This revised FIRST Award application outlines a series of electrophysiological and behavioral studies designed to address the recent proposal that schizophrenia is caused by reduced levels of the neurotransmitter glutamate in a brain region called the striatum. This theory proposes that a deficit in cortical glutamate projections causes the striatum to become hypersensitive to phasic increases in dopaminergic input, thus allowing for the classical treatment with drugs which block dopamine receptors. Extracellular, single-unit electrophysiological techniques will be used to record the activity of single brain cells in the striatum, and to measure their sensitivity to dopamine, following chronic administration of drugs which block glutamate transmission. Reduced glutamate activity will be studied by administering antagonists which are selective for NMDA or non- NMDA glutamate receptor subtypes. Neurons in both the dorsal and ventral striatum will be sampled for changes in firing rate, firing pattern, and their responsiveness to both dopamine agonists and dopamine pathway stimulation. In addition, some rats will be tested for prepulse inhibition of the acoustic startle reflex, a behavioral model of schizophrenia (prepulse inhibition of startle is also seen in schizophrenic patients). In accordance with the dopamine hypothesis of schizophrenia, activation of the dopaminergic system in rats disrupts the effects of prepulse inhibition. However, in accordance with the glutamate theory of schizophrenia, the glutamate antagonist MK 801 also disrupts prepulse inhibition in rats. The behavioral model will serve as an important control for identifying congruence between the electrophysiological and behavioral experiments. The prefrontal cortex receives an inhibitory dopamine input. Thus, increased dopamine activity may be the cause of reduced cortical glutamate projections to the striatum. In the final set of experiments, Alzet mini- pumps will be implanted for chronic administration of dopamine agonists directly into the prefrontal cortex. As above, the basal activity and pharmacological responsiveness of striatal neurons will then be examined. Schizophrenia is a severe neuropsychiatric disorder. These studies will help us better understand the role of cortical glutamate projections in the normal pharmacological responsiveness of striatal neurons to phasic changes in dopaminergic activity and will begin to test the glutamate deficiency model of the etiology of schizophrenia using electrophysiological and behavioral techniques. These studies should provide direct evidence pertaining to the validity of this recent theory, and may also help to direct new treatment strategies for this disorder.
