AMINO ACID NEUROTRANSMITTER DYSREGULATION IN ALCOHOLISM

酗酒时的氨基酸神经递质失调

• 批准号: 7446814
• 负责人: John H. Krystal
• 金额: $ 18.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446814
• 关键词: Abstinence; Accounting; Acute; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Amino Acid Neurotransmitters; Amino Acids; Anxiety Disorders; Award; Barbiturates; Benzodiazepine Receptor; Benzodiazepines; Binding; Brain imaging; Candidate Disease Gene; Catabolism; Cerebellum; Characteristics; Clinical; Cognitive; Cohort Studies; Cues; DNA; Data; Depressed mood; Depth; Disease; Dose; Double-Blind Method; Drops; Emission-Computed Tomography; Ethanol; Ethanol dependence; Euphoria; Excitatory Amino Acid Antagonists; Exhibits; Family history of; Feedback; Funding; GABA Agonists; GABA Receptor; GABA-A Receptor; Gene Expression; Genes; Genetic Polymorphism; Genotype; Glucose; Glutamates; Glutamine; Grant; Grant Review; Human; Image; Indiana; Individual; International; Intoxication; Intravenous; Journals; Ketamine; Knowledge; Ligand Binding; Link; Literature; Magnetic Resonance Spectroscopy; Measurement; Measures; Medial; Mediating; Mentors; Messenger RNA; Metabolic; Methods; Molecular; Molecular Genetics; Moods; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Neuroglia; Neurosciences; Normal Range; Paper; Patients; Pentothal; Pharmaceutical Preparations; Phenotype; Photons; Physiological; Placebo Control; Predisposition; Prefrontal Cortex; Prevention program; Principal Investigator; Procedures; Process; Property; Protons; Publishing; Randomized; Rate; Regulation; Relapse; Relative (related person); Research; Research Design; Research Personnel; Risk; Role; Saline; Scientific Advances and Accomplishments; Severities; Signal Transduction; Site; Smoke; Smoking; Sodium; Specificity; Synapses; System; Techniques; Technology; Testing; Thiopental; Thiopental Sodium; Time; Tobacco; Tracer; Training; Universities; Up-Regulation; Wages; Week; Withdrawal; Withdrawal Symptom; Work; alcohol abuse pharmacotherapy; alcohol craving; alcohol cue; alcohol effect; alcohol research; alcohol response; alcoholism prevention; alpha ketoglutarate; barbituric acid salt; career; cingulate cortex; craving; day; density; design; drinking; editorial; frontal lobe; gamma-Aminobutyric Acid; genetic analysis; intravenous administration; iomazenil; mRNA Expression; neurobiological mechanism; neurochemistry; neuroimaging; neurotransmission; non-smoking; prevent; programs; psychopharmacologic; radiotracer; receptor; receptor binding; receptor density; receptor function; response; sobriety; sodium barbiturate

DESCRIPTION (provided by applicant): The past 5 years has been the most productive epoch in my career. I supported my salary with an NIAAA Independent Investigator (KO2) Award that markedly reduced my clinical and administrative responsibilities. Consequently, since 1998, I published 128 research papers and reviews including the multicenter VA naltrexone alcohol dependence study, characterization of NMDA receptor function alterations with alcohol dependence and the familial risk for alcoholism, completion of studies exploring roles for glutamate receptor antagonist or glutamate release inhibiting drugs for treating alcohol dependent patients, and completion of an initial characterization of time-dependent changes in the regulation of GABA systems in patients using concurrent measurements of cortical GABA levels with 1H-magnetic resonance spectroscopy (MRS) and GABAA receptor regulation with single photon emission computerized tomography (SPECT). For this work, I received several awards including the Joel Elkes Award (ACNP) and the Hans-Jonas Weitbrecht Scientific Award (Bayer). During this period, I renewed our VA Alcohol Research Center, led the establishment of the NIAAA Center for the Translational Neuroscience of Alcoholism (CTNA), and received funding for two RO 1 grants and a VA Merit Review Grant. I also participated in several national and international committees, served on the Editorial Boards of several journals, and mentored several highly accomplished trainees. Over the next five years, I propose to advance the scientific theme of my KO2 Award: to further characterize alterations in amino acid neurotransmission associated with alcohol dependence. The principal new conceptual and educational focus of this application is to unite psychopharmacologic and neuroimaging techniques that were my focus for the past five years with molecular genetic (candidate gene) and molecular neuroscientific (mRNA expression arrays) techniques that may help to add significant explanatory power to the proposed studies. I also propose to characterize the specificity of alterations in glutamatergic and GABAergic alterations associated with the vulnerability to alcohol dependence by comparing ethanol, sodium pentothal (barbiturate), and ketamine (NMDA receptor antagonist) responses in healthy individuals with and without family histories of ethanol dependence.

描述（由申请人提供）：过去的五年是我职业生涯中最富有成效的时期。我通过 NIAAA 独立研究者 (KO2) 奖来支持我的工资，这显着减少了我的临床和行政职责。 因此，自 1998 年以来，我发表了 128 篇研究论文和评论，包括多中心 VA 纳曲酮酒精依赖性研究、酒精依赖性 NMDA 受体功能改变的特征和酗酒的家族风险、探索谷氨酸受体拮抗剂或谷氨酸释放抑制作用的研究的完成治疗酒精依赖患者的药物，并通过同时测量皮质 GABA 水平和完成患者 GABA 系统调节随时间变化的初步表征1H 磁共振波谱 (MRS) 和单光子发射计算机断层扫描 (SPECT) 的 GABAA 受体调节。由于这项工作，我获得了多个奖项，包括乔尔·埃尔克斯奖（ACNP）和汉斯·乔纳斯·魏特布雷希特科学奖（拜耳）。在此期间，我更新了我们的 VA 酒精研究中心，领导建立了 NIAAA 酒精中毒转化神经科学中心 (CTNA)，并获得了两项 RO 1 拨款和 VA 优异评审拨款的资助。我还参加了多个国家和国际委员会，担任多个期刊的编辑委员会成员，并指导了几位成就卓著的学员。在接下来的五年里，我建议推进 KO2 奖的科学主题：进一步表征与酒精依赖相关的氨基酸神经传递的变化。该应用程序的主要新概念和教育重点是将过去五年我关注的精神药理学和神经影像技术与分子遗传学（候选基因）和分子神经科学（mRNA 表达阵列）技术结合起来，这可能有助于增加显着的解释力到拟议的研究。我还建议通过比较有和没有乙醇依赖家族史的健康个体对乙醇、喷妥钠（巴比妥）和氯胺酮（NMDA 受体拮抗剂）的反应，来描述与酒精依赖脆弱性相关的谷氨酸和 GABA 能变化的特异性。 。

项目成果

First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients.

第一个体内证据表明未接受药物治疗的精神分裂症患者存在 NMDA 受体缺陷。

• 发表时间: 2006-02
• 影响因子: 11
• 作者: Pilowsky, L S;Bressan, R A;Stone, J M;Erlandsson, K;Mulligan, R S;Krystal, J H;Ell, P J
• 通讯作者: Ell, P J

Sex-related differences in amygdala activity influences immediate memory.

杏仁核活动的性别相关差异会影响即时记忆。

• 发表时间: 2010-03-10
• 影响因子: 1.7
• 作者: Aikins, Deane E;Anticevic, Alan;Kiehl, Kent A;Krystal, John H
• 通讯作者: Krystal, John H

N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.

N-乙酰半胱氨酸增强血清素再摄取抑制剂难治性强迫症。

• 发表时间: 2006-01
• 影响因子: 3.4
• 作者: Lafleur, Daniel L;Pittenger, Christopher;Kelmendi, Ben;Gardner, Tom;Wasylink, Suzanne;Malison, Robert T;Sanacora, Gerard;Krystal, John H;Coric, Vladimir
• 通讯作者: Coric, Vladimir

Pediatric psychopharmacology: mood, anxiety and disruptive behavior/pervasive developmental disorders.

儿科精神药理学：情绪、焦虑和破坏性行为/广泛性发育障碍。

• 发表时间: 2007-03
• 影响因子: 3.4
• 作者: McDougle, Christopher J;Krystal, John H
• 通讯作者: Krystal, John H

beta2 Nicotinic acetylcholine receptor availability in post-traumatic stress disorder.

β2 烟碱乙酰胆碱受体在创伤后应激障碍中的可用性。

• 发表时间: 2008-05
• 作者: Czermak, Christoph;Staley, Julie K;Kasserman, Sue;Bois, Frederic;Young, Theresa;Henry, Shannan;Tamagnan, Gilles D;Seibyl, John P;Krystal, John H;Neumeister, Alexander
• 通讯作者: Neumeister, Alexander