BACKGROUND Perinatal hypoxia alters the concentration of many neurochemicals in the brain, including adenosine, and promotes central nervous system (CNS) disorders in human infants such as periventricular leukomalacia or encephalopathy. OBJECTIVE Using the postnatal rat as a model of perinatal human development, we examined the effects of sustained increases in brain adenosine on CNS regions thought to be involved with both planning and execution of motor activity. METHODS To simulate hypoxia-induced changes in adenosine, Sprague-Dawley rats were injected twice daily from postnatal day (P) 3 to P14, with the adenosine uptake inhibitor dipyridamole (DIP) or the A(1) adenosine receptor agonist N(6)-cyclopentyladenosine (CPA). Vehicle-injected animals served as controls. Immunohistochemical and morphological analyses were then performed to examine the expression of calbindin D-28k (CB) and the thickness of the external granule cell layer (eGL) in the cerebellum. Additionally tyrosine hydroxylase (TH) expression in the caudate putamen and ventricular size were also examined. RESULTS In the cerebellum, both DIP and CPA reduced the number of CB-positive Purkinje cells as well as decreased the thickness of the eGL compared to vehicle. In the caudate putamen we found that DIP but not CPA decreased TH expression when compared to vehicle. Neither agent significantly altered ventricular size when compared to vehicle. CONCLUSIONS These observations suggest that elevations in brain adenosine, which can occur following hypoxia, leads to both neurochemical and cellular changes in regions of the brain which control the planning and execution of motor activity. Thus, therapeutic strategies that target brain regions most sensitive to adenosine may prevent or control at least some of the CNS damage observed following perinatal hypoxia.