ALCOHOL & PERIPHERAL-TYPE BENZODIAZEPINE RECEPTORS

长期目标是确定细胞内的分子变化。 调节乙醇效应的大脑，并将其应用于 关于预防和治疗酒精中毒的信息。这个 拟议研究的目的是提供基本信息 外周型苯二氮卓受体(PBR)的作用 在大脑中，研究乙醇对大脑PBR的急性影响 功能，检查慢性酒精暴露引起的变化 并确定这些变化的重要性 在调节酒精依赖方面的作用。具体目标为1) 研究脑PBR的功能并确定乙醇是否 改变他们的功能；2)确定是否有行为 作用于PBR的药物与乙醇的相互作用 描述慢性酒精暴露引起的变化 通过测定C57BL/6J小鼠脑内PBR的影响 对脑区或亚细胞部分有选择性；4) 描述酒精引起的脑变化的时间过程 C57BL/6J小鼠在酒精获得和丧失过程中的PBR 依赖；5)确定慢性应激引起的变化 酒精暴露在大脑PBR系统是一种普遍的反应 在老鼠性别和品系之间传播；以及6)调查 脑PBR系统在乙醇调节中的重要性 在C57BL/6J小鼠中通过确定是否发生改变来实现依赖 推测的内源性腿部的大脑水平和 测定PBR选择性激动剂或拮抗剂会改变 身体依赖的获得和表现。要实现 这些目标，雄性大鼠，雄性和雌性C57BL/6J和雄性WSP 将使用WSR和DBA/2小鼠。乙醇或等热量 葡萄糖将通过流质饮食长期服用。乙醇， 生理盐水、交通工具和药物将由IP进行严格管理。 注射或体外添加。酒精的急性影响将是 使用运动活动、睡眠时间、醒来的血液进行量化 乙醇浓度(BEC)和直肠温度(RT)。 慢性影响将使用醉酒分级、RT、 BEC，PBR结合特性，以及推定的 PBR内源性配体。酒精依赖的研究进展 将通过是否存在戒断反应来衡量。这个 退出的严重程度将通过退出来确定 共济失调、震颤、自发性抽搐和处理的指标- 诱发抽搐。这些研究将导致更好的 对脑内苯二氮类药物系统在脑损伤中作用的认识 酗酒和酗酒。

The long-term objective is to identify molecular changes in the brain that mediate the effects of ethanol and to apply this information in the prevention and treatment of alcoholism. The purpose of the proposed research is to provide basic information on the role of the peripheral-type benzodiazepine receptors (PBR) in the brain, study the acute effect of ethanol on brain PBR function, examine changes induced by chronic ethanol exposure in mouse brain PBR and determine the importance of these changes in mediating ethanol dependence. The specific aims are to 1) Study the function of brain PBR and determine whether ethanol alters their function; 2) Determine whether there are behavioral interactions between ethanol and drugs acting on the PBR; 3) Characterize the changes induced by chronic ethanol exposure on C57BL/6J mouse brain PBR by determining if the effect is selective for brain regions or sub-cellular fraction; 4) Characterize the time course for ethanol-induced changes in brain PBR in C57BL/6J mice during acquisition and loss of ethanol dependence; 5) Determine whether the changes induced by chronic ethanol exposure in the brain PBR system are a general response extending across mouse gender and strains; and 6) Investigate the importance of the brain PBR system in mediating ethanol dependence in C57BL/6J mice by determining if changes occurr in the brain level of a putative endogenous legnad and by determining PBR-selective agonists or antagonists alter the acquisition and expression of physical dependence. To achieve these goals, male rats, male and female C57BL/6J and male WSP WSR and DBA/2 mice will be used. Ethanol or equicaloric dextrose will be chronically administered by liquid diet. Ethanol, saline, vehicles and drugs will be acutely administered by i.p. injection or added in vitro. Acute effects of ethanol will be quantitated using locomotor activity, sleep-time, wake-up blood ethanol concentration (BEC) and rectal temperature (RT). Chronic effects will be quantitated using intoxication ratings, RT, BEC, PBR binding properties, and the brain levels of a putative PBR endogenous ligand. The development of ethanol dependence will be measured by the presence of a withdrawal reaction. The severity of withdrawal will be determined using a withdrawal index of ataxia, tremor, spontaneous convulsions and handling- induced convulsions. These studies will lead to a better understanding of the role of brain benzodiazepine systems in alcohol abuse and alcoholism.