At the basic level, this renewal of a Type II ADAMHA Research Scientist Development Award assesses the involvement of limbic serotonergic and dopaminergic pathways in rats in the modulation of behavioral responsiveness to environmental stimuli. At the preclinical interface, experiments are proposed to clarify deficits in sensorimotor gating and habituation observed in schizophrenic patients and to further develop po- tentially related animal models derived from the basic studies. Schizophrenic patients, exhibit deficits in prepulse inhibition of startle, a measure of sensorimotor gating, and in the habituation of startle. Using electromyographic measures of the blink reflex, the proposed studies will: compare prepulse inhibition and habituation functions in the same patients; assess these deficits using both acoustic and tactile stimuli; examine unmedicated schizophrenics; and test the suggested involvement of dopamine in sensorimotor gating by testing normal subjects after the administration of methylphenidate. In rats, prepulse inhibition of startle is reduced by dopamine agonists, apparently by activating mesolimbic dopamine systems. These effects may provide an animal model of the schizophrenic deficit in sensorimotor gating. The dopamine influences on prepulse inhibition in rats will be clarified by examining dopamine receptor specificity and identifying the relevant anatomical pathways. In rats, startle habituation is decreased by serotonin agonists and increased by serotonin antagonists. Studies using a behavioral pattern monitor which provides a detailed profile of investigatory and locomotor behaviors, reveal that serotonin agonists similarly potentiate other measures of responsiveness to environmental stimuli. These serotonin agonist effects may provide a model of the schizophrenic deficit in habituation. To identify the receptor subtypes and specific pathways involved in this serotonergic modulation of sensorimotor responsivity, rats will be tested in startle and investigatory response paradigms after serotonin agonists, antagonists, releasing drugs, their combinations, or regionally specific serotonergic lesions. The candidate's professional growth will be fostered by participation in graduate within the Department of Psychiatry and direct involvement in research with psychiatric patients.
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