Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

NIAA-NIDA临床精神神经内分泌学和神经精神药理学联合部门（CPN）进行转化和临床门诊和住院研究，以确定可能的新型成瘾药物。在Lorenzo Leggios博士的领导下，CPN团队对肠-肝-脑轴在饮酒行为中的作用特别感兴趣。临床前和人类方法都在进行中或正在开发中，以阐明肠-肝-脑轴在酒精使用障碍（AUD）中的可能作用。 巴氯芬已被确定为一种可能的药物，能够减少酒精依赖者的酒精渴望和摄入量。临床前和临床研究表明，巴氯芬在减少酒精渴望和摄入方面是有效的（综述：Farokhnia等人出版）。然而，一项试验发现了强有力的治疗效果，但巴氯芬和安慰剂之间没有差异（Garbutt等人，2010年）。这表明酗酒者可能对巴氯芬有不同的反应，例如，焦虑水平较高的患者可能对巴氯芬反应更好（Leggio等人，2010年）。因此，CPN部门制定了一项临床方案（13-AA-0040），以测试巴氯芬对具有高焦虑水平的酒精相关结果的作用。设计为受试者间随机双盲对照研究，以药物治疗条件作为受试者间因素。Leggio博士获得了大脑和行为研究基金会的NARSAD奖，以部分支持这项研究。数据分析和手稿准备（Farokhnia等人）正在进行中。 动物实验表明，中枢生长激素释放肽给药不仅刺激奖赏处理，而且也是酒精刺激该系统所必需的（Jerlhag et al.，2009; Suchankova等人，2013年）的报告。人体研究表明，生长激素释放肽水平和酒精渴望分数之间存在正相关性，静脉注射生长激素释放肽会急剧增加患有AUD的个体的酒精渴望。总之，临床前和临床研究表明，生长激素释放肽可能代表一种新的治疗药理学靶点（综述于：Leggio，2010）。一项受试者内、双盲、安慰剂对照人体实验室研究（方案13-AA-0043）由CPN科开发，以研究与安慰剂相比，IV生长激素释放肽是否增加酒精奖励的动机，如通过IV酒精自我输注的渐进比率时间表范例所测量的;以及与安慰剂相比，静脉注射饥饿素是否会增加功能性磁共振成像期间腹侧纹状体中BOLD的激活。 与动物研究相反，GHS-R1 a拮抗作用导致酒精使用减少的假设从未在人类中进行过测试。为了检验这一假设，CPN部门开发了一个翻译项目，以评估辉瑞公司生产的GHS-R1 a拮抗剂作为一种新型酒精中毒药物的作用。该项目是与Fatemeh Akhlaghi，Pharm.D.合作开发的，哲学博士、来自罗得岛大学，最近被授予NCATS补助金（UH 2/UH 3 TR 000963），以部分支持该项目。该项目在Leggios博士领导下在NIH内部研究项目中进行;药代动力学（PK）/药效学（PD）研究在Akhlaghis博士实验室中进行。一项Ib期临床研究（方案14-AA-0042）已完成，最近开始了一项IIa期临床研究（方案16-AA-0080）。 最近的研究表明，催产素（OT）可能在AUD的神经生物学中发挥作用。在动物中，OT给药可长期减少酒精强化，减少戒酒期间的酒精寻求，减弱药物耐受性，并减少戒断症状（Lee et al. 2016综述）。Dr.玛丽李，在博士临床工作人员Leggios CPN部分，被授予NIH B2B补助金奖（2014-2015），以部分支持这个项目。与NIDA和NIMH基础科学家合作的临床前工作即将完成。CPN部门开发的临床研究（方案16-AA-0082）计划很快开始。 越来越多的证据表明肠道微生物组在神经精神疾病中的作用。特别是，临床和转化研究表明肠道微生物组与焦虑，抑郁和自闭症症状之间存在因果关系（综述：Dinan和Cryan，2016）。最近的一项研究表明，AUD患者肠道微生物组的变化和肠道通透性增加与酒精渴望相关。然而，样本量小以及一些评估的回顾性和自我报告性质限制了对这些结果的解释。最近的一项系统综述 由我们的团队进行的一项研究（Temko，Bouhlal等人正在准备中）表明，对肠道微生物组在AUD中的作用的理解非常有限，值得进一步研究。因此，CPN部门开发了一个转化和临床项目，以研究肠道微生物组在AUD中的作用。Leggio博士获得了Peter G.道奇基金会部分支持这项研究。临床研究（T-AA-0037）目前正在审查中。

The joint NIAAA-NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN) conducts translational and clinical outpatient and inpatient studies in order to identify possible novel medications for addiction. Under Dr. Lorenzo Leggios leadership, 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 in order to shed light on the possible role of the gut-liver-brain axis in alcohol use disorder (AUD). Baclofen has been identified as a possible medication able to reduce alcohol craving and intake in alcohol dependent individuals. Preclinical and clinical studies indicated that baclofen is effective in reducing alcohol craving and intake (reviewed in: Farokhnia et al. in press). However, one trial found a robust treatment effect, but no differences between baclofen and placebo (Garbutt et al., 2010). This suggests that alcoholic individuals may respond differently to baclofen, e.g. patients with higher levels of anxiety may respond better to baclofen (Leggio et al., 2010). Thus, the CPN Section developed a clinical protocol (13-AA-0040) to test the role of baclofen on alcohol-related outcomes in alcoholic individuals with high anxiety levels. The design is a between-subject randomized double-blind controlled study with the medication conditions as the between subjects factor. Dr. Leggio received a NARSAD Award from the Brain and Behavior Research Foundation to partially support this study. Data analysis and manuscript preparation (Farokhnia et al.) are under way. Animal experiments demonstrate that central ghrelin administration not only stimulates reward processing but is also required for stimulation of that system by alcohol (Jerlhag et al., 2009; Suchankova et al., 2013). Human studies show a positive correlation between ghrelin levels and alcohol craving scores, and intravenous ghrelin acutely increases alcohol craving in individuals suffering with AUD. Together, preclinical and clinical studies suggest that ghrelin might represent a novel pharmacological target for treatment (reviewed in: Leggio, 2010). A within-subject, double-blind, placebo-controlled human laboratory study (protocol 13--AA-0043) was developed by the CPN Section to investigate whether IV ghrelin, as compared to placebo, increases motivation for alcohol reward, as measured by a progressive ratio schedule paradigm with IV alcohol self-infusion; and whether IV ghrelin, as compared to placebo, will increase the BOLD activation in the ventral striatum during an fMRI session. Contrary to animal studies, the hypothesis that GHS-R1a antagonism results in reduced alcohol use as never been tested in humans. In order 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 alcoholism. This project was developed in collaboration with Fatemeh Akhlaghi, Pharm.D., Ph.D., from the University of Rhode Island and was recently awarded with a NCATS grant award (UH2/UH3 TR000963) to partially support this project. This project is conducted at the NIH Intramural Research Program under Dr. Leggios leadership; pharmacokinetics (PK)/pharmacodynamic (PD) investigations are conducted in Dr. Akhlaghis lab. A Phase 1b clinical study (protocol 14-AA-0042) was completed and a Phase 2a clinical study (protocol 16-AA-0080) was recently started. Recent research suggests that oxytocin (OT) may play a role in the neurobiology of AUD. In animals, OT administration produces long-term decreases in alcohol reinforcement, decreases alcohol seeking during abstinence, attenuates drug tolerance, and decreases withdrawal symptoms (reviewed in Lee et al. 2016). Dr. Mary Lee, Staff Clinician in Dr. Leggios CPN Section, was awarded an NIH B2B grant award (2014-2015) to partially support this project. Preclinical work in collaboration with NIDA and NIMH basic scientists is close to completion. A clinical study developed by the CPN Section (protocol 16-AA-0082) is planned to start soon. Increasing evidence suggests a role of the gut microbiome in neuropsychiatric disorders. In particular, clinical and translational research has suggested a causality link between the gut microbiome and symptoms of anxiety, depression and autism (reviewed in: Dinan and Cryan, 2016). A recent study suggests that changes in the gut microbiome in patients with AUD and increased gut permeability correlate with alcohol craving. However, the small sample size and the retrospective and self-reported nature of some of the assessments limit the interpretation of these findings. A recent systematic review conducted by our team, (Temko, Bouhlal et al. in preparation) indicates that the understanding of the role of the gut microbiome in AUD is very limited and deserves additional investigation. Therefore, the CPN Section developed a translational and clinical project to investigate the role of the gut microbiome in AUD. Dr. Leggio received a grant award from the Peter G. Dodge Foundation to partially support this study. The clinical study (T-AA-0037) is currently under review.