Adolescence neurogenesis mechanisms of antipsychotic sensitization and tolerance

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 DESCRIPTION: Adolescence is a period in which the brain and various psychological functions undergo dramatic transitions. It is also the time when symptoms of a variety of severe mental disorders often manifest. In recent years, there has been a significant increase (~6 folds) in antipsychotic use in children and adolescents with schizophrenia and other severe mental illnesses. However, research on the long-term consequences of antipsychotic exposure on the brain and behavioral developments is lacking. As antipsychotic treatment is administered to patients of psychiatric illnesses, there is a need to evaluate the possible short-term and long-term impacts of antipsychotic medications on psychological functions and other aspects of brain maturation at various ages using a validated preclinical disease model of schizophrenia. The PI's long-term goal is to understand the impacts of antipsychotic treatment during adolescence on the behavioral and neurobiological functions throughout development. Previous work from the PI's laboratory shows that repeated intermittent administration of olanzapine induces a sensitization-like (increase in magnitude) effect in a conditioned avoidance response model in both adult and adolescent rats, whereas repeated intermittent administration of clozapine induces a tolerance- like (decrease in magnitude) effect. Preclinical studies also suggest that repeated antipsychotic treatment alters adolescent neurogenesis in the hippocampus. This R03 project will build upon these findings to assess olanzapine sensitization (Aim 1) and clozapine tolerance (Aim 2) and their possible link to alterations in neurogenesis in adolescent rats born from rat mothers that have been exposed to polycytidilic:polyinosinic acid (PolyI:C) - a validated rat maternal immune activation (MIA) model of schizophrenia. In addition, the project will reveal possible interactions between MIA and antipsychotic-induced changes in patterns of neurogenesis. The general approach is to generate immune activation in pregnant female rats using PolyI:C, then induce olanzapine sensitization or clozapine tolerance in the adolescent offspring through continuous drug administration, then test its expression after the animals become adults. The synthetic nucleoside bromodeoxyuridine (BrdU) will be used to identify regions of neuronal survival following antipsychotic treatments. Finally, double labeling of anti-BrdU with NeuN or glial fibrillary acidic protein antibodies is used to further confirm the differentiation of cells generated under the influence of antipsychotic treatment. This project wil not only increase our understanding of the behavioral and neurobiological mechanisms of antipsychotic action, but also allow a detailed study of the long-term impacts of such exposure on neuronal development. This project is significant as it will have implications for psychotropic drug evaluation, future drug development, and clinical practice.