Evaluating the Genetic Variability of Naltrexone Response

评估纳曲酮反应的遗传变异性

• 批准号: 7754444
• 负责人: RAYMOND F ANTON
• 金额: $ 28.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754444
• 关键词: Abstinence; Accounting; Acute; Address; Adenine; Affect; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; Amino Acid Substitution; Amino Acids; Area; Asparagine; Aspartate; Binding; Biological; Brain; Brain imaging; Brain scan; Catechol O-Methyltransferase; Catechols; Clinical; Clinical Trials; Code; Cues; Data; Development; Dopamine; Dose; Enzymes; Extracellular Domain; Functional Magnetic Resonance Imaging; Future; Genes; Genetic; Genetic Structures; Genetic Variation; Genotype; Goals; Guanine; Hour; Human; Imaging technology; Individual; Intoxication; Laboratories; Measures; Medical; Medicine; N-terminal; Naltrexone; Narcotic Antagonists; Nucleic Acids; Nucleotides; Nucleus Accumbens; Opioid Receptor; Other Genetics; Output; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Placebos; Population; Positioning Attribute; Proteins; Randomized; Receptor Gene; Relapse; Research; Role; Sedation procedure; Site; System; Testing; Time; Transferase; Transferase Gene; Treatment Efficacy; Variant; Work; alcohol abuse therapy; alcohol cue; alcohol research; alcoholism pharmacotherapy; alcoholism therapy; beta-Endorphin; craving; drinking; drinking behavior; experience; gene interaction; genetic profiling; genetic variant; meetings; mu opioid receptors; neurochemistry; neuroimaging; problem drinker; programs; receptor; response; treatment center; treatment response

Naltrexone has reduced craving and relapse in some, but not all, alcoholics. One potential variable that might predict naltrexone, and potentially other opiate antagonist responses, is a difference in a single nucleotide substitution in the mu opiate receptor protein that makes that receptor respond differently to endogenous beta-endorphin as well as to exogenous opiate antagonists like naltrexone. An (A)denine to (G)uanine substitution at position 118 (A118G) in the coding region of the mu opiate receptor accounts for an asparagines (asn) to aspartate (asp) amino acid substitution at position 40 (asn40asp) in the receptor protein that occurs in about 15% of the population. The purpose of this1 proposal is to examine the role of this allelic difference in naltrexone responsivity in a well-established sub-acute dosing, brain imaging, and bar-lab paradigm. Interaction with another functional allele difference (va!158met substitution) in catechol-omethyl- transferase (COMT), an enzyme that controls CNS dopamine tone, will be explored. Three hundred non-treatment seeking alcoholics will be assessed and subtyped for mu opiate receptor and COMT allelic variants. Eighty individuals (40 with the more common AA gene and 40 with either an AG or GG gene) will be randomly assigned to take either naltrexone (50 mg/day) or a matching placebo for 7 days. Val and Met alleles of the COMT gene will be equally distributed by urn randomization to all groups. After 5 days of natural drinking and one day of abstinence, subjects will undergo an alcohol cue-induced fMRI brain scan on day 6 of study drug. On day 7, after a standard alcohol drink, stimulation, sedation, intoxication, and craving will be evaluated over 40 minutes. Then subjects may choose to drink up to 8 minidrinks over a 2-hour period. It is hypothesized that when taking naltrexone, AG/GG (40asp) subjects compared to subjects with the AA (40asn) will show a greater reduction of cue-induced brain stimulation in the nucleus accumbens, less alcohol induced stimulation, and less free choice drinking. Those with both the asn40asp and val158met substitutions could have the strongest responses to naltrexone. This data will provide support for the use of genotyping in predicting which treatment seeking alcoholic will or will not respond to naltrexone. Also, this work brings pharmacogenetics to our Center for future medication/gene interaction studies.

纳曲酮在某些但不是全部酗酒者中降低了渴望和复发。一个潜在变量 可能可以预测纳曲酮，并且可能是其他鸦片拮抗剂的反应，是一个单一的差异 Mu鸦片受体蛋白中的核苷酸取代，使该受体对 内源性β-内啡肽以及纳曲酮等外源性鸦片拮抗剂。一个（a）denine to （g）在MU阿片受体的编码区域118（A118G）位置的Uanine替代 在受体中的40（ASN40ASP）处的天冬氨酸（ASN）到天冬氨酸（ASP）氨基酸取代 大约15％的人口中发生的蛋白质。本1提案的目的是检查 在公认的亚急性给药，脑成像和 棒状范式。与儿茶酚 - 甲基 - 其他功能性等位基因差异（VA！158met取代）的相互作用 将探索控制CNS多巴胺张力的酶转移酶（COMT）。 将评估三百种非治疗酗酒者，并将其亚型用于MU鸦片受体 和COMT等位基因变体。八十个人（40个具有更常见的AA基因和40个Ag的人 或GG基因）将被随机分配为服用纳曲酮（50 mg/day）或匹配安慰剂的7 天。 VAL和MED COMT基因的等位基因将通过URN随机分配给所有组。 经过5天的自然饮酒和节制的一天，受试者将接受酒精提示引起的 fMRI脑扫描在研究药物的第6天。在第7天，在标准酒精饮料，刺激，镇静剂之后 中毒和渴望将在40分钟内评估。然后，受试者可能会选择多达8个小链接 在2小时的时间内。 假设服用纳曲酮时，Ag/gg（40ASP）受试者与患有患者相比 AA（40ASN）将显示伏隔核中提示诱导的大脑刺激的降低，较少 酒精引起的刺激和较少的自由选择饮酒。具有ASN40ASP和Val158met的人 替代可能对纳曲酮具有最强的反应。这些数据将为使用 预测寻求酒精饮料的治疗方法或不会对纳曲酮反应的基因分型。另外，这个 工作将药物遗传学带到我们的未来药物/基因相互作用研究中心。