微RNA靶向BDNF的表达增加（Ehinger等人，成瘾生物学2020）。我们还发现，在没有酒精依赖性和高性状焦虑的非治疗的个体中，血清BDNF浓度与每个饮酒日的平均饮料负相关，并且与强迫性饮酒量表和状态特质焦虑量表呈正相关（Portelli，Portelli，Portelli，Farokhnia等）。我们还将关注心理内分泌学的关注扩展到了其他虐待药物以外的其他滥用药物。除了我们先前关于静脉可卡因神经内分泌作用的工作（Bouhlal等人，药物和酒精依赖2017），我们最近研究了口服，熏制和蒸发大麻对与食欲和代谢相关的内分泌途径的影响。与玛丽莲·霍斯蒂斯（Marilyn Huestis）（NIDA IRP）合作，我们发现大麻给药可显着降低血液胰岛素和GLP-1浓度（Farokhnia等人，转化精神病学2020年）。最后，与金·贾达（Kim Janda）（TSRI）博士合作，使用生长素蛋白疫苗和GHS-R1A拮抗剂，我们表明，生长素蛋白受体对可卡因奖励的影响并不直接依赖于外周酰基酰基 - 基因（Genthur ethur）（Wenthur等人（Wenthur等），科学报告，2019年）。越来越多的证据表明肠道菌群在神经精神疾病中的作用。我们的团队进行的系统审查（Temko等人，酒精和酒精中毒2017）表明，对肠道菌群在AUD中的作用的理解非常有限，值得进行额外的研究。因此，CPN实验室开发了一个翻译和临床项目，以研究肠道菌群在AUD中的作用。 Leggio博士获得了Peter G. Dodge基金会的赠款奖，以部分支持这项研究。这项临床研究（17-AA-0093）已经完成，并且正在进行数据分析。同时，我们正在进行一项研究，该研究研究了暴饮暴食的狒狒模型中的肠道微生物组和代谢组学 - 由JHU的Elise Weerts博士开发的模型。该项目实际上是与Weerts博士（JHU）和Fraser博士（UMB）合作的，并且正在进行分析。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Call to Action: Alcohol Interventions in HIV-Infected Patients.

行动呼吁：艾滋病毒感染者的酒精干预。

DOI：
10.3389/fpsyt.2012.00035
发表时间：
2012
期刊：
Frontiers in psychiatry
影响因子：
4.7
作者：
Leggio,Lorenzo;Promrat,Kittichai;Kenna,GeorgeA
通讯作者：
Kenna,GeorgeA

Erratum to: a preliminary double-blind, placebo-controlled randomized study of baclofen effects in alcoholic smokers.

勘误表：一项关于巴氯芬对酗酒者影响的初步双盲、安慰剂对照随机研究。

DOI：
10.1007/s00213-015-3916-z
发表时间：
2015
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Leggio,Lorenzo;Zywiak,WilliamH;Edwards,StevenM;Tidey,JenniferW;Swift,RobertM;Kenna,GeorgeA
通讯作者：
Kenna,GeorgeA

Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment.

酒精依赖个体对 GABA-B 受体激动的神经内分泌反应：门诊和人体实验室联合实验的结果。

DOI：
10.1016/j.neuropharm.2018.04.011
发表时间：
2018
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Farokhnia,Mehdi;Sheskier,MikelaB;Lee,MaryR;Le,AprilN;Singley,Erick;Bouhlal,Sofia;Ton,Timmy;Zhao,Zhen;Leggio,Lorenzo
通讯作者：
Leggio,Lorenzo

Combined pharmacotherapies for the management of alcoholism: rationale and evidence to date.

治疗酒精中毒的联合药物疗法：迄今为止的基本原理和证据。