This proposal is a continuation of our studies aimed at development and utilization of the primate model of the influence of cocaine abuse during pregnancy on formation and maturation of the brain. In the present cycle of this grant, we have shown that the cerebral cortex of two month-old macaque monkeys is abnormal when chronically treated with this drug in utero. The abnormalities consist of: 1) inappropriate positioning of cortical neurons due to their detention along the migratory pathway from the proliferative zones; 2) reduction in the total number of cortical neurons; and 3) multiple alterations in cortical astroglial elements. Here, we propose to investigate the mechanisms underlying these negative effects of cocaine on formation of the primate cerebral cortex. In particular, our main working hypothesis is that cocaine influences the morphological features, density, and arrangement of fetal radial glia. This class of elongated glial cells is essential for guiding newly- generated neurons from embryonic proliferative zones to their proper position in the cortical plate. They are also the major precursors of cortical astrocytes. Therefore, abnormalities in radial glial cells would explain both the disturbances in the migration of cortical neurons and the alterations in cortical astroglia observed in cocaine-treated animals. In addition, we plan to investigate whether cocaine treatment may interfere with cerebral cortical development by affecting the generation of cells in the cortical embryonic proliferative ventricular and subventricular zones. These transient embryonic zones supply neurons for the fetal cerebral cortex, and even slight alterations in their proliferative activity should have a significant negative impact on cortical development. Finally, we intend to continue our ongoing analysis of the long-term consequences of prenatal exposure to cocaine for the primate cerebral cortex. In this part of the study, we will evaluate structural changes which occur in the cerebral cortices of cocaine- treated animals as they mature beyond the first two postnatal months. This will allow us to assess the prospects for recovery from prenatal cocaine exposure for children of drug abusing mothers.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (SRCD (12))
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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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