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The Journal of Neuroscience, June 15, 2000, 20(12):4606-4614

In Utero Cocaine-Induced Dysfunction of Dopamine D₁ Receptor Signaling And Abnormal Differentiation of Cerebral Cortical Neurons

Liesl B. Jones², Gregg D. Stanwood¹, Blesilda S. Reinoso³, Ricardo A. Washington¹, Hoau-Yan Wang⁴, Eitan Friedman⁴, and Pat Levitt¹

¹ Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, ² Department of Anatomy and Neurobiology, Allegheny University of Health Sciences, Philadelphia, Pennsylvania 19129, ³ Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and ⁴ Department of Pharmacology and Physiology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania 19129

Monoamines modulate neuronal differentiation, and alteration of monoamine neurotransmission during development produces specific changes in neuronal structure, function, and pattern formation. We have previously observed that prenatal exposure to cocaine in a clinically relevant animal model produces increased length of pyramidal neuron dendrites in the anterior cingulate cortex (ACC) postnatally. We now report that cocaine administered intravenously to pregnant rabbits at gestational stages preceding and during cortical histogenesis results in the early onset of hypertrophic dendritic outgrowth in the embryonic ACC. Confocal microscopy of DiI-labeled neurons revealed that the atypical, tortuous dendritic profiles seen postnatally in ACC-cocaine neurons already are apparent in utero. No defects in neuronal growth were observed in visual cortex (VC), a region lacking prominent dopamine innervation. In striking correlation with our in vivo results, in vitro experiments revealed a significant enhancement of spontaneous process outgrowth of ACC neurons isolated from cocaine-exposed fetuses but no changes in neurons derived from visual cortex. The onset of modified growth in vivo is paralleled by reduced D_1A receptor coupling to its G-protein. These data suggest that the dynamic growth of neurons can be regulated by early neurotransmitter signaling in a selective fashion. Prenatal onset of defects in dopamine receptor signaling contributes to abnormal circuit formation and may underlie specific cognitive and behavioral dysfunction.

Key words: prenatal cocaine; dendritic outgrowth; anterior cingulate cortex; development; dopamine; DiI; neurite; D₁ receptor; Gs

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20124606-09$05.00/0

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