Moderate Human NMDA Receptor Function and Ethanol Response

中度人类 NMDA 受体功能和乙醇反应

• 批准号: 7622304
• 负责人: ISMENE L. PETRAKIS
• 金额: $ 17.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622304
• 关键词: Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; Basic Science; Biological Markers; Brain; Candidate Disease Gene; Case Study; Code; Consultations; DSM-IV; Data; Development; Disease; Drug Kinetics; EP300 gene; Equilibrium; Ethanol; Euphoria; Excitatory Amino Acid Antagonists; Exhibits; Family history of; Genes; Genetic; Genotype; Glutamates; Grant; Human; Individual; Individual Differences; Infusion procedures; Intravenous infusion procedures; Ketamine; Measurement; Measures; Methods; Motivation; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nicotine Dependence; Outcome; Procedures; Relative (related person); Research Design; Rewards; Risk; Risk Factors; Sedation procedure; Self Administration; Services; Signal Transduction; Single Nucleotide Polymorphism; Statistical Models; Stimulus; Testing; Variant; Visual; Visual Analogue Pain Scale; alcohol effect; alcohol response; attenuation; dopamine system; dysphoria; experience; knockout gene; receptor function; response; sedative; spinophilin

Family History and Spinophilin Genotype Influence on NMDA Receptor Function and Ethanol Response In the CTNA Overview, we hypothesize that disturbances in the interplay of glutamate and dopamine systems contribute to the vulnerability to alcohol dependence by: 1) impairing the normal engagement of reward/motivation circuitry and thereby increasing the relative motivational impact of alcohol-related rewards; and 2) by shifting the reward valence of the N-methyl-D aspartate (NMDA) glutamate receptor antagonist component of ethanol action toward reward, making ethanol a more addictive substance for those at risk. Project 3 will explore the latter hypothesis by evaluating whether increases in NMDA receptor function associated with a family history of alcohol dependence are associated with changes in the "reward valence" of ethanol. In this study, NMDA receptor function, assessed by evaluating the response to the NMDA receptor antagonist ketamine, and ethanol response, assessed using the ethanol "clamp" procedure (to minimize the impact of pharmacokinetic variability), will be determined. By exploring the relationship between ketamine and ethanol response, we can examine the extent to which NMDA receptor antagonism contributes to the balance of the positive (stimulant, euphoric) and negative (sedative, dysphoric) effects of ethanol, i.e. its reward valence. A family history of alcoholism is a risk factor for the development of alcohol dependence. A component of the familial risk for alcoholism appears to be expressed as a change in the reward valence to ethanol effects. This study will test the hypothesis that both ketamine and alcohol response will be similarly influenced by family history of alcoholism within subjects. If so, it would suggest that heritable factors influencing NMDA receptor function contribute to one of the most important biomarkers for the heritable risk for alcohol dependence. Further, this study will begin to explore the impact of variation in genes that contribute to alterations in NMDA receptor function associated with the familial vulnerability to alcohol dependence.

家族史和嗜脊髓蛋白基因型对NMDA受体功能和乙醇的影响