Cocaine abuse by pregnant women is often associated with neurological injury in the newborn. To explore a vascular-related mechanism of injury, we investigated the effect of cocaine on the cerebral circulation in newborn pigs. During normoxic conditions, cocaine administration (1.5 mg/kg i.v.), resulting in peak plasma cocaine levels on the order of 10-6M, decreased cerebral blood flow (CBF) by 14%, as measured by the tracer microsphere method. To elicit the mechanisms by which cocaine decreased CBF, closed cranial windows were placed and the diameter of pial arterioles was measured by intravital microscopy while cocaine (10 -6M) was applied onto the cortical surface. Topically applied cocaine decreased pial arteriolar diameter by 9%. Vasoconstriction induced by topically applied cocaine was blocked by tetrodotoxin (10-7M, Na+ channel blocker), whereas phentolamine (10-5M, nor-adrenergic receptor blocker) had no effect on the arteriolar response to cocaine, which suggested that cocaine effected constriction by an anesthetic and not a sympathomimetic mechanism. To evaluate this hypothesis further, cerebral vessels in the right hemibrain were sympathetically denervated while those in the left hemibrain remained innervated. During normoxia, cocaine (1.5 mg/kg i.v.) decreased CBF equally in both hemibrains, confirming the non-sympathomimetic mechanism. During asphyxia, cocaine administration attenuated cerebral hyperemia in both hemibrains, but in innervated more than in denervated, indicating that anesthetic and sympathomimetic vasoconstriction occurred during asphyxia. We conclude that cocaine constricts the immature cerebrovasculature and decreases CBF by an anesthetic mechanism during normoxic conditions and by both sympathomimetic and anesthetic mechanisms during asphyxia.