Based on the 'endogenous dopamine sensitization' hypothesis of schizophrenia the present study employed a repeated amphetamine administration regime in order to investigate the behavioral, neurochemical and neuroanatomical consequences following short- and long-term withdrawal periods. The escalating amphetamine administration schedule consisted of three injections per day over a 6-day period with the dosage ranging from 1 to 8 mg/kg. It was demonstrated that following both short- (4 days) and long-term (66 days) withdrawal periods latent inhibition (LI) and prepulse inhibition (PPI), two translational paradigms highly relevant to schizophrenia, were disrupted. A challenge injection verified sensitization in two different cohorts of animals at 40 and 70 days following cessation of treatment. Neurochemical evaluation demonstrated a reduction in dopamine levels in the caudate-putamen and nucleus accumbens core and shell as well as an enhanced utilization ratio in the caudate-putamen after both withdrawal periods. Similar to the findings from post-mortem studies of brains of schizophrenic patients, a downregulation of glutamic acid decarboxylase 67 (GAD67) immunoreactivity was found in the hippocampus, prefrontal cortex, thalamus, and amygdala in amphetamine pretreated animals following longer withdrawal periods. This was not accompanied by enhanced neurotoxicity or reactive gliosis as demonstrated by the immunohistological analysis using the apoptotic marker activated Caspase-3 and GFAP (glial fibrillary acidic protein; a marker for astrocytes) following both short- and long-term withdrawal periods. In conclusion, it is suggested that these findings constitute a highly reliable and valid animal model of schizophrenia.