several important, widely used neurotropic drugs including benzodiazepines, barbiturates, neurosteroids and others produce their effects by acting at the GABA-A receptor-chloride ionophore. Recently we discovered a new class of neuroactive chemicals, alkyl-substituted butyrolactones, which can also modulate GABA mediated chloride conductances. These compounds appear to have a mechanism and site of action at the GABA-A receptor- chloride ionophore which is clearly different from the other compounds noted above. The major goals of this proposed project are to characterize mechanisms and sites of action and behavioral effects of neuroactive butyrolactones and related compounds. This project tests the hypothesis that butyrolactones have specific actions and effects on neuronal activity in brain, which are different from other substances known to regulate CNS neuronal activity.
The specific aims of this project are: 1. To define and characterize the neurologic and behavioral effects of neuroactive butyrolactones and related compounds. Individual compounds will be studied extensively to characterize their anticonvulsant, anxiolytic, sedative/hypnotic and other neurologic and behavioral effects as well as their acute and chronic effects in an attempt to identify agents with high therapeutic potential. All studies will be performed on rats and mice. 2. To identify the sites and mechanisms of action of neuroactive butyrolactones and structurally related compounds. The binding characteristics of several selected butyrolactones will be studied in detail and we will attempt to determine whether or not the butyrolactone and picrotoxin effector sites are identical. We will attempt to define where butyrolactones act. We hope to employ newly developed butyrolactone radioligands. All these experiments will utilize tissues from rats or mice. We will also attempt to identify where butyrolactones act on the GABA-A receptor-chloride ionophore using molecular biology techniques and methods and receptor binding experiments. In addition, we will attempt to determine whether butyrolactones have an effector site on other ligand gated channels. The study of butyrolactones and related compounds can improve understanding of the GABA-A receptor-chloride ionophore, help explain normal and abnormal CNS function and help identify new neurotropic drugs useful for the treatment of several neurologic and psychiatric diseases and disorders.
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