EXCITATORY AMINO ACIDS--ROLE IN CNS DISORDERS

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The long range goal of the program project is to advance current knowledge of the role of excitatory amino acids (EAA) in CNS disorders, and to use this knowledge as a basis for developing new pharmacological agents effective in the treatment of neurological disorders. To achieve this goal, a set of strategies will be used by each principal investigator and these are as follows: (1) New information will be sought on the role of each subtype of EAA in CNS disorders. As yet, each particular EAA receptor subtype cannot be clearly correlated with specific CNS functions or dysfunctions. Clarification of the relationship of NMDA, quisqualate and kainate receptors to specific functions and dysfunctions will provide one basis for new drug development. (2) New information will be sought on the role of the strychnine-insensitive glycine receptor in allosteric modulation of the NMDA receptor. Focusing on this specific allosteric modulatory site represents a point of departure for understanding CNS disorders and for the development of a new generation of drugs for disorders such as epilepsy, muscle spasticity, learning and memory impairments, neuronal death, spinal cord trauma, and diseases of the cardiovascular and respiratory system. (3) New information will be sought on the mechanism of signal transduction at EAA receptors. A feature of EAA receptors is their ability to induce the formation of multiple intracellular messages which may be integrated with other incoming stimuli to produce distinct neuronal responses. Identification of each step in the formation of intracellular messages will help elucidate molecular mechanisms for normal cell function and disordered cell function, and provide a basis for developing drugs that act one or several steps beyond the EAA receptor. (4) New information will be sought on the role of other neurotransmitter systems that can regulate the EAA systems in the brain and spinal cord. Our assumption is that the EAA system may be manipulated by other neurotransmitter systems that either regulate EAA transmission or act independently to produce CNS disorders. Elucidation of these other transmitter systems will provide a basis for the development of new drugs, or a combination of drugs for treating neurological disorders. In summary, concentration on relating disorders of CNS function to a specific EAA receptor, side stepping the primary recognition site and focusing on the modulator site of the NMDA receptor complex, bypassing the EAA receptor by focusing on second messenger systems, and elucidating other neurotransmitter systems that interact with EAA transmitter systems offer the opportunities for the design of new drugs to treat a wide spectrum of CNS disorders.