Models of Antipsychotic Prophylaxis for Schizophrenia

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DESCRIPTION (provided by applicant): Clinical evidence suggests that a prolonged period of untreated psychosis may be associated with increased severity of symptoms and decreased overall quality of life. Taken together with the extremely debilitating nature of schizophrenia, there is a renewed interest in the early identification and treatment of psychotic disorders, including prodromal symptoms. While the efficacy, safety, and ethics of early intervention are being examined in the clinical arena, preclinical studies on the therapeutic potential and long-term consequences of prophylactic treatments in animals are warranted in order to inform this debate. Because some forms of schizophrenia appear to be attributable to early developmental perturbations, many animal studies have examined the influences of specific developmental manipulations on behaviors and neural circuitry relevant to schizophrenia. Two developmental rat models, isolation rearing and neonatal ventral hippocampal lesions, result in both sensorimotor gating deficits and locomotor hyperactivity. The use of these two complementary developmental manipulations is important because they differ in their timing and mode of insult, but result in similar behavioral and neuronal abnormalities. These models will allow the examination of the therapeutic potential of prophylactic treatment and the potential side effects of chronic treatment during ontogeny. Isolation rearing is a non-pharmacological, environmental perturbation that deprives the rats of social contact from weaning through adulthood. Neonatal ventral hippocampal lesions involve a discrete, neuroanatomical insult that has temporal and regional specificity. Studies in this application will test whether long-term early administration of antipsychotic medications will prevent the development of isolation rearing or neonatal hippocampal lesion-induced deficits in sensorimotor gating and locomotor habituation. Considering the potential sensitivity of the models to repeated handling, antipsychotic drugs will be administered through the drinking water for an 8 week period initially and then at different time points to determine the critical developmental window of antipsychotic treatment. The specific aims are: 1: To determine the optimal parameters and functional effects of early developmental antipsychotic administration in rats. 2. To assess the effects of prophylactic antipsychotic treatment on isolation rearing induced behavioral deficits. 3. To assess the effects of prophylactic antipsychotic treatment on neonatal ventral hippocampal lesion induced behavioral deficits.