Several lines of research suggest that GABA inhibits post synaptic neural transmission by increasing chloride conductance. There is substantial support for a role for gamma aminobutyric acid, the major inhibitory neurotransmitter in the mammalian brain, in the depressant effects of barbiturates and benzodiazepines. We have recently demonstrated and pharmacologically characterized a procedure that allows for the direct measure of GABA-mediated chloride influx in a cell-free preparation from neural tissue (Harris and Allan, 1985). Using this technique, the proposed research will define the role of the GABAergic neurotransmitter system in benzodiazepine and barbiturate tolerance and dependence using behavioral genetics as a tool. GABA-mediated 36CI- uptake as well as (35S)TBPS and (3H)diazepam binding parameters will be examined following in vitro acute in vivo and chronic treatment with diazepam and phenobarbital. Cross-tolerance and cross-dependence of the sedative hypnotics on the GABA system will be assessed. The functional importance of the effects of benzodiazepine and barbiturates on the GABA/BZ receptor chloride channel complex will be determined by comparing lines of mice selected for phenotypic differences to the ataxic effects of diazepam and for seizure susceptibility upon withdrawal from ethanol. It is anticipated that these studies will provide insight into the neural mechanisms responsible for benzodiazepine and barbiturate abuse.
|Allan, A M; Zhang, X; Baier, L D (1992) Barbiturate tolerance: effects on GABA-operated chloride channel function. Brain Res 588:255-60|
|Allan, A M; Baier, L D (1992) Effect of thiol group modification on ion flux and ligand binding properties of the GABAA-benzodiazepine receptor chloride channel complex. Synapse 10:310-6|
|Allan, A M; Baier, L D; Zhang, X (1992) Effects of lorazepam tolerance and withdrawal on GABAA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity. Life Sci 51:931-43|
|Allan, A M; Mayes, G G; Draski, L J (1991) gamma-Aminobutyric acid-activated chloride channels in rats selectively bred for differential acute sensitivity to alcohol. Alcohol Clin Exp Res 15:212-8|