Previously, we analyzed the effects of prenatal cocaine exposure during the neocortical neuronogenesis (which in primates corresponds to the second trimester of gestation) on the development of the neocortex in rhesus monkeys. We found that the neocortex in such prenatally-cocaine-exposed monkeys is characterized by: (i) a loss of the normal lamination, (ii) an inappropriate positioning of the cortical neurons, and (iii) a reduction in the density and number of these neurons. We have also demonstrated that cocaine can induce these long-term effects only if it is administered during the period of neocortical neuronogenesis, with no such abnormalities being observed in the animals exposed to cocaine either prior to or after that developmental period. It is reasonable to hypothesize that these structural neocortical abnormalities in monkeys exposed to cocaine in utero are accompanied by behavioral deficits. The demonstration such deficits is important because it would not only validate the functional significance of the detected morphological changes, but also suggest which specific aspects of behavior may be compromised in children of drug-abusing human mothers. It is well documented that postnatal development of the primate brain is very prolonged with new functional capabilities appearing throughout neonatal, infant, juvenile and adolescent periods. The brain is also known for its remarkable adaptability. Consequently various behavioral deficits in our animals may not necessarily be continuously present throughout life; some of them may be detected only transiently as developmental retardations at certain stages of brain maturation, while others may appear later in life with maturation of their adult neural substrates. Therefore, an evaluation of behavior in prenatally cocaine-exposed animals should be done in a format of a longitudinal study. The goal of the present study is to employ longitudinal behavioral tests and observations to address the hypothesis that the significant prenatal cocaine-induced cerebral cortical structural disorganization is associated with identifiable behavioral deficits: I) We will determine whether neonatal monkeys in our model of prenatal cocaine exposure display deficits on items of the Neonatal Behavioral Assessment Scale; 2) We will assess whether infant, juvenile and adolescent monkeys with significant central cortical structural abnormalities, which are generated in our model of prenatal cocaine exposure, display deficits in specific cognitive, motor, and perceptual functions which rely on cerebral cortex as one of their major neural substrates; and 3) We will evaluate whether prenatal cocaine exposure producing cerebral cortical neuropathology in our animals affects normal development of non-social and social behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA008057-13
Application #
6849760
Study Section
Biobehavioral and Behavioral Processes 3 (BBBP)
Program Officer
Thadani, Pushpa
Project Start
1993-02-01
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
13
Fiscal Year
2005
Total Cost
$259,875
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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