Isolation rearing of rats is a developmentally specific non-pharmacological manipulation that leads to deficits in sensorimotor gating, measured by prepulse inhibition of startle, that mimic those observed in schizophrenic patients. In rats, these gating deficits are reversed by both typical and atypical antipsychotic medications. The specific aims of this revised renewal application are to use the isolation rearing manipulation to better understand the neurobiological substrates underlying schizophrenia-spectrum disorders. In Aim 1 dose-response studies are proposed to further characterize the effects of selected pharmacological agents on isolation rearing effects in rats. First, the predictive validity of isolation-rearing-induced deficits in prepulse inhibition as a model of antipsychotic drug effects will be assessed by testing known antipsychotic drugs and drugs from other psychiatric treatment classes. Second, additional compounds having relatively selective actions at particular receptors will be examined to test hypotheses regarding the involvement of these particular receptors in the mediation of the behavioral effects of isolation rearing. Aim 2 studies will examine isolation rearing effects after manipulations of several neural substrates that are implicated in both the pathophysiology of schizophrenia and the regulation of prepulse inhibition, including the hippocampus, medial prefrontal cortex, striatum, and ventral pallidum. Neurochemically selective lesions and discrete microinjections of dopaminergic and serotonergic antagonists will be used to elucidate the neurobiological substrates of the isolation rearing induced gating deficit. Aim 3 will identify regionally specific neurochemical changes that are correlated specifically with isolation-induced deficits in prepulse inhibition. These hypotheses are closely linked to the questions being addressed using different methods in the Aim 2 studies. Thus, Aims 2 and 3 promise to provide converging evidence that should enable us to identify which parts of the circuitry known to regulate PPI are most relevant to the effects of isolation rearing on this animal model of the sensorimotor gating deficits observed in schizophrenia.