Schizophrenia (SZ) is a debilitating neuropsychiatric disorder that is manifested through a variety of behavioral deficits. Current antipsychotic medications, while successful in treating many of the core symptoms of SZ, are seriously limited in their use by profound extrapyramidal or agranulocytotic side effects. An understanding of the neural substrates mediating specific deficits of this disorder may lead to the revelation of novel mechanisms involved in SZ and might ultimately result in the development of new safer treatments. Prepulse inhibition (PPI) (a measure of sensorimotor gating in which a mild prestimulus attenuates the magnitude of the startle response to an intense stimulus) is a normal cross-species occurrence that is deficient in SZ patients. This impairment in PPI has been successfully modelled in rats by administration of noncompetitive NMDA antagonists such as the psychotogen phencyclidine (PCP). The goal of this project is to use this animal model of deficient PPI to better understand the psychotomimetic effects of PCP and ultimately uncover novel substrates of impaired sensorimotor gating in SZ patients. Initially, the hypothesis that multiple receptors mediate the PPI- disruptive effects of PCP will be tested using both selective and mixed profile antagonists to block the effects of PCP. The second hypothesis that multiple brain regions mediate these effects will be tested using intracranial drug microinfusion techniques. In summary, this project seeks to determine the pharmacological and neuroanatomical mechanisms of PCP- induced deficits in PPI in order to further our understanding of the neural substrates of deficient sensorimotor gating in SZ.
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