Nonuniform alteration of dendritic development in the cerebral cortex following prenatal cocaine exposure.
Prenatal exposure to cocaine has the potential to modify normal brain development and result in behavioral dysfunction. We used a new animal model in which cocaine was administered intravenously during prenatal development in pregnant rabbits twice daily at low dosages. Analysis of brain development focused on two areas of the cerebral cortex, anterior cingulate and primary visual, in which dopamine afferents, a target of cocaine, are differentially distributed. All postnatal rabbits exposed to cocaine prenatally exhibited normal features of cortical organization, including thickness, lamination patterns, and cytoarchitectonic differentiation. General axonal and astroglial organization, assessed by neurofilament-H and glial fibrillary acidic protein immunostaining, also was unchanged in the cocaine-exposed animals. Analysis of dendritic organization was done using antibodies against microtubule-associated protein 2 (MAP2), which reveals mostly the larger apical shafts of cortical pyramidal cells. In the anterior cingulate cortex of adolescent rabbits exposed to cocaine in utero, there is a marked decrease in both dendritic bundling and typical long, straight MAP2-stained profiles. In normal animals, the long, bundled dendrites area readily traced in a single focal plane from layer III or V pyramidal cell somata to the pial surface in saline-treated animals. Instead, the drug-exposed animals contained many more short segments of MAP2-stained dendrites that could be viewed coursing in and out of the plane of focus in the sections. Apical dendrites in mature visual cortex appeared normal in the cocaine-exposed rabbits. Examination of MAP2 staining at various postnatal ages revealed that the dendritic changes expressed in the adolescent anterior cingulate cortex appeared less robust, but still evident at birth. By P10-14, dendritic modifications were similar to the adult. Counts of the number of MAP2-positive dendritic profiles crossing the layer II-III interface reached a nadir of 50% in the cocaine-exposed animals, indicative of a change in the organization of the apical dendrites compared to the control animals. Dendritic profiles of anterior cingulate neurons, filled by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil), confirmed that in the cocaine offspring, the dendrites coursed in an irregular, wavy manner from deep to superficial layers, suggestive of dendrites that were longer than normal, although cortical thickness was unchanged. The altered dendritic profiles also were seen in Golgi-impregnated neurons. The data indicate that prenatal exposure to cocaine can lead to specific alterations of neuronal growth that are long lasting. The lack of dendritic changes in visual cortex suggests that the drug does not modify development of cortical regions uniformly. This study also provides a new focus on the anterior cingulate cortex as a site in which aberrant structure-function relationships following prenatal cocaine exposure should be examined in both animal models and clinically.
Jones
L
L
Department of Anatomy and Neurobiology, Medical College of PA, Philadelphia, PA 19129, USA.
Fischer
I
I
Levitt
P
P
D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D002232:Carbocyanines; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D003712:Dendrites / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D005456:Fluorescent Dyes; D006179:Gyrus Cinguli / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D007150:Immunohistochemistry; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009294:Narcotics / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011817:Rabbits; D016622:Silver Staining; D014793:Visual Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
D002232:Carbocyanines; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D009294:Narcotics; C024286:3,3'-dioctadecylindocarbocyanine; D003042:Cocaine