The basis hypothesis of this proposal is that the central depressants, i.e. the barbiturates, exert a significant portion of their pharmacological effects by potentiating the inhibitory actions of GABA, a major inhibitory transmitter in the CNS. It is further hypothesized that adaptations in the GABA system to long term potentiation induced by chronic treatment with the barbiturates are important factors in the development of tolerance to and dependence on these compounds. Two adaptations are hypothesized (1) a reduction in functional GABA receptors and/or (2) a decrease in the activity of GABA neurons. As a result of these adaptations the abrupt withdrawal of the barbiturate would lead to a period of insufficient GABA inhibitory regulation in the CNS and a period of hyperexcitability evidenced as the barbiturate abstinence syndrome. A new model for GABA receptor-mediated inhibition in the retina, measurements of high affinity GABA binding and measurements of GABA turnover will be the principal analytical procedures employed. Collaborative efforts with Dr. Salvatore Enna in Houston and Drs. Susan Weintraub, Bill Stavinoha and David Jones are planned during the course of this project. The results of this study will provide considerable insight into the role of GABA in the development of tolerance to and dependence on the depressant barbiturates. Some studies will also determine the role of GABA in the development of benzodiazepine tolerance. The results of these studies may lead to better pharmacological methods for controlling the life-threatening-manifestations of barbiturate withdrawal and may lead to an understanding of the basic neurochemical mechanisms involved in the development of tolerance to and/or dependence on the barbiturates and other central depressant agents.
