This application for an ADAMHA Research Scientist Award follow,s ten years of NIMH support via the Type II Research Scientist Development Award. At the basic level, the project assesses the involvement of limbic dopaminergic, glutamatergic, and serotonergic systems in rats in the modulation of behavioral responsiveness to environmental stimuli. At the preclinical interface, the proposed experiments will further characterize deficits in sensorimotor gating and habituation observed in schizophrenic patients and extend related animal models derived from the basic studies. Schizophrenic patients exhibit deficits in prepulse inhibition of startle, gating of P3O event-related potentials, and habituation of startle. The proposed studies will: compare prepulse inhibition, P5O gating, and habituation functions in the same patients; relate these deficits to several clinical factors; and examine unmedicated schizophrenics, family members of schizophrenics, and schizotypal patients. In rats, prepulse inhibition of startle is reduced by D2 dopaminergic activation and by related manipulations of neuronal circuitry involving the hippo-campus, nucleus accumbens, ventral pallidum, and pedunculopontine nucleus. Prepulse inhibition is also disrupted by direct and indirect serotonin agonists, non-competitive antagonists at the N-methyl-d-aspartate receptor complex, and isolation rearing. The proposed studies will examine the psychopharmacology and neurobiological substrates relevant to this animal model of the schizophrenic deficit in sensorimotor gating. In rats, startle habituation is deceased by serotonin agonists and increased by serotonin antagonists. These serotonin agonist effects may provide a model of the schizophrenic deficit in habituation. Studies using a behavioral pattern monitor which provides a detailed profile of investigatory and locomotor behaviors, reveals that direct serotonin agonists similarly potentiate other measures of responsiveness to environmental stimuli. The release of presynaptic serotonin by indirect agonists reduces investigatory behavior while increasing locomotor activity. A variety of manipulations of serotonergic systems in rats are proposed to identify the receptor subtypes and, pathways involved in the serotonergic modulation of sensorimotor responsivity and behavioral activity.
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