Schizophrenia is a devastating, yet poorly understood psychiatric disorder, with genetic and non-genetic factors implicated in its etiology. Central dopaminergic dysfunction and sensory gating abnormalities may be central to a number of signs and symptoms of the illness. Dopaminergic, as well as other catecholamine systems, have effects on sensory gating. Age dependent effects of brain insult may be relevant to the pathogenesis of schizophrenia, with early brain insult more frequent in this patient population, and sensory/motor deficits due to brain insult being highly age dependent. Careful definition of sensory gating in normal animals, dopamine lesioned animals, and gating changes caused by typical and 'atypical' neuroleptics, may provide insight into one aspect of schizophrenic symptomatology. These insights might provide a better understanding of, and indicate better treatments for, schizophrenic patients with early brain injury. The current study proposes: 1) training of the principal investigator in animal research skills relevant to testing sensory gating phenomena in animals (acoustic startle/habituation, conditioning/testing paradigms), including specific lesioning techniques, electrophysiological testing skills, administration of centrally acting drugs, HPLC analyses, and analysis of experimental data, 2) Participation in Ph.D. level Neuroscience course work relevant to the research, 3) Phase I studies of sensory gating in the normal rat, defining the functional role of Dl and D2 dopamine receptors, 4) Phase I studies of sensory gating, testing for age dependent effects of dopaminergic lesioning, with special attention to effects of Dl/D2 receptor manipulation, 5) Phase II studies of changes in sensory gating induced by typical vs 'atypical"""""""" neuroleptics in normal animals and animals with dopaminergic lesions. This training and research experience would provide a sound foundation in psychopharmacology, fundamentals of animal research techniques, and the ability to integrate basic science and clinical findings, with the goal of generating and testing hypotheses relevant to the pathophysiology and treatment of schizophrenia.
