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Abstract
The present paper reports on the results obtained in a rabbit model of prenatal cocaine exposure that mimics the pharmacokinetics of crack
cocaine in humans, and relates these findings to studies in other species including humans. A general finding is that prenatal exposure to
cocaine during neurogenesis produces dysfunctions in signal transduction via the dopamine D1 receptor and alterations in cortical neuronal
development leading to permanent morphological abnormalities in frontocingulate cortex and other brain structures. Differences in the
precise effects obtained appear to be due to the dose, route and time of cocaine administration. Related to these effects of in utero cocaine
exposure, animals demonstrate permanent deficits in cognitive processes related to attentional focus that have been correlated with
impairment of stimulus processing in the anterior cingulate cortex. The long-term cognitive deficits observed in various species are in
agreement with recent reports indicating that persistent attentional and other cognitive deficits are evident in cocaine-exposed children as
they grow older and are challenged to master more complex cognitive tasks.
q 2003 Elsevier Ltd. All rights reserved.
Keywords: Prenatal cocaine; Neurogenesis; Dopamine; Frontocingulate cortex; Learning; Attention; Eyeblink conditioning, rabbit, rodent, primate, human
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Choice of animal model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pharmacology of cocaine actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Development of the dopaminergic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. In utero cocaine exposure produces a permanent uncoupling of the dopamine D1 receptor. . . . . . . . . . . . . . . . . . . .
6. Anatomic consequences of dopamine D1 receptor uncoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Behavioral consequences of prenatal exposure to cocaine: relationship to dopamine D1 receptor uncoupling and altered
cortical morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Comparison of behavioral effects of prenatal cocaine in other species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9. Relationship of animal studies to human clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Approximately 12 years ago, NIDA funded a program
project grant that was the first to examine the effects of in
utero exposure to cocaine in an animal model from an
integrated neuroscience perspective. This project was
possible because of the development of a neuroscience
section at NIDA under the leadership of Roger Brown.
There were four separate components to this project that
involved PIs who were experts in neuroanatomy (E. Hazel
Murphy), developmental neurobiology (Pat Levitt),
molecular Biology (Eitan Friedman) and behavioral
* Fax: 1-215-762-2299.
E-mail address: john.harvey@drexel.edu (J.A. Harvey).
0149-7634/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2003.11.006
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Table 1
Protocol for breeding of Dutch belted rabbits
Day
Procedures
Gestational day 0
Gestational day 8
Gestational day 29
Gestational day 3031
Postnatal day 56
Postnatal day 40144
Fig. 2. Cartoon showing four major projections of the dopamine system and
their targets (dotted circles) in a sagittal view of the brain. Each projection
system is numbered: (1) nigrostriatal bundle, (2) mesolimbic pathway, (3)
mesocortical pathway, and (4) tuberoinfundibular pathway. Abbreviations:
NA, nucleus accumbens; SN, substantia nigra pars compacta; VTA, ventral
tegmental area.
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Fig. 4. In utero exposure to cocaine produces a long-lasting decrease in coupling to the dopamine D1 but not to the D2 receptor in frontal cortex of the rabbit.
Data are expressed as percent of basal (unstimulated) coupling [33].
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Fig. 7. Photomicrographs of MAP2-stained embryonic day E21 medial frontal cortical (including the anterior cingulate cortex) (A, B) and visual cortical (C, D)
culture preparations from saline-exposed (A, C) and cocaine-exposed (B, D) embryos. Neurons taken from the anterior cingulate cortex (ACC) of cocaine
(COC)-exposed embryos (B) demonstrate an exuberant growth of neurites as compared to those taken from saline (SAL)-exposed embryos (A). There were no
differences between neurons taken from the visual cortex (VIS) of saline (C) and cocaine (D)-exposed embryos [52].
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Fig. 10. Multiple unit activity in the anterior cingulate cortex during
acquisition of an instrumental discrimination. Average integrated multiunit activity in 30 consecutive, 10 ms intervals after onset of brief
(200 ms) CSs in rabbits exposed to cocaine in utero and in saline-exposed
controls. The onset of the CS and CS 2 occurred at the leftmost
position on the horizontal axis of each panel. Dark bars indicate the neural
response to the CS and light (open) bars to the CS 2 . Data are shown
for pretraining in which tones and unpaired footshock presentations were
given, the first session of conditioning and the session of criterion
attainment. Note the absence of training-induced discriminative neuronal
activity in the first session of training (left panel, second row) in rabbits
exposed to cocaine in utero as compared to their saline-exposed controls
(right panel, second row) [83].
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Fig. 11. Average anterior cingulate cortical multi-unit spike frequency in 40 consecutive, 10-ms intervals after onset of brief (200-ms) CS in rabbits exposed to
cocaine in utero and in saline-exposed controls. Data in each histogram are averages for all rabbits and training stages from pretraining to the session of
criterion attainment. The onset of the CSs occurred at the leftmost position on the horizontal axis. Asterisks indicate the occurrence of significantly greater
discharges in the indicated condition (prenatal exposure to saline or cocaine) than in the corresponding interval in the other condition [83].
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Acknowledgements
This research was supported by NIDA Grant DA 11164
and MH16841.
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