Exposure to cocaine during development has been shown to cause structural and functional alterations in the nervous system. In the current study, the mechanisms underlying these effects were examined in neonatal rats through measurement of ornithine decarboxylase activity, a key regulatory enzyme in the control of neural cell differentiation. Animals were given cocaine (30 mg/kg SC) and ornithine decarboxylase measured 1 and 4 h later in midbrain + brainstem, cerebral cortex and cerebellum. Cocaine caused inhibition of ornithine decarboxylase activity that was not secondary to local anesthesia, as lidocaine was ineffective. The effect of cocaine was independent of direct central actions, as introduction of the drug into the central compartment via intracisternal injection failed to inhibit ornithine decarboxylase. In contrast, prevention of cocaine-induced ischemia by peripheral alpha-adrenergic blockade (phenoxybenzamine) reversed the ornithine decarboxylase inhibition caused by cocaine, and actually unmasked potential stimulatory actions. These data indicate that cocaine-induced ischemia is a major contributor to the net effect of the drug on central nervous system cellular development.