ALCOHOL & PERIPHERAL-TYPE BENZODIAZEPINE RECEPTORS

长期目标是确定分子的变化

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.