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.
