Attentional and information processing deficits have frequently been implicated in the psychopathology of schizophrenia. In recent years, the hypothesis of dopamine (DA) overactivity has also assumed significance in understanding schizophrenia. This proposal specifically outlines studies with humans and related animal models that will extend our knowledge of how DA overactivity relates to the sensory gating and habituation deficits that may underlie the cognitive fragmentation and thought disorder characteristic of schizophrenia. In animal experiments, we will further explore dopaminergic, noradrenergic, and specific anatomical pathways involved in the observed sensory gating deficits. To accomplish these goals, we propose to utilize the prepulse inhibition (PPI) and habituation of the startle reaction in humans and rats using the very similar paradigms, stimulus parameters, dependent measures, and statistical analyses that we have developed in our previous work. In humans, we will use electromyographic monitoring of the blink reflex component of the startle reaction (SR). In rats, we will use measures of whole body startle. Sensory gating will be accomplished by weak prestimulation and habituation using 121-trial tests in both humans and animals. Schizophrenic and control patients will be tested longitudinally and through various phases of their illness, while their clinical, symptomatic, neuropsychological, homovanillic acid levels, radioreceptor assay levels, and other measures are obtained. As an animal model of DA overactivity, rats having 6-hydroxydopamine-induced depletions of nucleus accumbens DA will be tested in the PPI paradigm following systemic treatments with apomorphine, noradrenergic agonists, and/or various dopaminergic antagonists. Liquid chromatography will be used to confirm the DA depletions. Our objectives are to clarify the neurochemical and anatomical pathways that underlie sensory gating and habituation deficits in schizophrenia and to explore the functional importance of dopamine overactivity in schizophrenia. We intend to further our understanding of how DA overactivity and its underlying neuroanatomic correlates may relate to the specific cognitive dysfunction, symptoms, and outcome of the schizophrenic disorders.
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