Approaches to modeling schizophrenia in the rat

Schizophrenia is a complicated and variable disorder that is notoriously difficult to study. Converging lines of evidence support the hypothesis that schizophrenia is characterized by a diverse array of distributed changes in limbic and cortical areas of the brain involving abnormalities in dopamine and glutamate transmission. Furthermore, genetic and behavioral studies indicate that abnormalities in normal development contribute to the etiology of the disorder. The present dissertation used two general strategies in an attempt to model some of the basic characteristics of the disorder. In Chapter Two, experiments were conducted that demonstrate short periods of higher frequency stimulation applied to the ventral, but not dorsal, hippocampus in adult rats reversibly reduce prepulse inhibition, a pre-attentive processing mechanism that is disrupted in schizophrenic patients. In Chapters Three and Four, the behavioral effects of reversible pharmacological manipulation of glutamate receptors early in development on prepulse inhibition and locomotor activity were assessed both before and after puberty. Additional experiments tested the putative role of dopaminergic abnormalities following these manipulations. Results from Chapter Three demonstrate that administration of a convulsive dose of the glutamate receptor agonist kainic acid to neonatal rats on postnatal day seven results in the delayed emergence of PPI deficits in early adulthood. Levels of locomotor activity were not reliably altered in a novel environment or following amphetamine administration. The experiments conducted in Chapter Four were designed to assess alterations in prepulse inhibition and locomotor activity following administration of the NR2B-subunit selective NMDA antagonist Ro25-6981. Unexpectedly, Ro25-6981 administration resulted in behavioral convulsions when administered during the first postnatal week; however, no consistent behavioral abnormalities were revealed in rats treated with the drug. Although the present results are somewhat mixed, the experiments were successful at providing novel insights into the symptoms and etiology of schizophrenia. In general, they support the assertion that short periods of altered activity in the limbic system, and hippocampus in particular, at different points during development may underlie the expression of some of the most basic symptoms of schizophrenia. These data also suggest that the nature and anatomical location of these alterations critically determines their long-term functional effects.Arts, Faculty ofPsychology, Department ofGraduat