According to the neurodevelopmental hypothesis of schizophrenia, early brain damage renders the brain vulnerable to adverse effects during puberty, which precipitate the disease in young adults. Animal models can be used to test this hypothesis. We investigated the potentially independent or interactive effects of neonatal (postnatal day 7) excitotoxic lesions of the rat medial prefrontal cortex (mPFC) and subchronic pubertal phencyclidine (PCP)-treatment on adult rat behaviour. Sham-lesioned (vehicle-injection) and naive (unoperated) rats served as controls. On postnatal days 42-48 rats were systemically injected with 5 mg/kg PCP or vehicle twice daily. Behavioural testing started at postnatal day 70. Rats were tested for locomotor activity (open field), anxiety (elevated plus maze), social behaviour (conditioned place preference for cage-mates), reward-related operant behaviour [progressive ratio (PR)] and spatial learning (four-arm baited eight-arm radial maze task). Nissl-stained sections revealed considerable regeneration of much of the lesioned tissue in the mPFC, however, with disturbed cytoarchitecture. Locomotor activity was increased by neonatal lesions but reduced after pubertal PCP-treatment. Neonatal lesions alone increased operant behaviour in the PR-test and reduced anxiety in the elevated plus maze. In contrast, PCP-treatment disturbed social behaviour while neonatal lesions had no effect. Different aspects of leaning and memory in the radial maze task were independently disturbed after neonatal lesions and PCP-treatment. Neonatal lesions and pubertal PCP-treatment differentially affected adult rat behaviour and no interactions were found.