This is a proposal to characterize molecular mechanisms and sites of action and neurologic effects of the newly discovered neuroactive butyrolactones and related compounds. This project will test the hypothesis that these compounds have highly specific sites and mechanisms of action in nervous tissue, are responsible for controlling specific neurological functions, and have the potential for development as useful drugs for the treatment of some neurologic disorders. The objectives of this project are complementary with those of the three other component components of the program project """"""""Basic Mechanisms of Seizures."""""""" Our specific objectives are: (1) To fully characterize the convulsant, anticonvulsant, and other neurologic effects of several butyrolactones and related compounds using behavioral studies of experimental animals (rats and mice). We will compare the neurologic effects of these compounds with other drugs which are known to regulate neuronal excitability in brain. (2) To identify, characterize and possibly locate the receptors mediating the action of neuroactive butyrolactones and related compounds using receptor binding studies of brain tissue membranes from rats and mice. We will define the mechanism and character of butyrolactone receptor-ligand interaction and characterize interactive processes among the GABA, benzodiazepine and butyrolactone receptors. (3) To characterize the chronological development of butyrolactone receptors and neurologic actions during postnatal maturation. (4) To attempt to define the role of neuroactive butyrolactones and related compounds in pathophysiologic mechanisms of neurological diseases and disorders by determining whether butyrolactone effects and/or actions are altered in brain tissue from animals and humans with known neurological diseases or disorders. The medical significance of the above studies seems obvious. We believe that obtaining the information described above will help us identify compounds with high therapeutic potential, particularly agents that may be more effective and less toxic anticonvulsants, anxiolytics, sedative/hypnotics and, perhaps, stimulants and cognitive enhancers, than presently available drugs.
