This revised R03 proposal, submitted in response to a RFA (PA-00-114) encouraging research on developmental psychopharmacology, will study behavioral and molecular effects of antipsychotic drugs on cerebral dopamine (DA) and serotonin (5-HT) systems in developing vs. adult rats. DA and 5-HT receptors are critical sites of action of most antipsychotics, probably mediating, at least in part, clinically useful psychiatric benefits as well as adverse neurological effects. DA and 5-HT receptors are also implicated in the neurobiology of several neuropsychiatric disorders including schizophrenia, which affects children and adolescents as well as adults. Childhood-onset schizophrenia, an uncommon form of the disease, produces severe developmental and life-long morbidity and disability. Nevertheless, the neuropathology and pathophysiology of juvenile schizophrenia are far less well studied than in the adult disorder largely owing to the lack of access to postmortem brain tissue from young patients. There is also a striking paucity of systematic investigation of the pharmacology of antipsychotic agents in pediatric psychotic patients or of parallel studies in maturing laboratory animals. This project will examine effects of antipsychotic drug administration on brain and behavior in young and mature animals, and will compare rats at three selected ages: juveniles, adolescents, and adults. Behavioral effects of representative typical (fluphenazine), atypical (clozapine) and newer (olanzapine) antipsychotic agents will be assessed in behavioral paradigms that are predictive of antipsychotic activity or neurological side effects at the three ages to compare responses developmentally, and to establish age-specific half-maximal effective doses (ED50) for each tested agent. The calculated ED50 doses will be used to examine long-term effects of the same agents on expression of representative DA (D2 and D4) and 5-HT (5-HT1A and 5-HT2A) receptors, that we have found to be altered by repeated administration of antipsychotic drugs in adult rats. Expression of genes (mRNA) for these receptors will then be quantified to further clarify age related molecular mechanisms underlying hypothesized changes in receptor levels. Expected findings should clarify potency and mechanisms of action of antipsychotic drugs in juvenile and adolescent vs. adult rats, and should evolve new principles for improved treatments for childhood-onset schizophrenia and other major pediatric psychiatric disorders. ? ?
