Structural alterations in the brains of some schizophrenic patients suggest an impairment of brain development, possibly as a result of intrauterine compromise. In this study we have tested the hypothesis that placental insufficiency during the second half of pregnancy in the guinea pig results in structural alterations similar to those seen in some schizophrenic patients. Placental insufficiency was induced in pregnant guinea pigs via uterine artery ligation at midgestation. At 60 days gestation (term: 68 days gestation) the fetal brains were prepared for quantitative histological and immunohistochemical analysis and compared with controls. Placental insufficiency resulted in growth-restricted animals with significantly larger cerebral ventricles, reduced cross-sectional area of the cerebral cortex and the striatum and reduced hippocampal volume compared with controls. There were fewer neuronal nitric oxide synthase (nNOS)-positive cells in layers 5-6 of the cingulate cortex, and in layer 1 of the frontal and temporal cortices. In contrast, there were no significant alterations in the optical density of tyrosine hydroxylase (TH), a rate-limiting enzyme in the biosynthesis of catecholamines and the dopamine transporter (DAT) in the striatum in growth-restricted animals compared with controls. These findings indicate that developmental disturbances can produce anatomical changes that resemble those found in some individuals with schizophrenia.