Transplacental Cocaine Exposure: A Mouse Model Demonstrating Neuroanatomic and Behavioral Abnormalities

Kosofsky, Barry E.; Wilkins, Aaron S.; Gressèns, Pierre; Evrard, Philippe

doi:10.1177/088307389400900303

Cited by 84 publications

(53 citation statements)

References 30 publications

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“…The potential mechanisms mediating such delayed cell death in our model may involve elimination of cells which are misplaced or altered in their pattern of connectivity. What is provocative is that such mechanisms appear to be operative days to weeks following the delay and imprecision of fetal neuronal migration we have previously reported (Gressens et al 1992;Kosofsky et al 1994;Crandall et al 2004). Moreover, as evidenced by our P9 DiI data, the 'misplaced' cells in the cocaine-exposed animals that do send descending collateral axons to subcortical targets such as the internal capsule and thalamus are located at slightly deeper positions than controls.…”

Section: Mechanistic Implications Of Our Findingsmentioning

confidence: 49%

“…Our previous work (Gressens et al 1992;Kosofsky et al 1994) provides evidence that many of the processes underlying corticogenesis are disrupted by gestational exposure of the developing mouse brain to cocaine, and that from the earliest phases of corticogenesis that there is an imprecision in the development of cortical lamination. By measuring the bi-parietal diameter of offspring (Wilkins et al 1998a;1998b;1998c) we have established that there is a decrement in the cortical volume of newborns following prenatal exposure to cocaine at the highest doses we utilize (i.e., Coc40), findings coordinate with that observed in clinical studies of human babies born to cocaine-abusing mothers.…”

Section: Introductionmentioning

confidence: 99%

“…By measuring the bi-parietal diameter of offspring (Wilkins et al 1998a;1998b;1998c) we have established that there is a decrement in the cortical volume of newborns following prenatal exposure to cocaine at the highest doses we utilize (i.e., Coc40), findings coordinate with that observed in clinical studies of human babies born to cocaine-abusing mothers. To summarize the qualitative neuroanatomic findings from our mouse model (Gressens et al 1992;Kosofsky et al 1994): early brain growth is compromised, particularly evident as cortical thinning. The density of fascicles of radial glial processes is decreased without a change in the number of glial fibers per fascicle, and the normal timing of radial glial defasciculation is delayed.…”

Section: Introductionmentioning

confidence: 99%

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Neuropathological consequences of prenatal cocaine exposure in the mouse

Ren

Malanga

Tabit

et al. 2004

Intl J of Devlp Neuroscience

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We have developed an animal model in Swiss Webster mice to identify mechanisms by which prenatal exposure to cocaine results in persistent alterations in brain structure and function. Clinical data suggests that children who demonstrate the largest impairments in prenatal brain growth, which are positively correlated with the highest level of prenatal cocaine exposure, are more likely to demonstrate selective impairment in postnatal brain growth, as well as postnatal impairments in motor function, attention and language skills. We conducted neuroanatomic studies to identify the postnatal evolution of structural changes in the primary somatosensory (SI) cortex of the developing mouse brain following prenatal exposure to cocaine. Our previous work, and that of others, provides evidence that many of the processes underlying corticogenesis are disrupted by gestational exposure of the developing mouse brain to cocaine, and that from the earliest phases of corticogenesis that there is an imprecision in the development of cortical lamination. We performed morphometric comparisons between the brains of animals prenatally exposed to varying amounts of cocaine with vehicle and malnutrition controls on postnatal (P) days P9 and P50. We found that on P50, but not P9, the relative number of cortical neurons in S1 is significantly less in cocaine exposed animals as compared with controls. The significant decrease in the number of cells in cocaine exposed animals on P50 is evident as a decreased density of cells restricted to the infragranular compartment (layers 5 and 6). Those changes are not seen in malnourished animals.Taken together our findings support the conclusion that cocaine-induced alterations in SI cortical cytoarchitectonics are in part a consequence of altered postnatal survival of infragranular cortical neurons, which are lost during the interval between P9 and P50. Determining whether a similar process is evident in a subset of humans following in utero cocaine exposure is a high priority for future clinical brain imaging studies, because analogous structural changes could impact the brain function and behavioral repertoire of infants and children following significant prenatal exposures.

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Section: Mechanistic Implications Of Our Findingsmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuropathological consequences of prenatal cocaine exposure in the mouse

Ren

Malanga

Tabit

et al. 2004

Intl J of Devlp Neuroscience

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“…Dopamine imbalance can occur following maternal intake of drugs such as cocaine that cross the placental barrier and interfere with dopaminergic signaling mechanisms in the fetal brain [1,19,23,28,35,36,52,67]. Neuro-functional disorders such as schizophrenia, autism spectrum disorder and attention deficit hyperactivity disorder also appear to be associated with imbalance in dopamine and other neurotransmitters in the developing brain [10,34,47,66].…”

Section: Introductionmentioning

confidence: 99%

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

2007

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Dopamine levels in the fetal brain were increased by administering the dopamine precursor 3,4-dihydroxy-L-phenylalanine (L-DOPA) to pregnant mice in drinking water. The L-DOPA exposure decreased bromodeoxyuridine (BrdU) labeling in the lateral ganglionic eminence and frontal cortical neuroepithelium but not medial or caudal ganglionic eminences. The regional differences appear to reflect heterogeneity in precursor cells' responses to dopamine receptor activation. Relative numbers of E15 generated neurons were decreased at postnatal day 21 (P21) in the caudate-putamen, nucleus accumbens and frontal cortex but not globus pallidus in the L-DOPA group. TUNEL labeling did not show significant differences on P0, P7 or P14 in the caudate-putamen or frontal cortex, suggesting that cell death was not altered. Although virtually all cells in the P21 brains that were labeled with the E15 BrdU injection were NeuN-positive, stereological analyses showed no significant changes in total numbers of NeuN-positive or NeuN-negative cells in the P21 caudate-putamen or frontal cortex. Thus persisting deficits in neuronal numbers were evident in the L-DOPA group only by birth-dating analyses and not upon gross histological examination of brain sections or analysis of total numbers of neurons or glia. One explanation for this apparent discrepancy is that L-DOPA exposure decreased cell proliferation at E15 but not at E13. By E15, expansion of the neuroepithelial precursor pool is complete and any decrease in cell proliferation likely produces only marginal decreases in the total numbers of cells generated. Our L-DOPA exposure model may be pertinent to investigations of neurological dysfunction produced by developmental dopamine imbalance.

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“…Resulting alterations include a decreased myelination (18); multifocal inhibition of DNA synthesis (19); a severe disorganization of neocortical architecture (20,21); poor development and function of dopaminergic (22)(23)(24), cholinergic (25), and serotonergic systems (24,26); and impaired synaptic activity. This jeopardizes the establishment of neuronal pathways mediating motor, limbic, and neuroendocrine functions.…”

mentioning

confidence: 99%

Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures.

Nassogne¹,

Evrard²,

Courtoy³

1995

Proc. Natl. Acad. Sci. U.S.A.

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Cocaine exposure in utero causes severe alterations in the development of the central nervous system. To study the basis of these teratogenic effects in vitro, we have used cocultures of neurons and glial cells from mouse embryonic brain. Cocaine selectively affected embryonic neuronal cells, causing first a dramatic reduction of both number and length of neurites and then extensive neuronal death. Scanning electron microscopy demonstrated a shift from a multipolar neuronal pattern towards bi-and unipolarity prior to the rounding up and eventual disappearance of the neurons. Selective toxicity of cocaine on neurons was paralleled by a concomitant decrease of the culture content in microtubuleassociated protein 2 (MAP2), a neuronal marker measured by solid-phase immunoassay. These effects on neurons were reversible when cocaine was removed from the culture medium. In contrast, cocaine did not affect astroglial cells and their glial fibrillary acidic protein (GFAP) content. Thus, in embryonic neuronal-glial cell cocultures, cocaine induces major neurite perturbations followed by neuronal death without affecting the survival of glial cells. Provided similar neuronal alterations are produced in the developing human brain, they could account for the qualitative or quantitative defects in neuronal pathways that cause a major handicap in brain function following in utero exposure to cocaine.

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Transplacental Cocaine Exposure: A Mouse Model Demonstrating Neuroanatomic and Behavioral Abnormalities

Cited by 84 publications

References 30 publications

Neuropathological consequences of prenatal cocaine exposure in the mouse

Neuropathological consequences of prenatal cocaine exposure in the mouse

Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers

Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures.

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