GABAA RECEPTOR GAMMA2 SUBUNIT--ACUTE ETHANOL WITHDRAWAL

GABAA 受体 GAMMA2 亚基--急性乙醇戒断

• 批准号: 6509127
• 负责人: Heather M Hood
• 金额: $ 2.99万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-04 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6509127
• 关键词: GABA receptor; RNase protection assay; alcoholism /alcohol abuse; benzodiazepines; chloride ion; drug receptors; drug withdrawal; ethanol; genetic polymorphism; laboratory mouse; neuropharmacology; protein structure function; receptor expression; vesicle /vacuole

Alcoholism is a complex disease that has both environmental and genetic determinants. The identification of the genes that predispose an individual to alcoholism is difficult due to genetic heterogeneity within the human population. Animal models (e.g. inbred mice) offer an alternative approach to identify genes that influence the susceptibility to alcoholism because mice and humans share largely conserved chromosomal regions. DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains are well-characterized models of severe vs. mild acute ethanol withdrawal. The GABAA receptor gamma2 subunit gene (Gabrg2) is polymorphic between the D2 and B6 strains. In this proposal, we will test the hypothesis that genetically determined differences in acute ethanol withdrawal severity are due, at least in part, to Gabrg2 variation. We will assess Gabrgl mRNA content in congenic, D2 and B6 strains to test the hypothesis that increased acute ethanol withdrawal severity is associated with decreased mRNA content. We will also test the effect that this polymorphism has on GABAA receptor function/subunit assembly by examining 36Cl- influx in membrane vesicles prepared from discrete brain regions in the same populations of mice. Lastly, we will also address the hypothesis that different Gabrg2 allelic dosages affects acute ethanol withdrawal severity by assessing mice that have a hemizygous deletion of Gabrg2. These studies will help provide the foundation for future studies investigating how genetic variation regulates alcohol abuse and alcoholism.

酗酒是一种复杂的疾病，具有环境和遗传决定因素。由于人群内的遗传异质性，识别导致个体酗酒的基因很困难。动物模型（例如近交小鼠）提供了另一种方法来识别影响酗酒易感性的基因，因为小鼠和人类在很大程度上共享保守的染色体区域。 DBA/2J (D2) 和 C57BL/6J (B6) 近交小鼠品系是严重与轻度急性乙醇戒断的良好表征模型。 GABAA 受体 gamma2 亚基基因 (Gabrg2) 在 D2 和 B6 菌株之间具有多态性。在本提案中，我们将测试以下假设：急性乙醇戒断严重程度的基因决定差异至少部分归因于 Gabrg2 变异。我们将评估同源菌株、D2 菌株和 B6 菌株中的 Gabrgl mRNA 含量，以检验急性乙醇戒断严重程度增加与 mRNA 含量减少相关的假设。我们还将通过检查从同一小鼠群体的离散脑区域制备的膜囊泡中的 36 Cl-流入来测试这种多态性对 GABAA 受体功能/亚基组装的影响。最后，我们还将通过评估 Gabrg2 半合子缺失的小鼠来解决不同 Gabrg2 等位基因剂量影响急性乙醇戒断严重程度的假设。 这些研究将有助于为未来研究遗传变异如何调节酒精滥用和酗酒奠定基础。