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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA009635-01
Application #
3113676
Study Section
Clinical and Treatment Subcommittee (ALCP)
Project Start
1993-04-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Iwata, N; Cowley, D S; Radel, M et al. (1999) Relationship between a GABAA alpha 6 Pro385Ser substitution and benzodiazepine sensitivity. Am J Psychiatry 156:1447-9
Bowdle, T A; Radant, A D; Cowley, D S et al. (1998) Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology 88:82-8
Radant, A D; Bowdle, T A; Cowley, D S et al. (1998) Does ketamine-mediated N-methyl-D-aspartate receptor antagonism cause schizophrenia-like oculomotor abnormalities? Neuropsychopharmacology 19:434-44
Howard, M O; Cowley, D S; Roy-Byrne, P P et al. (1996) Tridimensional personality traits in sons of alcoholic and nonalcoholic fathers. Alcohol Clin Exp Res 20:445-8
Roy-Byrne, P; Wingerson, D K; Radant, A et al. (1996) Reduced benzodiazepine sensitivity in patients with panic disorder: comparison with patients with obsessive-compulsive disorder and normal subjects. Am J Psychiatry 153:1444-9
Cowley, D S; Roy-Byrne, P P; Greenblatt, D J et al. (1996) Effect of diazepam on plasma gamma-aminobutyric acid in sons of alcoholic fathers. Alcohol Clin Exp Res 20:343-7