DIAZEPAM RESPONSE IN CHILDREN OF ALCOHOLICS

酗酒儿童的地西泮反应

• 批准号: 2045896
• 负责人: DEBORAH S COWLEY
• 金额: $ 25.42万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045896
• 关键词: GABA receptor; alcoholism /alcohol abuse; benzodiazepine receptor; biomarker; diazepam; drug metabolism; drug tolerance; family genetics; human subject; memory; receptor sensitivity; saccades; smooth pursuit eye movement

The long-term aim of this research is to determine whether increased risk for alcoholism is associated with differences in the functional sensitivity of the GABA-A-benzodiazepine receptor system. Alcoholism is in part genetically determined. Sons of alcoholic fathers, who are at particularly high risk for alcoholism, differ from male control subjects in response to ethanol. Since ethanol affects membrane fluidity and numerous neurotransmitter systems, the reason for these differences remains to be elucidated. One possible site determining SOA-control differences is the GABA-A-benzodiazepine receptor system. Ethanol increases chloride conductance at the GABA-A-benzodiazepine receptor, thus potentiating GABA-ergic neurotransmission. Animal studies have implicated effects of ethanol on the GABA-A-benzodiazepine receptor system in ethanol intoxication, tolerance, and dependence. Since the GABA-A receptor is the primary site of action of benzodiazepines, this research has used the effects of acute administration of diazepam as a specific measure of receptor function in sons of alcoholics and male controls. SOAs display significantly less diazepam effects on saccadic eye movement velocity (SEV), smooth pursuit eye movement gain (SPEM), memory and self-rated sedation but significantly more diazepam-induced euphoria and feeling "high." The current proposal aims to replicate these findings of SOA-control differences in an independent sample. In addition, daughters of alcoholics, who are also at increased risk for alcoholism, will be studied. Possible biological determinants of risks for alcoholism in daughters of alcoholics have been studied infrequently, and no prior studies of benzodiazepine sensitivity have been performed in this group. Diazepam effects will be assessed in sons and daughters of alcoholics and male and female control subjects using reduction in saccadic eye movement velocity (SEV), a reliable quantitative, dose-dependent index of GABA-A-benzodiazepine receptor function, as well as smooth pursuit eye movement gain, and non-visually guided saccadic accuracy and velocity, two additional eye movement measures which are also affected by diazepam in a dose-dependent manner. Memory, self-rated sedation, and both pleasurable and negative subjective drug effects will be measured. Daughters of alcoholics with multigenerational family histories of alcoholism will be studied to maximize detection of differences between these subjects and female controls. Differences between SOAs with multigenerational and unigenerational family histories will be assessed. Findings of differences in benzodiazepine sensitivity between high-risk individuals and matched controls may provide a possible neurochemical basis for risk for alcoholism and a potential biological marker linked with the actions of ethanol at the receptor level.

这项研究的长期目的是确定是否增加了风险 因为酗酒与功能的差异有关 GABA-A-Benzodiazepine受体系统的敏感性。 酒精中毒部分是遗传确定的。 酗酒父亲的儿子， 谁在酒精中毒的风险特别高，与男性不同 响应乙醇的控制对象。 由于乙醇会影响膜 流动性和众多神经递质系统，原因 差异仍然有待阐明。 一个可能的网站确定 SOA控制差异是GABA-A-Benzodiazepine受体系统。 乙醇在GABA-A-Benzodiazepine上增加氯化物电导 受体，从而增强了GABA - 凝胶神经传递。 动物研究 具有乙醇对GABA-A-Benzodiazepine受体的影响 乙醇中毒，耐受性和依赖性系统。 由于GABA-A受体是主要作用部位 苯二氮卓类药物，这项研究使用了急性的影响 地西ep剂作为受体功能的特定度量 酗酒者和男性控制的儿子。 肥皂显示大得多 地西epa对囊状眼动速度（SEV）的影响，平滑追击 眼动增长（SPEM），记忆和自我评估镇静，但 地西epa引起的欣快感和感觉“高”。这 当前的建议旨在复制SOA-Control的这些发现 独立样本的差异。 此外， 酗酒者也有酗酒的风险，将是 研究。 酒精中毒风险的可能生物决定因素 酗酒者的女儿很少研究，没有先前 该组已经进行了苯二氮卓敏感性的研究。 地西epa效应将在酗酒者的儿子和女儿中进行评估 男性和女性控制受试者使用saccadic Eye运动减少 速度（SEV），一种可靠的定量，剂量依赖性指数 gaba-a-苯并二氮卓受体功能，以及光滑的追捕眼 运动增益以及非视觉指导性的阳性准确性和速度， 另外两个受地西ep am影响的眼睛运动措施 以剂量依赖的方式。 记忆，自我评估的镇静以及两者 将测量愉悦和负面的主观药物作用。 与多代家庭历史的酗酒女儿 酗酒将被研究以最大化发现 这些受试者和女性对照。 SOA之间的差异与 将评估多代和单成本的家庭历史。 高危之间苯二氮卓敏感性差异的发现 个体和匹配的对照可能会提供可能的神经化学 酒精中毒风险的基础和潜在的生物标记物相关 乙醇在受体水平上的作用。