We explored how two independent variables. one genetic (i.e., specific rat strains) and another environmental (i.e., a developmental excitotoxic hippocampal lesion), contribute to phenotypic variation. Sprague-Dawley (SD), Fischer 344 (F344), and Lewis rats underwent two grades of neonatal excitotoxic damage: small and large ventral hippocampal (SVH and LVH) lesions. Locomotion was tested before puberty [postnatal day 35 (P35)] and after puberty (P56) following exposure to a novel environment or administration of amphetamine. The behavioral effects were strainand lesion-specific. As shown previously, SD rats with LVH lesions displayed enhanced spontaneous and amphetamineinduced locomotion as compared with controls at P56, but not at P35. SVH lesions in SD rats had no effect at any age. In F344 rats with LVH lesions, enhanced spontaneous and amphetamine-induced locomotion appeared early (P35) and was exaggerated at P56. SVH lesions in F344 rats resulted in a pattern of effects analogous to LVH lesions in SD rats-i.e., postpubertal onset of hyperlocomotion (P56). In Lewis rats, LVH lesions had no significant effect on novelty-or amphetamine-induced locomotion at any age. These data show that the degree of genetic predisposition and the extent of early induced hippocampal defect contribute to the particular pattern of behavioral outcome. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia, a disorder characterized by phenotypic heterogeneity, genetic predisposition, a developmental hippocampal abnormality, and vulnerability to environmental stress.Genetic factors that affect brain function can be studied in genetically inbred animal strains. For instance, three strains of rats-Sprague-Dawley (SD), Lewis, and Fischer 344 (F344)-differ substantially in a number of respects, including responsiveness to stress, predisposition to inflammatory diseases, and preference for drugs of abuse (1-5). Moreover, it has been suggested that these differences are associated with differential responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stressful or inflammatory stimuli (3, 6, 7), differential interactions between neurotransmitter systems and the HPA axis (8), and the functional state of the mesolimbic dopamine (DA) system (9-12). F344 and Lewis rats appear to represent two ends of a spectrum of stress responsivity; F344 rats are hyperresponsive to stress whereas Lewis rats are hyporesponsive to stress as assessed by behavioral and neuroendocrine responses to an open field, swim test, restraint, etc. Outbred SD rats exhibit an intermediate response to stress compared with these two inbred straiins. Thus, comparisons of these rat strains may provide insights into how genetic factors influence stress-related behaviors.We have demonstrated that SD rats with neonatally induced excitotoxic lesions of the ventral hippocampal formation exhibit a variety of abnormal behaviors, including enhanced locomotor hyperresponsiveness to stress, acce...