Prenatal cocaine abuse has reached epidemic proportions. IN certain high risk populations, over 33% of pregnant women expose their fetuses to cocaine. The effects of cocaine on the fetus are not fully understood. However, numerous reports have associated prenatal cocaine abuse with perinatal neurological damage. Complications include intracranial hemorrhage, cerebral infarction, microcephaly, and seizures. Although most reports describe full-term babies, sick preterm babies are a highest risk for intracranial hemorrhages, in part because they have immature capillary vessels and because they may have impaired cerebral autoregulation. The mechanism through which cocaine causes neurological damage is not fully understood. It is believed that cocaine may cause cerebral vasoconstriction leading to intracranial hemorrhage or cerebral infarction. This vasoconstriction may be indirectly mediated through inhibition of synaptic monoamine uptake at the nerve terminal, increasing alpha-adrenergic stimulation. This may alter the response of the cerebral arteries to various stimuli. Recent reports, including data from this laboratory, demonstrate that cerebral vasoconstriction may be mediated directly or through cocaine's major vasoactive metabolite benzoylecgonine. In order to better understand the neurological complications of prenatal cocaine abuse, the proposed project will study the vascular effects of cocaine and benzoylecgonine on cerebral arteries from perinatal lambs. To determine if cocaine affects preterm babies differently than full- term babies, cerebral vessels from preterm fetal lambs (120d gestation) will be compared to vessels from 7-14d postnatal newborn lambs. To determine if cocaine alters the normal cerebral vascular response, the effects of cocaine and benzoylecgonine on cerebral vascular response to standard vasoactive stimuli (norepinephrine, serotonin, and KC) and cerebral autoregulation will be studied. The mechanism of cocaine effect will be studied by comparing umbilical vessels (which lack alpha- adrenergic receptors) to cerebral arteries and by pretreating vessels with alpha-adrenergic receptor antagonists. These studies will be performed utilizing an innovative in vitro technique of isolated, cannulated, and perfused vascular segments. Vascular segments from cerebral arteries and umbilical vessels are threaded onto glass cannulae and perfused with warmed, aerated physiological saline solution. Intraluminal pressure and flow are controlled. The exterior of the vascular segment is suffused in a organ bath. Vascular response is assessed by change in vascular diameter measured with video system containing a video camera and monitor, stereomicroscope, videorecorder and video microscaler. These studies will provide a better understanding of the vascular effects of cocaine on the developing fetal neurovasculature and of the clinical neurological complications associated with prenatal cocaine abuse.
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