The multicomponantal GABA receptor-ionophore complex is a site of action for a variety of centrally acting drugs. This complex is composed of a least GABA receptor sites, benzodiazepine sites and picrotoxin sites. This proposal seeks to characterize the convulsant and anticonvulsant receptors on this complex using radioligand and behavioral studies. The major aims include: i) determining the effect of convulsants, anticonvulsants and GABA agonists on the dissociation kinetics of (35S)t-butyl-bicyclophosphorothionate (TBPT), a ligand which binds to the picrotoxin site on the GABA receptor complex; ii) determine if anticonvulsants and/or hypnotic effects of barbiturates are mediated via GABA receptor system; iii) determine the effect of chronic barbiturate administration during its withdrawal and on the binding constants of GABA, TBPT and flunitrazepam;; iv) characterize GABA pharmacology by studying the effect of modulators of GABA transmission in the absence and presence of GABA on 35C1 fluxes; and v) determine if GABA receptor populations are interconvertible. Spinal cord cultures will provide us with a system to correlate binding studies with GABA receptor function in vitro. Further, cultures can be grown in the presence of various modulators to determine up or down regulation of receptors. Preliminary results indicate that convulsants and nonbenzodiazepine anticonvulsant/hypnotics bind to two distinct but coupled sites at the GABA receptor complex. These studies are aimed at increasing our understanding of the major inhibitory transmitters mediated by GABA and define the molecular mechanism of drug action at this receptor complex. GABAergic transmission has relevance to epilepsy, Huntington's chorea, anxiety and hypertension. A clearer understanding of the GABAergic transmission is a prerequisite to our understanding of normal biology and in the rational development of drugs for disorders involving a dysfunction of the GABA system.
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