This research proposal is to investigate the role of the GABA system in the actions of barbiturates as well as the development of tolerance to and physical dependence on barbiturates. The primary focus of this project will be on the role of the GABA/benzodiazepineionophore complex (GABA-BZD- BARB/TBPS complex) in pentobarbital actions. Additionally, other parameters of GABA synapse, e.g., GABA-b receptor, steadystate GABA levels and the enzymes relating to GABA metabolism will also be investigated.
The specific aims for these studies are: I. Studies on the effects of acute and continuous administration of pentobarbital on the GABABZDBARB/TBPS complex in the whole brain and discrete areas of the brain involved during the course of the development of tolerance to and physical dependence on pentobarbital. The specific studies planned are: (a) To study the acute administration (dose-response and time course) of pentobarbital on the GABABZDBARB/TBPS complex. The binding characteristics of each component of the complex, e.g., GABA, BZD and TBPSreceptor, will be carried out. (b) To study the changes of the GABABZDBARB/TBPS complex during the course of the development of tolerance to or physical dependence on pentobarbital. (c) To study the in vitro effect of pentobarbital on the GABA-BZD-BARB/TBPS complex in membranes prepared form naive and pentobarbital tolerantdependent animals. II. Studies on other parameters of GABA synapse after acute and continuous administration of pentobarbital. The other parameters (e.g., GABA-b, steadystate level, and GABArelated enzymes) will also be studied. These additional studies on the GABA synapse should contribute additional insight as to how the GABA system is involved in pentobarbital actions. All treatment protocols for these studies will be the same as those of studies on GABABZDBARB/TBPS complex. III. Confirmation of the role of GABA in pentobarbital actions by pharmacological manipulation. IV. Assessment of pharmacological responses after acute and continuous administration of pentobarbital. V. Using similar approaches, the longacting barbiturate, barbital, will be studied to determine if there is a common mechanism of CNS tolerance to and physical dependence on barbiturates. Hopefully these studies will lead to a better understanding of the mechanism of barbiturate tolerance and dependence and thus provide a rational basis for the development of pharmacological agents for clinical applications which will prevent the development of barbiturate tolerance and physical dependence without modifying therapeutic and hypnotic efficacies.
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