Cocaine abuse has increased dramatically over the past decade particularly among young adults of child-bearing age. It has been reported that up to 20% of births at metropolitan and suburban hospitals are complicated by the use of this drug. This prompted a great interest in understanding of the developmental effects of cocaine. Present proposals focus on the effect of prenatal cocaine exposure on the development of the cerebral cortex. Cocaine affects cortical development in different ways. For example, it interferes with maintenance of normal extracellular concentrations of monoaminergic neurotransmitters. In the developing cortex, these neurotransmitters play an important role as neurotrophic factors regulating neuronal proliferation differentiation and connectivity. Cocaine also causes placental vasoconstriction resulting in fetal hypoxia which could produce augmentation in cell proliferation as well as cell death. Moreover, cocaine itself may act as a direct mitotic suppressant in developing cerebral cortex. Indeed, there are indications that cocaine use during pregnancy may cause substantial changes in the cerebral cortex. Infants born from cocaine-abusing mothers and offsprings of drug-treated animals are often microcephalic and have cortical lesions. They display abnormal behavior and cognitive deficits. Abnormalities in the cytoarchitecture of the cortex and underlying white matter has also been observed in infants prenatally exposed to cocaine. The character of the latter findings suggests that cocaine may interfere with migration of postmitotic cortical cells from ventricular surface to the cortical plate. Cocaine-induced changes in the development of cortical cytoarchitecture could have profound consequences for the quality of life of the children of drug-abusing parents. The study of these changes should produce essential information for understanding the long-term effects of the fetal cocaine exposure as well as provide the basis for possible treatment. In this project, we propose to investigate whether chronic cocaine treatment during cortical neurogenesis affects the time frame of the generation of the neurons in the primate cerebral cortex. We will also study the effect of cocaine treatment on cell migration during the formation of the cortical plate. We will evaluate the ultrastructure of inappropriately migrated cells. Finally, we will examine the effect of cocaine exposure on the packing density and total number of cells, the neuronal:glial ratio, neuronal morphology and synaptic density in the primate cerebral cortex.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Yale University
Schools of Medicine
New Haven
United States
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Novikova, Svetlana I; He, Fang; Bai, Jie et al. (2008) Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring. PLoS One 3:e1919
He, Fang; Lidow, Irina A; Lidow, Michael S (2006) Inhalational model of cocaine exposure in mice: neuroteratological effects. Neurotoxicol Teratol 28:181-97
He, Fang; Lidow, Irina A; Lidow, Michael S (2006) Consequences of paternal cocaine exposure in mice. Neurotoxicol Teratol 28:198-209
Novikova, Svetlana I; He, Fang; Bai, Jie et al. (2005) Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall. Neurotoxicol Teratol 27:3-14
Zhang, Ling; Bai, Jie; Undie, Ashiwel S et al. (2005) D1 dopamine receptor regulation of the levels of the cell-cycle-controlling proteins, cyclin D, P27 and Raf-1, in cerebral cortical precursor cells is mediated through cAMP-independent pathways. Cereb Cortex 15:74-84
Novikova, Svetlana I; He, Fang; Bai, Jie et al. (2005) Neuropathology of the cerebral cortex observed in a range of animal models of prenatal cocaine exposure may reflect alterations in genes involved in the Wnt and cadherin systems. Synapse 56:105-16
He, Na; Bai, Jie; Champoux, Maribeth et al. (2004) Neurobehavioral deficits in neonatal rhesus monkeys exposed to cocaine in utero. Neurotoxicol Teratol 26:13-21
He, Na; Lidow, Michael S (2004) Cerebral cortical abnormalities seen in a non-human primate model of prenatal cocaine exposure are not related to vasoconstriction. Neurotoxicology 25:419-32
Lidow, Michael S (2003) Consequences of prenatal cocaine exposure in nonhuman primates. Brain Res Dev Brain Res 147:23-36
Song, Z-M; Undie, A S; Koh, P O et al. (2002) D1 dopamine receptor regulation of microtubule-associated protein-2 phosphorylation in developing cerebral cortical neurons. J Neurosci 22:6092-105

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