This is a proposal to continue our program project entitled """"""""Basic Mechanisms of Seizures"""""""". This application describes a program which represents a major change in direction and emphasis in our research. Recent studies in our laboratories have led to the discovery of a new class of neuroactive chemicals -- alkyl substituted gamma- and thiobutyrolactones. These compounds appear to have novel mechanisms of action by which they can regulate neuronal excitability in brain. We believe that neuroactive butyrolactone and related chemical compounds have great potential diseases and disorders. Because of this we wish to mount a major research effort to learn more about these compounds and their molecular and cellular mechanisms and sites of action. The present program consists of four component projects and an administrative core. The major goals of the component projects are: (1) to study the chemistry of neuroactive butyrolactones and chemically related compounds: (2) to characterize the neurologic effects molecular mechanisms and sites of action of these agents: (3) to define cellular mechanisms of neuroactive butyrolactones and chemically related compounds and characterize some of the mechanisms of inhibitory neurotransmission in mammalian nervous tissue: (4) to define the functional anatomy responsible for the neurologic effects of the above chemicals and for the expression of seizures. Our present program brings together a group of talented and productive medical scientists. Each of the principal investigators has a special find of knowledge and research skills which make him particularly suited to carry out our research goals. They have already demonstrated that they work well together and direct closely interrelated and complementary research projects. Our project should provide substantial information that will improve our knowledge of both normal and abnormal brain function and should lead to a greater understanding and improved treatment of nervous system diseases.
